Tang Y

References (84)

Title : Trace Amount of Bi-Doped Core-Shell Pd@Pt Mesoporous Nanospheres with Specifically Enhanced Peroxidase-Like Activity Enable Sensitive and Accurate Detection of Acetylcholinesterase and Organophosphorus Nerve Agents - Lei_2024_Anal.Chem__
Author(s) : Lei M , Ding X , Liu J , Tang Y , Chen H , Zhou Y , Zhu C , Yan H
Ref : Analytical Chemistry , : , 2024
Abstract : The urgent need for sensitive and accurate assays to monitor acetylcholinesterase (AChE) activity and organophosphorus pesticides (OPs) arises from the imperative to safeguard human health and protect the ecosystem. Due to its cost-effectiveness, ease of operation, and rapid response, nanozyme-based colorimetry has been widely utilized in the determination of AChE activity and OPs. However, the rational design of nanozymes with high activity and specificity remains a great challenge. Herein, trace amount of Bi-doped core-shell Pd@Pt mesoporous nanospheres (Pd@PtBi(2)) have been successfully synthesized, exhibiting good peroxidase-like activity and specificity. With the incorporation of trace bismuth, there is a more than 4-fold enhancement in the peroxidase-like performance of Pd@PtBi(2) compared to that of Pd@Pt. Besides, no significant improvement of oxidase-like and catalase-like activities of Pd@PtBi(2) was found, which prevents interference from O(2) and undesirable consumption of substrate H(2)O(2). Based on the blocking impact of thiocholine, a colorimetric detection platform utilizing Pd@PtBi(2) was constructed to monitor AChE activity with sensitivity and selectivity. Given the inhibition of OPs on AChE activity, a biosensor was further developed by integrating Pd@PtBi(2) with AChE to detect OPs, capitalizing on the cascade amplification strategy. The OP biosensor achieved a detection limit as low as 0.06 ng mL(-1), exhibiting high sensitivity and anti-interference ability. This work is promising for the construction of nanozymes with high activity and specificity, as well as the development of nanozyme-based colorimetric biosensors.
ESTHER : Lei_2024_Anal.Chem__
PubMedSearch : Lei_2024_Anal.Chem__
PubMedID: 38577757

Title : NSUN2 relies on ALYREF to regulate Nrf2-mediated oxidative stress and alleviate Dox-induced liver injury - Huang_2024_Biol.Direct_19_32
Author(s) : Huang Y , Li X , Wei L , Ma S , Ma L , Zan Y , He X , Tang Y , Ding Y
Ref : Biol Direct , 19 :32 , 2024
Abstract : BACKGROUND: Doxorubicin (Dox) is associated with various liver injuries, limiting its clinical utility. This study investigates whether NSUN2 participates in Dox-induced liver injury and the associated molecular mechanism. METHODS: In vivo and in vitro liver cell injury models were constructed based on Dox therapy. The protein levels of NSUN2 and oxidative stress indicators Nrf2, HO-1, and NQO1 were evaluated by Western blot. The RNA binding potential was detected by RNA methylation immunoprecipitation (RIP). Additionally, the effect of NSUN2 on Nrf2 mRNA synthesis and localization was evaluated using an RNA fluorescence probe. RESULTS: NSUN2 was downregulated, and liver tissue suffered significant pathological damage in the Dox group. The levels of ALT and AST significantly increased. NSUN2 interference exacerbated Dox-induced liver cell damage, which was reversed by NSUN2 overexpression. RIP demonstrated that NSUN2 recognized and bound to Nrf2 mRNA. Western blot analysis showed the protein level of Nrf2 in the NSUN2-WT group was significantly higher than that of the control group, whereas there was no significant change in Nrf2 level in the mutant NSUN2 group. Luciferase analysis demonstrated that NSUN2 could recognize and activate the Nrf2 5'UTR region of LO2 cells. In addition, RIP analysis revealed that ALYREF could recognize and bind to Nrf2 mRNA and that ALYREF controls the regulatory effect of NSUN2 on Nrf2. CONCLUSION: NSUN2 regulates Dox-induced liver cell damage by increasing Nrf2 mRNA m5C methylation to inhibit inhibiting antioxidant stress. The regulatory effect of NSUN2 on Nrf2 depends on ALYREF.
ESTHER : Huang_2024_Biol.Direct_19_32
PubMedSearch : Huang_2024_Biol.Direct_19_32
PubMedID: 38685056

Title : The proteomic landscape of fall armyworm oral secretion reveals its role in plant adaptation - Zhang_2024_Pest.Manag.Sci__
Author(s) : Zhang X , Li P , Tang Y , Mu YP , Liu J , Wang MY , Wang W , Mao YB
Ref : Pest Manag Sci , : , 2024
Abstract : BACKGROUND: The fall armyworm (FAW, Spodoptera frugiperda (J.E. Smith)) is a polyphagous agricultural pest with rapidly evolving adaptations to host plants. We found the oral secretion (OS) of FAW from different plants influences plant defense response differentially, suggesting its role in adapting to host plants. However, the protein expression profile of FAW OS respond to different plants is largely unknown. RESULTS: Here, from the mass spectrometry assay, we identified a total of 256 proteins in the OS of FAW fed on cotton (Gossypium hirsutum L.), tobacco (Nicotiana benthamiana Domin), maize (Zea mays L.) and artificial diet. The FAW OS primarily comprise of 60 proteases, 32 esterases and 92 non-enzymatic proteins. It displays high plasticity across different diets. We found that more than half of the esterases are lipases which have been reported as insect elicitors to enhance plant defense response. The lipase accumulation in cotton-fed larvae was the highest, followed by maize-fed larvae. In the presence of lipase inhibitors, the enhanced induction on defense genes in wounded leaves by OS was attenuated. On the other hand, the putative effectors were most highly accumulated in the OS from FAW larvae fed on maize compared to those fed on other diets. We identified that one of them (VRLP4) reduces the OS-mediated induction on defense genes in wounded leaves. CONCLUSION: Together, our investigation presents the proteomic landscape of the OS of FAW influenced by different diets and reveals diet-mediated plasticity of OS is involved in FAW adaptation to host plants. This article is protected by copyright. All rights reserved.
ESTHER : Zhang_2024_Pest.Manag.Sci__
PubMedSearch : Zhang_2024_Pest.Manag.Sci__
PubMedID: 38587094

Title : Bifunctional enzyme-mimicking metal-organic frameworks for sensitive acetylcholine analysis - Wen_2024_Talanta_275_126112
Author(s) : Wen Y , Xu W , Wu Y , Tang Y , Liu M , Sha M , Li J , Xiao R , Hu L , Lin Y , Zhu C , Gu W
Ref : Talanta , 275 :126112 , 2024
Abstract : The development of nanomaterials with multi-enzyme-like activity is crucial for addressing challenges in multi-enzyme-based biosensing systems, including cross-talk between different enzymes and the complexities and costs associated with detection. In this study, Pt nanoparticles (Pt NPs) were successfully supported on a Zr-based metal-organic framework (MOF-808) to create a composite catalyst named MOF-808/Pt NPs. This composite catalyst effectively mimics the functions of acetylcholinesterase (AChE) and peroxidase (POD). Leveraging this capability, we replaced AChE and POD with MOF-808/Pt NPs and constructed a biosensor for sensitive detection of acetylcholine (ACh). The MOF-808/Pt NPs catalyze the hydrolysis of ACh, resulting in the production of acetic acid. The subsequent reduction in pH value further enhances the POD-like activity of the MOFs, enabling signal amplification through the oxidation of a colorimetric substrate. This biosensor capitalizes on pH variations during the reaction to modulate the different enzyme-like activities of the MOFs, simplifying the detection process and eliminating cross-talk between different enzymes. The developed biosensor holds great promise for clinical diagnostic analysis and offers significant application value in the field.
ESTHER : Wen_2024_Talanta_275_126112
PubMedSearch : Wen_2024_Talanta_275_126112
PubMedID: 38677169

Title : Design, synthesis, and biological evaluation of novel donepezil-tacrine hybrids as multi-functional agents with low neurotoxicity against Alzheimer's disease - Wang_2023_Bioorg.Chem_143_107010
Author(s) : Wang N , Jia W , Wang J , Yang Z , Liu Y , Huang D , Mei X , Xiong X , Shi J , Tang Y , Chen G , Di D , Hou Y
Ref : Bioorg Chem , 143 :107010 , 2023
Abstract : Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and deficits in cognitive domains. Low choline levels, oxidative stress, and neuroinflammation are the primary mechanisms implicated in AD progression. Simultaneous inhibition of acetylcholinesterase (AChE) and reactive oxygen species (ROS) production by a single molecule may provide a new breath of hope for AD treatment. Here, we describe donepezil-tacrine hybrids as inhibitors of AChE and ROS. Four series of derivatives with a beta-amino alcohol linker were designed and synthesized. In this study, the target compounds were evaluated for their ability to inhibit AChE and butyrylcholinesterase (BuChE) in vitro, using tacrine (hAChE, IC(50) = 305.78 nM; hBuChE, IC(50) = 56.72 nM) and donepezil (hAChE, IC(50) = 89.32 nM; hBuChE, IC(50) = 9137.16 nM) as positive controls. Compound B19 exhibited an excellent and balanced inhibitory potency against AChE (IC(50) = 30.68 nM) and BuChE (IC(50) = 124.57 nM). The cytotoxicity assays demonstrated that the PC12 cell viability rates of compound B19 (84.37 %) were close to that of tacrine (87.73 %) and donepezil (79.71 %). Potential therapeutic effects in AD were evaluated using the neuroprotective effect of compounds against H(2)O(2)-induced toxicity, and compound B19 (68.77 %) exhibited substantially neuroprotective activity at the concentration of 25 microM, compared with the model group (30.34 %). Furthermore, compound B19 protected PC12 cells from H(2)O(2)-induced apoptosis and ROS production. These properties of compound B19 suggested that it was a multi-functional agent with AChE inhibition, anti-oxidative, anti-inflammatory activities, and low toxicity and that it deserves further investigation as a promising agent for AD treatment.
ESTHER : Wang_2023_Bioorg.Chem_143_107010
PubMedSearch : Wang_2023_Bioorg.Chem_143_107010
PubMedID: 38056387

Title : Citrobacter sp. Y3 harbouring novel gene HBCD-hd-1 mineralizes hexabromocyclododecane via new metabolic pathways according to multi-omics characterization - Peng_2023_J.Hazard.Mater_442_130071
Author(s) : Peng X , Li T , Zheng Q , Lu Y , He Y , Tang Y , Qiu R
Ref : J Hazard Mater , 442 :130071 , 2023
Abstract : Hexabromocyclododecane (HBCD) is a typical persistent organic pollutant that is widely detected in the environment. Despite the significant efforts put into its mineralisation, there is still a lack of microorganism resources that can completely mineralise HBCD. Stable isotope analysis revealed that the Citrobacter sp. Y3 can use [(13)C]HBCD as its sole carbon source and degrade or even mineralise it into (13)CO(2), with a maximum conversion rate of 100% in approximately 14 days. Strain Y3 could completely mineralise HBCD, which it used as its only carbon source, and six debromination enzymes related to HBCD degradation were found in Y3, including haloalkane dehalogenase (DhaA), haloacid dehalogenase (HAD), etc. A functional gene named HBCD-hd-1, encoding a HAD, was found to be upregulated during HBCD degradation and heterologously expressed in Escherichia coli. Recombinant E. coli with the HBCD-hd-1 gene transformed the typical intermediate 4-bromobutyric acid to 4-hydroxybutanoic acid and showed excellent degradation performance on HBCD, accompanied by nearly 100% bromine (Br) ion generation. The expression of HBCD-hd-1 in Y3 rapidly accelerated the biodegradation of HBCD. With HBCD as its sole carbon source, strain Y3 could potentially degrade HBCD, especially in a low-nutrient environment.
ESTHER : Peng_2023_J.Hazard.Mater_442_130071
PubMedSearch : Peng_2023_J.Hazard.Mater_442_130071
PubMedID: 36183513

Title : Circadian Rhythm and Neurotransmitters Are Potential Pathways through Which Ocean Acidification and Warming Affect the Metabolism of Thick-Shell Mussels - Tang_2022_Environ.Sci.Technol__
Author(s) : Tang Y , Du X , Sun S , Shi W , Han Y , Zhou W , Zhang J , Teng S , Ren P , Liu G
Ref : Environ Sci Technol , : , 2022
Abstract : Although the impacts of ocean acidification and warming on marine organisms have been increasingly documented, little is known about the affecting mechanism underpinning their interactive impacts on physiological processes such as metabolism. Therefore, the effects of these two stressors on metabolism were investigated in thick-shell mussel Mytilus coruscus in this study. In addition, because metabolism is primarily regulated by circadian rhythm and neurotransmitters, the impacts of acidification and warming on these two regulatory processes were also analyzed. The data obtained demonstrated that the metabolism of mussels (indicated by the clearance rate, oxygen consumption rate, ammonia excretion rate, O:N ratio, ATP content, activity of pyruvate kinase, and expression of metabolism-related genes) were significantly affected by acidification and warming, resulting in a shortage of energy supply (indicated by the in vivo content of ATP). In addition, exposure to acidification and warming led to evident disruption in circadian rhythm (indicated by the heartrate and the expression rhythm of Per2, Cry, and BMAL1) and neurotransmitters (indicated by the activity of acetyl cholinesterase and in vivo contents of ACh, GABA, and DA). These findings suggest that circadian rhythms and neurotransmitters might be potential routes through which acidification and warming interactively affect the metabolism of mussels.
ESTHER : Tang_2022_Environ.Sci.Technol__
PubMedSearch : Tang_2022_Environ.Sci.Technol__
PubMedID: 35293730

Title : Subchronic toxicity of oral deltamethrin in laying chickens - Liu_2022_Front.Vet.Sci_9_1079580
Author(s) : Liu Y , Han M , Liu C , Tang Y , Jia M , Chen X , Liang H , Gao Y , Gu X
Ref : Front Vet Sci , 9 :1079580 , 2022
Abstract : Pyrethroid pesticides, with low toxicity to birds and mammals and short persistence in the environment, are widely used now. With the development of intensive poultry farming, pesticide application leads to residues in poultry products and pollution in ecological environment. The aim of the present study was to examine deltamethrin subchronic toxicity in laying chickens. One hundred and twelve laying chickens were randomly assigned to 14 groups including 13 groups medicated with deltamethrin (n = 8) and one unmedicated group used as control (n = 8). Tissue samples were collected during and after administration for weighing and histopathological analysis. A single dose of deltamethrin (20 mg.kg(-1).BW.d) was administered orally to laying chickens for 14 days. The results showed that deltamethrin has no significant effect on the relative organ weight of laying chickens (p > 0.05). The activities of aspartate aminotransferase and cholinesterase in the plasma gradually decreased over time in the medicated group (p < 0.05). Plasma concentrations of urea nitrogen, uric acid, cholesterol, triglycerides, and creatinine significantly increased during treatment (p < 0.05), and significant liver damage and loss of intestinal villous epithelium were observed. The intestinal wall thickness, villus height, and crypt depth of laying chickens were altered by deltamethrin treatment. During treatment was withdrawn, the intestinal repair was more extensive than the liver repair.
ESTHER : Liu_2022_Front.Vet.Sci_9_1079580
PubMedSearch : Liu_2022_Front.Vet.Sci_9_1079580
PubMedID: 36570503

Title : 5-Methyltetrahydrofolate Alleviates Memory Impairment in a Rat Model of Alzheimer's Disease Induced by D-Galactose and Aluminum Chloride - Zhang_2022_Int.J.Environ.Res.Public.Health_19_
Author(s) : Zhang Z , Wu H , Qi S , Tang Y , Qin C , Liu R , Zhang J , Cao Y , Gao X
Ref : Int J Environ Research Public Health , 19 : , 2022
Abstract : The effects of 5-methyltetrahydrofolate (5-MTHF) on a rat model of Alzheimer's disease (AD) induced by D-galactose (D-gal) and aluminum chloride (AlCl(3)) were investigated. Wistar rats were given an i.p. injection of 60 mg/kg D-gal and 10 mg/kg AlCl(3) to induce AD and three doses of 1 mg/kg, 5 mg/kg or 10 mg/kg 5-MTHF by oral gavage. A positive control group was treated with 1 mg/kg donepezil by gavage. Morris water maze performance showed that 5 and 10 mg/kg 5-MTHF significantly decreased escape latency and increased the number of platform crossings and time spent in the target quadrant for AD rats. The administration of 10 mg/kg 5-MTHF decreased the brain content of amyloid beta-protein 1-42 (Abeta(1-42)) and phosphorylated Tau protein (p-Tau) and decreased acetylcholinesterase and nitric oxide synthase activities. Superoxide dismutase activity, vascular endothelial growth factor level and glutamate concentration were increased, and malondialdehyde, endothelin-1, interleukin-6, tumor necrosis factor-alpha and nitric oxide decreased. The administration of 10 mg/kg 5-MTHF also increased the expression of disintegrin and metallopeptidase domain 10 mRNA and decreased the expression of beta-site amyloid precursor protein cleavage enzyme 1 mRNA. In summary, 5-MTHF alleviates memory impairment in a D-gal- and AlCl(3)-exposed rat model of AD. The inhibition of Abeta(1-42) and p-Tau release, reduced oxidative stress, the regulation of amyloid precursor protein processing and the release of excitatory amino acids and cytokines may be responsible.
ESTHER : Zhang_2022_Int.J.Environ.Res.Public.Health_19_
PubMedSearch : Zhang_2022_Int.J.Environ.Res.Public.Health_19_
PubMedID: 36554305

Title : Twin drug design, synthesis and evaluation of diosgenin derivatives as multitargeted agents for the treatment of vascular dementia - Yang_2021_Bioorg.Med.Chem_37_116109
Author(s) : Yang GX , Sun JM , Zheng LL , Zhang L , Li J , Gan HX , Huang Y , Huang J , Diao XX , Tang Y , Wang R , Ma L
Ref : Bioorganic & Medicinal Chemistry , 37 :116109 , 2021
Abstract : A novel series of multitargeted molecules were designed and synthesized by combining the pharmacological role of cholinesterase inhibitor and antioxidant of steroid as potential ligands for the treatment of Vascular Dementia (VD). The oxygen-glucose deprivation (OGD) model was used to evaluate these molecules, among which the most potent compound ML5 showed the highest activity. Firstly, ML5 showed appropriate inhibition of cholinesterases (ChEs) at orally 15 mg/kg in vivo. The further test revealed that ML5 promoted the nuclear translocation of Nrf2. Furthermore, ML5 has significant neuroprotective effect in vivo model of bilateral common carotid artery occlusion (BCCAO), significantly increasing the expression of Nrf2 protein in the cerebral cortex. In the molecular docking research, we predicted the ML5 combined with hAChE and Keap1. Finally, compound ML5 displayed normal oral absorption and it was nontoxic at 500 mg/kg, po, dose. We can draw the conclusion that ML5 could be considered as a new potential compound for VD treatment.
ESTHER : Yang_2021_Bioorg.Med.Chem_37_116109
PubMedSearch : Yang_2021_Bioorg.Med.Chem_37_116109
PubMedID: 33780813

Title : Putative carboxylesterase gene identification and their expression patterns in Hyphantria cunea (Drury) - Ye_2021_PeerJ_9_e10919
Author(s) : Ye J , Mang D , Kang K , Chen C , Zhang X , Tang Y , E RP , Song L , Zhang QH , Zhang L
Ref : PeerJ , 9 :e10919 , 2021
Abstract : The olfactory system of insects is important for behavioral activities as it recognizes internal and external volatile stimuli in the environment. Insect odorant degrading enzymes (ODEs), including antennal-specific carboxylesterases (CXEs), are known to degrade redundant odorant molecules or to hydrolyze important olfactory sex pheromone components and plant volatiles. Compared to many well-studied Type-I sex pheromone-producing lepidopteran species, the molecular mechanisms of the olfactory system of Type-II sex pheromone-producing Hyphantria cunea (Drury) remain poorly understood. In the current study, we first identified a total of ten CXE genes based on our previous H. unea antennal transcriptomic data. We constructed a phylogenetic tree to evaluate the relationship of HcunCXEs with other insects' CXEs, and used quantitative PCR to investigate the gene expression of H. cunea CXEs (HcunCXEs). Our results indicate that HcunCXEs are highly expressed in antennae, legs and wings, suggesting a potential function in degrading sex pheromone components, host plant volatiles, and other xenobiotics. This study not only provides a theoretical basis for subsequent olfactory mechanism studies on H. cunea, but also offers some new insights into functions and evolutionary characteristics of CXEs in lepidopteran insects. From a practical point of view, these HcunCXEs might represent meaningful targets for developing behavioral interference control strategies against H. cunea.
ESTHER : Ye_2021_PeerJ_9_e10919
PubMedSearch : Ye_2021_PeerJ_9_e10919
PubMedID: 33717687
Gene_locus related to this paper: cname-a0a1u9x1s5 , cname-a0a1u9x1s9 , cname-a0a1u9x1t4 , cname-a0a1u9x1t5 , cname-a0a1u9x1t2 , cname-a0a1u9x1t3 , cname-a0a1u9x1t0 , cname-a0a1u9x1s7 , cname-a0a1u9x1t1 , cname-a0a1u9x1s8 , cname-a0a1u9x1t9 , cname-a0a1u9x1t7 , cname-a0a1u9x1t8 , cname-a0a1u9x1u2 , cname-a0a1u9x1u1

Title : A Polyketide Cyclase That Forms Medium-Ring Lactones - Gao_2021_J.Am.Chem.Soc_143_80
Author(s) : Gao DW , Jamieson CS , Wang G , Yan Y , Zhou J , Houk KN , Tang Y
Ref : Journal of the American Chemical Society , 143 :80 , 2021
Abstract : Medium-ring lactones are synthetically challenging due to unfavorable energetics involved in cyclization. We have discovered a thioesterase enzyme DcsB, from the decarestrictine C1 (1) biosynthetic pathway, that efficiently performs medium-ring lactonizations. DcsB shows broad substrate promiscuity toward linear substrates that vary in lengths and substituents, and is a potential biocatalyst for lactonization. X-ray crystal structure and computational analyses provide insights into the molecular basis of catalysis.
ESTHER : Gao_2021_J.Am.Chem.Soc_143_80
PubMedSearch : Gao_2021_J.Am.Chem.Soc_143_80
PubMedID: 33351624
Gene_locus related to this paper: beab2-j4wat9

Title : Design, synthesis and evaluation of diosgenin carbamate derivatives as multitarget anti-Alzheimer's disease agents - Yang_2020_Eur.J.Med.Chem_187_111913
Author(s) : Yang GX , Huang Y , Zheng LL , Zhang L , Su L , Wu YH , Li J , Zhou LC , Huang J , Tang Y , Wang R , Ma L
Ref : Eur Journal of Medicinal Chemistry , 187 :111913 , 2020
Abstract : In order to produce an effective and multi-targeted clinical drug that could prevent progressive neurodegeneration, a series of diosgenin carbamate derivatives were designed, synthesized and tested for their anti-inflammatory, antioxidant and anti-Abeta activities. The results demonstrated that compound M15 was the most promising derivative against inflammatory (NO inhibition 22.7 +/- 2.2%,10 muM) and cellular damage induced by H2O2 (SH-SY5Y cell protection = 75.3 +/- 3.4%, 10 muM) or Abeta (astrocytes protection = 70.2 +/- 6.5%, 10 muM). Molecular docking studies revealed the strong binding affinity of M15 to the active site of nNOS, Abeta42 and pro-inflammatory proteins. Western blot demonstrated that M15 decreased IL-1beta, IL-6 and TNF-alpha level, which may contribute to its anti-inflammatory effects. In addition, M15 maintained mitochondrial function as well as cell viability through reducing H2O2-induced ROS production. The results indicated that oral administration of M15 attenuated memory deficits and played a neuroprotective effect on subcutaneous (s.c.) D-gal aging mice. In summary, M15 could be considered as a potential multifunctional neuroprotective agent due to the effects of anti-inflammatory, antioxidant and anti-Abeta activities.
ESTHER : Yang_2020_Eur.J.Med.Chem_187_111913
PubMedSearch : Yang_2020_Eur.J.Med.Chem_187_111913
PubMedID: 31837501

Title : Lotus japonicus karrikin receptors display divergent ligand-binding specificities and organ-dependent redundancy - Carbonnel_2020_PLoS.Genet_16_e1009249
Author(s) : Carbonnel S , Torabi S , Griesmann M , Bleek E , Tang Y , Buchka S , Basso V , Shindo M , Boyer FD , Wang TL , Udvardi M , Waters MT , Gutjahr C
Ref : PLoS Genet , 16 :e1009249 , 2020
Abstract : Karrikins (KARs), smoke-derived butenolides, are perceived by the alpha/beta-fold hydrolase KARRIKIN INSENSITIVE2 (KAI2) and thought to mimic endogenous, yet elusive plant hormones tentatively called KAI2-ligands (KLs). The sensitivity to different karrikin types as well as the number of KAI2 paralogs varies among plant species, suggesting diversification and co-evolution of ligand-receptor relationships. We found that the genomes of legumes, comprising a number of important crops with protein-rich, nutritious seed, contain two or more KAI2 copies. We uncover sub-functionalization of the two KAI2 versions in the model legume Lotus japonicus and demonstrate differences in their ability to bind the synthetic ligand GR24ent-5DS in vitro and in genetic assays with Lotus japonicus and the heterologous Arabidopsis thaliana background. These differences can be explained by the exchange of a widely conserved phenylalanine in the binding pocket of KAI2a with a tryptophan in KAI2b, which arose independently in KAI2 proteins of several unrelated angiosperms. Furthermore, two polymorphic residues in the binding pocket are conserved across a number of legumes and may contribute to ligand binding preferences. The diversification of KAI2 binding pockets suggests the occurrence of several different KLs acting in non-fire following plants, or an escape from possible antagonistic exogenous molecules. Unexpectedly, L. japonicus responds to diverse synthetic KAI2-ligands in an organ-specific manner. Hypocotyl growth responds to KAR1, KAR2 and rac-GR24, while root system development responds only to KAR1. This differential responsiveness cannot be explained by receptor-ligand preferences alone, because LjKAI2a is sufficient for karrikin responses in the hypocotyl, while LjKAI2a and LjKAI2b operate redundantly in roots. Instead, it likely reflects differences between plant organs in their ability to transport or metabolise the synthetic KLs. Our findings provide new insights into the evolution and diversity of butenolide ligand-receptor relationships, and open novel research avenues into their ecological significance and the mechanisms controlling developmental responses to divergent KLs.
ESTHER : Carbonnel_2020_PLoS.Genet_16_e1009249
PubMedSearch : Carbonnel_2020_PLoS.Genet_16_e1009249
PubMedID: 33370251

Title : Toxic effects of different-sized graphene oxide particles on zebrafish embryonic development - Chen_2020_Ecotoxicol.Environ.Saf_197_110608
Author(s) : Chen Z , Yu C , Khan IA , Tang Y , Liu S , Yang M
Ref : Ecotoxicology & Environmental Safety , 197 :110608 , 2020
Abstract : Graphene oxide (GO) has broad application potential in many fields, such as biomedicine and energy. Due to the wide-ranging GO applications, its entry into the environment is inevitable along with the potential for ecological and environmental risks. In the present study, we systematically investigated the dose-dependent effects of three different-sized GO particles (50-200 nm, <500 nm, and >500 nm) on zebrafish during the very early developmental stages (4-124 h post-fertilization). The results showed that GOs could accumulate in the eyes, heart, yolk sac, and blood vessels of fish larvae. Consequently, their effects on multiple toxic endpoints were observed, including delayed hatching times, shortened body lengths, alterations in heart rate and blood flow, changes in swimming activity and responses to photoperiod stimulation, and the enhanced activity of total superoxide dismutase, inducible nitric oxide synthase, acetylcholinesterase, caspase-3, and induction of apoptosis-related gene expression. As a result, the occurrence of oxidative stress and the induction of apoptosis are suggested in fish larvae exposed to all three different-sized GO particles. In addition, our results highlight the impacts of waterborne-GO exposure on zebrafish during early development, which were not merely dependent on GO concentration but also on the associated GO sizes. This study hereby provides a basis for the potential ecological and health risks of GO exposure.
ESTHER : Chen_2020_Ecotoxicol.Environ.Saf_197_110608
PubMedSearch : Chen_2020_Ecotoxicol.Environ.Saf_197_110608
PubMedID: 32305822

Title : Characterization and Genome Analysis of a Zearalenone-Degrading Bacillus velezensis Strain ANSB01E - Guo_2020_Curr.Microbiol_77_273
Author(s) : Guo Y , Zhou J , Tang Y , Ma Q , Zhang J , Ji C , Zhao L
Ref : Curr Microbiol , 77 :273 , 2020
Abstract : Zearalenone, a nonsteroidal estrogenic mycotoxin mainly produced by Fusarium species, causes reproductive disorders and hyperestrogenic syndromes in animals and humans. The bacterial strain Bacillus velezensis ANSB01E, isolated from chicken cecal content, was capable of effectively degrading zearalenone in both liquid medium and mouldy corn. Moreover, Bacillus velezensis ANSB01E exhibited good antimicrobial activities against animal pathogenic bacteria, including Escherichia coli, Staphylococcus aureus, and Salmonella spp. Genome-based analysis revealed the presence of genes coding peroxiredoxin and alpha/beta hydrolase in Bacillus velezensis ANSB01E, which may be involved in zearalenone degradation. The study on the genome provides insights into the zearalenone degradation mechanisms and advances the potential application of Bacillus velezensis ANSB01E in food and feed industry.
ESTHER : Guo_2020_Curr.Microbiol_77_273
PubMedSearch : Guo_2020_Curr.Microbiol_77_273
PubMedID: 31748861
Gene_locus related to this paper: 9baci-QBK11187

Title : sEH Inhibitor Tppu Ameliorates Cecal Ligation and Puncture-Induced Sepsis by Regulating Macrophage Functions - Chen_2020_Shock_53_761
Author(s) : Chen Z , Tang Y , Yu J , Dong R , Yang Y , Fu M , Luo J , Hu S , Wang DW , Tu L , Xu X
Ref : Shock , 53 :761 , 2020
Abstract : BACKGROUND: Sepsis is a life-threatening organ dysfunction initiated by a dysregulated response to infection, with imbalanced inflammation and immune homeostasis. Macrophages play a pivotal role in sepsis. N-[1-(1-oxopropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy)phenyl)-urea (TPPU) is an inhibitor of soluble epoxide hydrolase (sEH), which can rapidly hydrolyze epoxyeicosatrienoic acids (EETs) to the bio-inactive dihydroxyeicosatrienoic acids. TPPU was linked with the regulation of macrophages and inflammation. Here, we hypothesized that sEH inhibitor TPPU ameliorates cecal ligation and puncture (CLP)-induced sepsis by regulating macrophage functions. METHODS: A polymicrobial sepsis model induced by CLP was used in our study. C57BL/6 mice were divided into four groups: sham+ phosphate buffer saline (PBS), sham+TPPU, CLP+PBS, CLP+TPPU. Mice were observed 48h after surgery to assess the survival rate. For other histological examinations, mice were sacrificed 6h after surgery. Macrophage cell line RAW264.7 was used for in vitro studies. RESULTS: TPPU treatment, accompanied with increased EETs levels, markedly improved the survival of septic mice induced by CLP surgery, which was associated with alleviated organ damage and dysfunction triggered by systemic inflammatory response. Moreover, TPPU treatment significantly inhibited systemic inflammatory response via EETs-induced inactivation of mitogen-activated protein kinase signaling due to enhanced macrophage phagocytic ability and subsequently reduced bacterial proliferation and dissemination, and decreased inflammatory factors release. CONCLUSION: sEH inhibitor TPPU ameliorates cecal ligation and puncture-induced sepsis by regulating macrophage functions, including improved phagocytosis and reduced inflammatory response. Our data indicate that sEH inhibition has potential therapeutic effects on polymicrobial-induced sepsis.
ESTHER : Chen_2020_Shock_53_761
PubMedSearch : Chen_2020_Shock_53_761
PubMedID: 31318834

Title : Ambient light sensor based colorimetric dipstick reader for rapid monitoring organophosphate pesticides on a smart phone - Fu_2019_Anal.Chim.Acta_1092_126
Author(s) : Fu Q , Zhang C , Xie J , Li Z , Qu L , Cai X , Ouyang H , Song Y , Du D , Lin Y , Tang Y
Ref : Anal Chim Acta , 1092 :126 , 2019
Abstract : Organophosphate pesticides (OPs) are widely used around the world to control pests in agricultural, residential, and commercial settings. Ingestion of high-dose OPs could lead to acute toxicity, and persistent influence on health could result from acute poisoning or long-term exposure to low dose OPs. An easy to operate, low cost and home available OPs testing platform is urgently needed. Ambient light sensor (ALS) based smart phone colorimetric reader has the advantages of easy to operate, low cost, high accuracy and versatility. In this work, a novel ALS based smart phone colorimetric dipsticks (CDs) reader was reported for rapid monitoring OPs. In this method, acetylcholinesterase (ACHE) CDs was used to test OPs and results were analyzed using an ALS based reader according to the absorbance of ACHE CDs. The results obtained using the ALS based CDs reader were comparable to those obtained using gas chromatography-mass spectrometry (GC-MS) and Ellman assay. The ALS based CDs reader has the advantages of portable, low cost, and high accuracy, and therefore could act an effective platform for OPs monitoring.
ESTHER : Fu_2019_Anal.Chim.Acta_1092_126
PubMedSearch : Fu_2019_Anal.Chim.Acta_1092_126
PubMedID: 31708025

Title : Thioesterase-Catalyzed Aminoacylation and Thiolation of Polyketides in Fungi - Tang_2019_J.Am.Chem.Soc_141_8198
Author(s) : Tang MC , Fischer CR , Chari JV , Tan D , Suresh S , Chu A , Miranda M , Smith J , Zhang Z , Garg NK , St Onge RP , Tang Y
Ref : Journal of the American Chemical Society , 141 :8198 , 2019
Abstract : Fungal highly reducing polyketide synthases (HRPKSs) biosynthesize polyketides using a single set of domains iteratively. Product release is a critical step in HRPKS function to ensure timely termination and enzyme turnover. Nearly all of the HRPKSs characterized to date employ a separate thioesterase (TE) or acyltransferase enzyme for product release. In this study, we characterized two fungal HRPKSs that have fused C-terminal TE domains, a new domain architecture for fungal HRPKSs. We showed that both HRPKS-TEs synthesize aminoacylated polyketides in an ATP-independent fashion. The KU42 TE domain selects cysteine and homocysteine and catalyzes transthioesterification using the side-chain thiol group as the nucleophile. In contrast, the KU43 TE domain selects leucine methyl ester and performs a direct amidation of the polyketide, a reaction typically catalyzed by nonribosomal peptide synthetase (NRPS) domains. The characterization of these HRPKS-TE enzymes showcases the functional diversity of HRPKS enzymes and provides potential TE domains as biocatalytic tools to diversify HRPKS structures.
ESTHER : Tang_2019_J.Am.Chem.Soc_141_8198
PubMedSearch : Tang_2019_J.Am.Chem.Soc_141_8198
PubMedID: 31051070
Gene_locus related to this paper: punst-KU42

Title : Hepatoprotective Potential of Partially Hydrolyzed Guar Gum against Acute Alcohol-Induced Liver Injury in Vitro and Vivo - Wu_2019_Nutrients_11_
Author(s) : Wu C , Liu J , Tang Y , Li Y , Yan Q , Jiang Z
Ref : Nutrients , 11 : , 2019
Abstract : Natural polysaccharides, particularly galactomannans, are potential candidates for treatment of alcoholic liver diseases (ALD). However, applications are restricted due to the physicochemical properties associated with the high molecular weight. In this work, guar gum galactomannans were partially hydrolyzed by beta-mannanase, and the molecular mechanisms of hepatoprotective effects were elucidated both in vitro and in vivo. Release of lactate dehydrogenase and cytochrome C were attenuated by partially hydrolyzed guar gum (PHGG) in HepG2 cells, due to protected cell and mitochondrial membrane integrity. PHGG co-administration decreased serum amino transaminases and cholinesterase levels of acute alcohol intoxicated mice, while hepatic pathologic morphology was depleted. Activity of superoxide dismutase, catalase, and glutathione peroxidase was recovered to 198.2, 34.5, 236.0 U/mg protein, respectively, while malondialdehyde level was decreased by 76.3% (PHGG, 1000 mg/kgday). Co-administration of PHGG induced a 4.4-fold increment of p-AMPK expression, and lipid metabolism was mediated. PHGG alleviated toll-like-receptor-4-mediated inflammation via the signaling cascade of MyD88 and IkappaBalpha, decreasing cytokine production. Moreover, mediated expression of Bcl-2 and Bax was responsible for inhibited acute alcohol-induced apoptosis with suppressed cleavage of caspase 3 and PARP. Findings gained suggest that PHGG can be used as functional food supplement for the treatment of acute alcohol-induced liver injury.
ESTHER : Wu_2019_Nutrients_11_
PubMedSearch : Wu_2019_Nutrients_11_
PubMedID: 31035540

Title : Antioxidant defence system is responsible for the toxicological interactions of mixtures: A case study on PFOS and PFOA in Daphnia magna - Yang_2019_Sci.Total.Environ_667_435
Author(s) : Yang HB , Zhao YZ , Tang Y , Gong HQ , Guo F , Sun WH , Liu SS , Tan H , Chen F
Ref : Sci Total Environ , 667 :435 , 2019
Abstract : Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are two types of perfluorinated compounds (PFCs) frequently studied in recent years due to their potential for bioaccumulation and toxicity to humans. Usually, PFCs can co-exist in various environment. Therefore, over- or under-estimated risk assessments would result if antagonism or synergism occurred in mixture toxicity. In the present study, the acute and chronic toxicities of single and mixtures of PFOA and PFOS to Daphnia magna were investigated. PFOS was more toxic than PFOA, both in 48-h acute toxicity and 21-d chronic toxicity. In acute toxicity tests, mixture toxicities showed strong synergistic effects on mortality. The experimental EC50 of the mixture is 4.44x10(-5)mol/L, whereas the predicted EC50 is 8.19x10(-5)mol/L by Concentration Addition Model and 9.73x10(-5)mol/L by Independent Action Model. In chronic toxicity tests, synergistic effects were also found in the aspects of offspring. The offspring rate is reduced significantly to 39.8% at the 9.61x10(-7)mol/L of mixture, while, PFOS and PFOA do not have effects when they are tested individually at corresponding concentrations. To explore the potential mechanism of the synergistic effect, the interactions between PFCs and proteins, including acetylcholinesterase, superoxide dismutase, catalase, ecdysone receptor and glutathione-S-transferase, were investigated by the Molecular Docking. The docking results revealed that the driving forces for the binding of PFCs with proteins were predominantly hydrophobic and hydrogen-bonding interactions. Based on the binding models, we deduced that the potential mechanism of synergism is that PFOS and PFOA have similar binding modes with catalase and have different binding modes with superoxide dismutase. Overall, these data provide experimental evidence that there is strong synergism in acute and chronic toxicity of mixtures to D. magna and demonstrate that molecular structure of some components of the antioxidant defence system contributes to the synergistic interaction.
ESTHER : Yang_2019_Sci.Total.Environ_667_435
PubMedSearch : Yang_2019_Sci.Total.Environ_667_435
PubMedID: 30833242

Title : The Genome of Artemisia annua Provides Insight into the Evolution of Asteraceae Family and Artemisinin Biosynthesis - Shen_2018_Mol.Plant_11_776
Author(s) : Shen Q , Zhang L , Liao Z , Wang S , Yan T , Shi P , Liu M , Fu X , Pan Q , Wang Y , Lv Z , Lu X , Zhang F , Jiang W , Ma Y , Chen M , Hao X , Li L , Tang Y , Lv G , Zhou Y , Sun X , Brodelius PE , Rose JKC , Tang K
Ref : Mol Plant , 11 :776 , 2018
Abstract : Artemisia annua, commonly known as sweet wormwood or Qinghao, is a shrub native to China and has long been used for medicinal purposes. A. annua is now cultivated globally as the only natural source of a potent anti-malarial compound, artemisinin. Here, we report a high-quality draft assembly of the 1.74-gigabase genome of A. annua, which is highly heterozygous, rich in repetitive sequences, and contains 63 226 protein-coding genes, one of the largest numbers among the sequenced plant species. We found that, as one of a few sequenced genomes in the Asteraceae, the A. annua genome contains a large number of genes specific to this large angiosperm clade. Notably, the expansion and functional diversification of genes encoding enzymes involved in terpene biosynthesis are consistent with the evolution of the artemisinin biosynthetic pathway. We further revealed by transcriptome profiling that A. annua has evolved the sophisticated transcriptional regulatory networks underlying artemisinin biosynthesis. Based on comprehensive genomic and transcriptomic analyses we generated transgenic A. annua lines producing high levels of artemisinin, which are now ready for large-scale production and thereby will help meet the challenge of increasing global demand of artemisinin.
ESTHER : Shen_2018_Mol.Plant_11_776
PubMedSearch : Shen_2018_Mol.Plant_11_776
PubMedID: 29703587
Gene_locus related to this paper: artan-a0a2u1ns65 , artan-a0a2u1nuf0 , artan-a0a2u1pw87 , artan-a0a2u1ql98 , artan-a0a2u1n9p7.2 , artan-a0a2u1ky94 , artan-a0a2u1pvq0 , artan-a0a2u1q8x4 , artan-a0a2u1mtd1 , artan-a0a2u1l9j8 , artan-a0a2u1lak5 , artan-a0a2u1lfl1 , artan-a0a2u1lzs1 , artan-a0a2u1m5v6 , artan-a0a2u1n4s5 , artan-a0a2u1qgg7

Title : Suxiao Jiuxin pill promotes exosome secretion from mouse cardiac mesenchymal stem cells in vitro - Ruan_2018_Acta.Pharmacol.Sin_39_569
Author(s) : Ruan XF , Ju CW , Shen Y , Liu YT , Kim IM , Yu H , Weintraub N , Wang XL , Tang Y
Ref : Acta Pharmacol Sin , 39 :569 , 2018
Abstract : Cardiac mesenchymal stem cells (C-MSCs) are endogenous cardiac stromal cells that play a role in heart repair after injury. C-MSC-derived exosomes (Exo) have shown protective effects against apoptosis induced by acute myocardial ischemia/reperfusion. Suxiao Jiuxin pill (SJP) is a traditional Chinese medicine (TCM) formula used in China for the treatment of acute myocardial ischemia, which contains tetramethylpyrazine (TMP) and borneol (BOR) as major components. In this study, we investigated whether SJP treatment affected exosome release from C-MSCs in vitro. C-MSCs prepared from mice were treated with SJP (62.5 mug/mL), TMP (25 mug/mL) or BOR (15 mug/mL). Using an acetylcholinesterase activity assay, we found that both SJP and TMP treatment significantly increased exosome secretion compared to the control ethanol treatment. The neutral sphingomyelinase 2 (nSMase2) pathway was important in exosome formation and packaging. But neither the level of nSMase2 mRNA nor the level of protein changed following SJP, TMP or BOR treatment, suggesting that SJP stimulated exosome release via an nSMase2-independent pathway. The Rab27a and Rab27b GTPases controlled different steps of the exosome secretion pathway. We showed that SJP treatment significantly increased the protein levels of Rab27a, SYTL4 (Rab27a effector) and Rab27b compared with the control treatment. SJP treatment also significantly upregulated the mRNA level of Rab27b, rather than Rab27a. Moreover, SJP-induced increase of C-MSC-exosome release was inhibited by Rab27b knockdown, suggesting that SJP promotes exosome secretion from C-MSCs via a GTPase-dependent pathway. This study reveals a novel mechanism for SJP in modulating cardiac homeostasis.
ESTHER : Ruan_2018_Acta.Pharmacol.Sin_39_569
PubMedSearch : Ruan_2018_Acta.Pharmacol.Sin_39_569
PubMedID: 29542682

Title : Genome Mining and Assembly-Line Biosynthesis of the UCS1025A Pyrrolizidinone Family of Fungal Alkaloids - Li_2018_J.Am.Chem.Soc_140_2067
Author(s) : Li L , Tang MC , Tang S , Gao S , Soliman S , Hang L , Xu W , Ye T , Watanabe K , Tang Y
Ref : Journal of the American Chemical Society , 140 :2067 , 2018
Abstract : UCS1025A is a fungal polyketide/alkaloid that displays strong inhibition of telomerase. The structures of UCS1025A and related natural products are featured by a tricyclic furopyrrolizidine connected to a trans-decalin fragment. We mined the genome of a thermophilic fungus and activated the ucs gene cluster to produce UCS1025A at a high titer. Genetic and biochemical analysis revealed a PKS-NRPS assembly line that activates 2S,3S-methylproline derived from l-isoleucine, followed by Knoevenagel condensation to construct the pyrrolizidine moiety. Oxidation of the 3S-methyl group to a carboxylate leads to an oxa-Michael cyclization and furnishes the furopyrrolizidine. Our work reveals a new strategy used by nature to construct heterocyclic alkaloid-like ring systems using assembly line logic.
ESTHER : Li_2018_J.Am.Chem.Soc_140_2067
PubMedSearch : Li_2018_J.Am.Chem.Soc_140_2067
PubMedID: 29373009
Gene_locus related to this paper: acrsp-ucsc

Title : Lychee seed extract protects against neuronal injury and improves cognitive function in rats with type II diabetes mellitus with cognitive impairment - Tang_2018_Int.J.Mol.Med_41_251
Author(s) : Tang Y , Yu C , Wu J , Chen H , Zeng Y , Wang X , Yang L , Mei Q , Cao S , Qin D
Ref : Int J Mol Med , 41 :251 , 2018
Abstract : Lychee seed is a traditional Chinese medicine and has many beneficial effects such as modulation of blood sugar and lipids, antioxidation, antivirus and antitumor. Studies have indicated that type II diabetes mellitus (T2DM) and Alzheimer's disease (AD) share common biological mechanisms including insulin resistance, impaired glucose metabolism, betaamyloid (Abeta) formation, oxidative stress and presence of advanced glycation end products (AGEs). The present study investigated the effects of lychee seed extract (LSE) on neuroprotection, cognitive function improvement and possible underlying mechanisms in a rat model of T2DM with cognitive impairment. We analyzed the chemical profile of LSE using a UHPLCSPD chromatogram and evaluated its effect on the improvement of spatial learning and memory of rats by a Morris water maze. The levels of glucose, insulin, Abeta, AGEs, Tau protein and acetylcholinesterase in the blood and/or hippocampus of rats were determined by bloodglucose meter, radioimmunoassay, chemical chromatometry, enzymelinked immunosorbent assay (ELISA) and immunohistochemical analysis, respectively. Results demonstrated that LSE consists of eight major and around 20 minor ingredients, and it remarkably prevents neuronal injury and improves cognitive functions in T2DM rats. The levels of glucose, insulin, Abeta, AGEs and Tau protein were significantly increased in the blood and/or hippocampus of T2DM rats, while LSE remarkably decreased their levels compared to vehicle treatment (P<0.01). The possible mechanisms may be associated with IR improvement and decreased formations of Abeta, AGEs and Tau protein in the hippocampus of T2DM rats. LSE may be developed as the agent for the treatment of T2DM and/or AD clinically.
ESTHER : Tang_2018_Int.J.Mol.Med_41_251
PubMedSearch : Tang_2018_Int.J.Mol.Med_41_251
PubMedID: 29138799

Title : Muscarinic cholinergic signaling and overactive bladder-like symptoms associated with invasive bladder cancer - Wei_2018_Oncol.Lett_16_775
Author(s) : Wei W , Wang M , Li Y , Meng Q , Tang Y , Lu H , Yu W , Cheng Q , Xu L , Jian S , Wu Y , Yi X , Xie K
Ref : Oncol Lett , 16 :775 , 2018
Abstract : The objective of the present study was to explore the association between muscarinic cholinergic signaling and urothelial bladder tumors. Possible associations among overactive bladder (OAB) symptoms and bladder tumors were retrospectively investigated using a multicenter Chinese database with prospectively collected data since 2010. Firstly, it was demonstrated that OAB symptoms, such as urgency, were more severe in patients with invasive bladder cancer and were associated with a reduced prognosis. Following this, muscarinic cholinergic receptor 3 (M3R) expression in urothelium was determined to be lower in invasive cancer tissue than in adjacent non-cancerous tissue, yet M3R upregulation was associated with a reduced progression free survival (PFS) time. Additionally, it was also demonstrated that muscarinic cholinergic receptor 2 (M2R) was upregulated in the sub-urothelium, and this was also associated with a reduced PFS time. Furthermore, it was determined that cholinesterase and acetylcholinesterase were lower in invasive cancer than in non-invasive cancer. In conclusion, the results indicated that M3R expression was downregulated in invasive bladder cancer, which may have a role as a protective anti-oncogene, in contrast to its oncogenic role in numerous other cancer types. Therefore, muscarinic cholinergic signaling may be a novel therapeutic target for treating bladder cancer.
ESTHER : Wei_2018_Oncol.Lett_16_775
PubMedSearch : Wei_2018_Oncol.Lett_16_775
PubMedID: 29963145

Title : Diagnostic value of complete blood count in paraquat and organophosphorus poisoning patients - Tang_2018_Toxicol.Ind.Health__748233718770896
Author(s) : Tang Y , Hu L , Hong G , Zhong D , Song J , Zhao G , Lu Z
Ref : Toxicol Ind Health , :748233718770896 , 2018
Abstract : Complete blood count (CBC) is one of the most extensively used tests in clinical practice. In order to determine the diagnostic value of the CBC in paraquat (PQ) and organophosphorus (OPPs) poisoning, the CBC indices of PQ- and OPPs-poisoned patients were investigated in this study. A total of 96 PQ poisoning patients, 90 OPPs poisoning patients, and 188 healthy subjects were included in this study. The PQ- and OPPs-poisoned patients were divided into different groups according to their clinical symptoms. All CBC indices were analyzed by Fisher discriminant, partial least-squares discriminant analysis (PLS-DA), variance analysis, and receiver operating characteristic (ROC). The discriminant results showed that 87.7% of original grouped cases correctly classified between PQ-poisoned patients, OPPs-poisoned patients, and healthy subjects. The PLS-DA results showed that the important variable order was different in PQ- and OPPs-poisoned patients. Both white blood cell (WBC) and neutrophil (NE) counts were the most important indexes in PQ- and OPPs-poisoned patients. In OPPs poisoning patients, WBC and NE showed statistical differences between the severe poisoning group and the moderate poisoning group. Their areas under the ROC curve (AUC) were 0.673 (WBC) and 0.669 (NE), which were higher than cholinesterase (CHE; AUC 0.326). In conclusion, the CBC indices had a diagnostic value in PQ and OPPs poisoning; WBC and NE were the first responses and had clinical significance in PQ and OPPs poisoning; moreover, they are better than CHE in diagnosing OPPs poisoning.
ESTHER : Tang_2018_Toxicol.Ind.Health__748233718770896
PubMedSearch : Tang_2018_Toxicol.Ind.Health__748233718770896
PubMedID: 29669481

Title : Enhanced lincomycin production by co-overexpression of metK1 and metK2 in Streptomyces lincolnensis - Xu_2018_J.Ind.Microbiol.Biotechnol_45_345
Author(s) : Xu Y , Tan G , Ke M , Li J , Tang Y , Meng S , Niu J , Wang Y , Liu R , Wu H , Bai L , Zhang L , Zhang B
Ref : J Ind Microbiol Biotechnol , 45 :345 , 2018
Abstract : Streptomyces lincolnensis is generally utilized for the production of lincomycin A (Lin-A), a clinically useful antibiotic to treat Gram-positive bacterial infections. Three methylation steps, catalyzed by three different S-adenosylmethionine (SAM)-dependent methyltransferases, are required in the biosynthesis of Lin-A, and thus highlight the significance of methyl group supply in lincomycin production. In this study, we demonstrate that externally supplemented SAM cannot be taken in by cells and therefore does not enhance Lin-A production. Furthermore, bioinformatics and in vitro enzymatic assays revealed there exist two SAM synthetase homologs, MetK1 (SLCG_1651) and MetK2 (SLCG_3830) in S. lincolnensis that could convert L-methionine into SAM in the presence of ATP. Even though we attempted to inactivate metK1 and metK2, only metK2 was deleted in S. lincolnensis LCGL, named as DeltametK2. Following a reduction of the intracellular SAM concentration, DeltametK2 mutant exhibited a significant decrease of Lin-A in comparison to its parental strain. Individual overexpression of metK1 or metK2 in S. lincolnensis LCGL either elevated the amount of intracellular SAM, concomitant with 15% and 22% increase in Lin-A production, respectively. qRT-PCR assays showed that overexpression of either metK1 or metK2 increased the transcription of lincomycin biosynthetic genes lmbA and lmbR, and regulatory gene lmbU, indicating SAM may also function as a transcriptional activator. When metK1 and metK2 were co-expressed, Lin-A production was increased by 27% in LCGL, while by 17% in a high-yield strain LA219X.
ESTHER : Xu_2018_J.Ind.Microbiol.Biotechnol_45_345
PubMedSearch : Xu_2018_J.Ind.Microbiol.Biotechnol_45_345
PubMedID: 29574602
Gene_locus related to this paper: strln-a0a1b1ma73 , strln-a0a1b1m575

Title : Carboxylesterase and UDP-glucuronosyltransferases mediated metabolism of irinotecan: In vitro and in vivo insights from quantitative ultra-performance liquid chromatography-mass spectrometry analysis - Qin_2018_Biomed.Chromatogr__e4320
Author(s) : Qin Y , Kang A , Zhou G , Wang H , Wei W , Cao Y , Chen Y , Wang J , Shi Y , Tang Y , Jiang J
Ref : Biomedical Chromatography , :e4320 , 2018
Abstract : Carboxylesterase and UDP-glucuronosyltransferases mediated metabolism of irinotecan (CPT-11) has long been proposed to be responsible for its anti-tumor activity and toxicity, like delayed-onset diarrhea. However, recent studies failed to gain more comprehensive in vivo and in vitro pharmacokinetic profiles of irinotecan. Herein, we choose rat plasma, human liver microsomes and immortalized HepG2 cell as experimental subjects to describes an sensitive and versatile UHPLC-MS/MS method for simultaneously quantify CPT-11 and its metabolites, including SN-38 and SN-38G. Meanwhile, we have adopted the method to investigate the pharmacokinetic or metabolism behavior of CPT-11 in the above biological samples. Calibration curves for all bio-matrices showed desirable linearity (r(2) >0.99). The intra-day and inter-day precision (RSD, %) were within 15 % and the excellent accuracy (RE, %) was between 2.96% and 14.12%. In addition, the specificity, matrix effect and extraction recovery were all meet the requirements of biological sample analysis. We have successfully applied this method to investigating pharmacokinetic of irinotecan in different biological samples, which mediated by carboxylesterase and UDP-glucuronosyltransferases. And this method could be emplyed in monitoring the metabolic status and clinical efficacy of irinotecan in the future.
ESTHER : Qin_2018_Biomed.Chromatogr__e4320
PubMedSearch : Qin_2018_Biomed.Chromatogr__e4320
PubMedID: 29920713

Title : Identification and Heterologous Production of a Benzoyl-Primed Tricarboxylic Acid Polyketide Intermediate from the Zaragozic Acid A Biosynthetic Pathway - Liu_2017_Org.Lett_19_3560
Author(s) : Liu N , Hung YS , Gao SS , Hang L , Zou Y , Chooi YH , Tang Y
Ref : Org Lett , 19 :3560 , 2017
Abstract : Zaragozic acid A (1) is a potent cholesterol lowering, polyketide natural product made by various filamentous fungi. The reconstitution of enzymes responsible for the initial steps of the biosynthetic pathway of 1 is accomplished using an engineered fungal heterologous host. These initial steps feature the priming of a benzoic acid starter unit onto a highly reducing polyketide synthase (HRPKS), followed by oxaloacetate extension and product release to generate a tricarboxylic acid containing product 2. The reconstitution studies demonstrated that only three enzymes, HRPKS, citrate synthase, and hydrolase, are needed in A. nidulans to produce the structurally complex product.
ESTHER : Liu_2017_Org.Lett_19_3560
PubMedSearch : Liu_2017_Org.Lett_19_3560
PubMedID: 28605916
Gene_locus related to this paper: coclu-clz11

Title : Collaborative Biosynthesis of Maleimide- and Succinimide-Containing Natural Products by Fungal Polyketide Megasynthases - Sato_2017_J.Am.Chem.Soc_139_5317
Author(s) : Sato M , Dander JE , Sato C , Hung YS , Gao SS , Tang MC , Hang L , Winter JM , Garg NK , Watanabe K , Tang Y
Ref : Journal of the American Chemical Society , 139 :5317 , 2017
Abstract : Fungal polyketide synthases (PKSs) can function collaboratively to synthesize natural products of significant structural diversity. Here we present a new mode of collaboration between a highly reducing PKS (HRPKS) and a PKS-nonribosomal peptide synthetase (PKS-NRPS) in the synthesis of oxaleimides from the Penicillium species. The HRPKS is recruited in the synthesis of an olefin-containing free amino acid, which is activated and incorporated by the adenylation domain of the PKS-NRPS. The precisely positioned olefin from the unnatural amino acid is proposed to facilitate a scaffold rearrangement of the PKS-NRPS product to forge the maleimide and succinimide cores of oxaleimides.
ESTHER : Sato_2017_J.Am.Chem.Soc_139_5317
PubMedSearch : Sato_2017_J.Am.Chem.Soc_139_5317
PubMedID: 28365998
Gene_locus related to this paper: penox-poxo

Title : Functional similarities between the dictyostelium protein AprA and the human protein dipeptidyl-peptidase IV - Herlihy_2017_Protein.Sci_26_578
Author(s) : Herlihy SE , Tang Y , Phillips JE , Gomer RH
Ref : Protein Science , 26 :578 , 2017
Abstract : Autocrine proliferation repressor protein A (AprA) is a protein secreted by Dictyostelium discoideum cells. Although there is very little sequence similarity between AprA and any human protein, AprA has a predicted structural similarity to the human protein dipeptidyl peptidase IV (DPPIV). AprA is a chemorepellent for Dictyostelium cells, and DPPIV is a chemorepellent for neutrophils. This led us to investigate if AprA and DPPIV have additional functional similarities. We find that like AprA, DPPIV is a chemorepellent for, and inhibits the proliferation of, D. discoideum cells, and that AprA binds some DPPIV binding partners such as fibronectin. Conversely, rAprA has DPPIV-like protease activity. These results indicate a functional similarity between two eukaryotic chemorepellent proteins with very little sequence similarity, and emphasize the usefulness of using a predicted protein structure to search a protein structure database, in addition to searching for proteins with similar sequences.
ESTHER : Herlihy_2017_Protein.Sci_26_578
PubMedSearch : Herlihy_2017_Protein.Sci_26_578
PubMedID: 28028841
Gene_locus related to this paper: dicdi-apra

Title : Annotinolide F and lycoannotines A-I, further Lycopodium alkaloids from Lycopodium annotinum - Tang_2017_Phytochemistry_143_1
Author(s) : Tang Y , Xiong J , Zou Y , Wang W , Huang C , Zhang HY , Hu JF
Ref : Phytochemistry , 143 :1 , 2017
Abstract : Seven lycopodine-type (annotinolide F and lycoannotines A-F), two lycodine-type (lycoannotines G and H), and one fawcettimine-type (lycoannotine I) previously undescribed naturally occurring Lycopodium alkaloids together with thirteen known ones were isolated from the whole plant of Lycopodium annotinum. Their structures and absolute configurations were determined by extensive spectroscopic methods, single-crystal X-ray diffraction, chemical transformation, and electronic circular dichroism (ECD) calculations. Among the isolates, annotinolide F, lycoannotines A and B are unusual 7,8-seco-lycopodane derivatives, and annotinolide F even further possesses a rare 8,5-lactone framework through a lactonization after the C-7/C-8 bond cleavage. Lycoannotine C is an uncommon 8,15-seco lycopodine-type alkaloid, whereas lycoannotine I represents the first example of a naturally occurring C-9/N bond cleavage product of fawcettimine-type alkaloid. Among them, only lycoannotine I was found to show considerable anti-butyrylcholinesterase (anti-BuChE) activity.
ESTHER : Tang_2017_Phytochemistry_143_1
PubMedSearch : Tang_2017_Phytochemistry_143_1
PubMedID: 28738241

Title : Enzyme-Catalyzed Intramolecular Enantioselective Hydroalkoxylation - Gao_2017_J.Am.Chem.Soc_139_3639
Author(s) : Gao SS , Garcia-Borras M , Barber JS , Hai Y , Duan A , Garg NK , Houk KN , Tang Y
Ref : Journal of the American Chemical Society , 139 :3639 , 2017
Abstract : Hydroalkoxylation is a powerful and efficient method of forming C-O bonds and cyclic ethers in synthetic chemistry. In studying the biosynthesis of the fungal natural product herqueinone, we identified an enzyme that can perform an intramolecular enantioselective hydroalkoxylation reaction. PhnH catalyzes the addition of a phenol to the terminal olefin of a reverse prenyl group to give a dihydrobenzofuran product. The enzyme accelerates the reaction by 3 x 10(5)-fold compared to the uncatalyzed reaction. PhnH belongs to a superfamily of proteins with a domain of unknown function (DUF3237), of which no member has a previously verified function. The discovery of PhnH demonstrates that enzymes can be used to promote the enantioselective hydroalkoxylation reaction and form cyclic ethers.
ESTHER : Gao_2017_J.Am.Chem.Soc_139_3639
PubMedSearch : Gao_2017_J.Am.Chem.Soc_139_3639
PubMedID: 28240554
Gene_locus related to this paper: penhr-phna

Title : Production of New Cladosporin Analogues by Reconstitution of the Polyketide Synthases Responsible for the Biosynthesis of this Antimalarial Agent - Cochrane_2016_Angew.Chem.Int.Ed.Engl_55_664
Author(s) : Cochrane RV , Sanichar R , Lambkin GR , Reiz B , Xu W , Tang Y , Vederas JC
Ref : Angew Chem Int Ed Engl , 55 :664 , 2016
Abstract : The antimalarial agent cladosporin is a nanomolar inhibitor of the Plasmodium falciparum lysyl-tRNA synthetase, and exhibits activity against both blood- and liver-stage infection. Cladosporin can be isolated from the fungus Cladosporium cladosporioides, where it is biosynthesized by a highly reducing (HR) and a non-reducing (NR) iterative typeI polyketide synthase (PKS) pair. Genome sequencing of the host organism and subsequent heterologous expression of these enzymes in Saccharomyces cerevisiae produced cladosporin, confirming the identity of the putative gene cluster. Incorporation of a pentaketide intermediate analogue indicated a 5+3 assembly by the HR PKS Cla2 and the NR PKS Cla3 during cladosporin biosynthesis. Advanced-intermediate analogues were synthesized and incorporated by Cla3 to furnish new cladosporin analogues. A putative lysyl-tRNA synthetase resistance gene was identified in the cladosporin gene cluster. Analysis of the active site emphasizes key structural features thought to be important in resistance to cladosporin.
ESTHER : Cochrane_2016_Angew.Chem.Int.Ed.Engl_55_664
PubMedSearch : Cochrane_2016_Angew.Chem.Int.Ed.Engl_55_664
PubMedID: 26783060
Gene_locus related to this paper: clacd-cla3

Title : Sodium Tanshinone IIA Sulfonate Attenuates Scopolamine-Induced Cognitive Dysfunctions via Improving Cholinergic System - Xu_2016_Biomed.Res.Int_2016_9852536
Author(s) : Xu QQ , Xu YJ , Yang C , Tang Y , Li L , Cai HB , Hou BN , Chen HF , Wang Q , Shi XG , Zhang SJ
Ref : Biomed Res Int , 2016 :9852536 , 2016
Abstract : Sodium Tanshinone IIA sulfonate (STS) is a derivative of Tanshinone IIA (Tan IIA). Tan IIA has been reported to possess neuroprotective effects against Alzheimer's disease (AD). However, whether STS possesses effect on AD remains unclear. This study aims to estimate whether STS could protect against scopolamine- (SCOP-) induced learning and memory deficit in Kunming mice. Morris water maze results showed that oral administration of STS (10 mg/kg and 20 mg/kg) and Donepezil shortened escape latency, increased crossing times of the original position of the platform, and increased the time spent in the target quadrant. STS decreased the activity of acetylcholinesterase (AChE) and increased the activity of choline acetyltransferase (ChAT) in the hippocampus and cortex of SCOP-treated mice. Oxidative stress results showed that STS increased the activity of superoxide dismutase (SOD) and decreased the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in hippocampus and cortex. In addition, western blot was carried out to detect the expression of apoptosis related proteins (Bcl-2, Bax, and Caspase-3). STS upregulated the protein expression of Bcl-2 and downregulated the proteins expression of Bax and Caspase-3. These results indicated that STS might become a promising therapeutic candidate for attenuating AD-like pathological dysfunction.
ESTHER : Xu_2016_Biomed.Res.Int_2016_9852536
PubMedSearch : Xu_2016_Biomed.Res.Int_2016_9852536
PubMedID: 27556046

Title : Phenalenone Polyketide Cyclization Catalyzed by Fungal Polyketide Synthase and Flavin-Dependent Monooxygenase - Gao_2016_J.Am.Chem.Soc_138_4249
Author(s) : Gao SS , Duan A , Xu W , Yu P , Hang L , Houk KN , Tang Y
Ref : Journal of the American Chemical Society , 138 :4249 , 2016
Abstract : Phenalenones are polyketide natural products that display diverse structures and biological activities. The core of phenalenones is a peri-fused tricyclic ring system cyclized from a linear polyketide precursor via an unresolved mechanism. Toward understanding the unusual cyclization steps, the phn biosynthetic gene cluster responsible for herqueinone biosynthesis was identified from the genome of Penicillium herquei. A nonreducing polyketide synthase (NR-PKS) PhnA was shown to synthesize the heptaketide backbone and cyclize it into the angular, hemiketal-containing naphtho-gamma-pyrone prephenalenone. The product template (PT) domain of PhnA catalyzes only the C4-C9 aldol condensation, which is unprecedented among known PT domains. The transformation of prephenalenone to phenalenone requires an FAD-dependent monooxygenase (FMO) PhnB, which catalyzes the C2 aromatic hydroxylation of prephenalenone and ring opening of the gamma-pyrone ring simultaneously. Density functional theory calculations provide insights into why the hydroxylated intermediate undergoes an aldol-like phenoxide-ketone cyclization to yield the phenalenone core. This study therefore unveiled new routes and biocatalysts for polyketide cyclization.
ESTHER : Gao_2016_J.Am.Chem.Soc_138_4249
PubMedSearch : Gao_2016_J.Am.Chem.Soc_138_4249
PubMedID: 26978228
Gene_locus related to this paper: penhr-phna

Title : P450-Mediated Coupling of Indole Fragments To Forge Communesin and Unnatural Isomers - Lin_2016_J.Am.Chem.Soc_138_4002
Author(s) : Lin HC , McMahon TC , Patel A , Corsello M , Simon A , Xu W , Zhao M , Houk KN , Garg NK , Tang Y
Ref : Journal of the American Chemical Society , 138 :4002 , 2016
Abstract : Dimeric indole alkaloids are structurally diverse natural products that have attracted significant attention from the synthetic and biosynthetic communities. Here, we describe the characterization of a P450 monooxygenase CnsC from Penicillium that catalyzes the heterodimeric coupling between two different indole moieties, tryptamine and aurantioclavine, to construct vicinal quaternary stereocenters and yield the heptacyclic communesin scaffold. We show, via biochemical characterization, substrate analogues, and computational methods that CnsC catalyzes the C3-C3' carbon-carbon bond formation and controls the regioselectivities of the pair of subsequent aminal bond formations to yield the communesin core. Use of omega-N-methyltryptamine and tryptophol in place of tryptamine led to the enzymatic synthesis of isocommunesin compounds, which have not been isolated to date.
ESTHER : Lin_2016_J.Am.Chem.Soc_138_4002
PubMedSearch : Lin_2016_J.Am.Chem.Soc_138_4002
PubMedID: 26963294
Gene_locus related to this paper: penen-cnsh

Title : Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion - Venkatesh_2015_Cell_161_803
Author(s) : Venkatesh HS , Johung TB , Caretti V , Noll A , Tang Y , Nagaraja S , Gibson EM , Mount CW , Polepalli J , Mitra SS , Woo PJ , Malenka RC , Vogel H , Bredel M , Mallick P , Monje M
Ref : Cell , 161 :803 , 2015
Abstract : Active neurons exert a mitogenic effect on normal neural precursor and oligodendroglial precursor cells, the putative cellular origins of high-grade glioma (HGG). By using optogenetic control of cortical neuronal activity in a patient-derived pediatric glioblastoma xenograft model, we demonstrate that active neurons similarly promote HGG proliferation and growth in vivo. Conditioned medium from optogenetically stimulated cortical slices promoted proliferation of pediatric and adult patient-derived HGG cultures, indicating secretion of activity-regulated mitogen(s). The synaptic protein neuroligin-3 (NLGN3) was identified as the leading candidate mitogen, and soluble NLGN3 was sufficient and necessary to promote robust HGG cell proliferation. NLGN3 induced PI3K-mTOR pathway activity and feedforward expression of NLGN3 in glioma cells. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth.
ESTHER : Venkatesh_2015_Cell_161_803
PubMedSearch : Venkatesh_2015_Cell_161_803
PubMedID: 25913192
Gene_locus related to this paper: human-NLGN3

Title : Comparison of 10,11-Dehydrocurvularin Polyketide Synthases from Alternaria cinerariae and Aspergillus terreus Highlights Key Structural Motifs - Cochrane_2015_Chembiochem_16_2479
Author(s) : Cochrane RV , Gao Z , Lambkin GR , Xu W , Winter JM , Marcus SL , Tang Y , Vederas JC
Ref : Chembiochem , 16 :2479 , 2015
Abstract : Iterative typeI polyketide synthases (PKSs) from fungi are multifunctional enzymes that use their active sites repeatedly in a highly ordered sequence to assemble complex natural products. A phytotoxic macrolide with anticancer properties, 10,11-dehydrocurvularin (DHC), is produced by cooperation of a highly reducing (HR) iterative PKS and a non-reducing (NR) iterative PKS. We have identified the DHC gene cluster in Alternaria cinerariae, heterologously expressed the active HR PKS (Dhc3) and NR PKS (Dhc5) in yeast, and compared them to corresponding proteins that make DHC in Aspergillus terreus. Phylogenetic analysis and homology modeling of these enzymes identified variable surfaces and conserved motifs that are implicated in product formation.
ESTHER : Cochrane_2015_Chembiochem_16_2479
PubMedSearch : Cochrane_2015_Chembiochem_16_2479
PubMedID: 26493380
Gene_locus related to this paper: aspte-curs2 , altci-dhc5

Title : Elucidation of the concise biosynthetic pathway of the communesin indole alkaloids - Lin_2015_Angew.Chem.Int.Ed.Engl_54_3004
Author(s) : Lin HC , Chiou G , Chooi YH , McMahon TC , Xu W , Garg NK , Tang Y
Ref : Angew Chem Int Ed Engl , 54 :3004 , 2015
Abstract : The communesins are a prominent class of indole alkaloids isolated from Penicillium species. Owing to their daunting structural framework and potential as pharmaceuticals, communesins have inspired numerous synthetic studies. However, the genetic and biochemical basis of communesin biosynthesis has remained unexplored. Herein, we report the identification and characterization of the communesin (cns) biosynthetic gene cluster from Penicillium expansum. We confirmed that communesin is biosynthesized by the coupling of tryptamine and aurantioclavine, two building blocks derived from L-tryptophan. The postmodification steps were mapped by targeted-gene-deletion experiments and the structural elucidation of intermediates and new analogues. Our studies set the stage for the biochemical characterization of communesin biosynthesis. This knowledge will aid our understanding of how nature generates remarkable structural complexity from simple precursors.
ESTHER : Lin_2015_Angew.Chem.Int.Ed.Engl_54_3004
PubMedSearch : Lin_2015_Angew.Chem.Int.Ed.Engl_54_3004
PubMedID: 25571861
Gene_locus related to this paper: penen-cnsh

Title : Genome sequence and transcriptome analyses of the thermophilic zygomycete fungus Rhizomucor miehei - Zhou_2014_BMC.Genomics_15_294
Author(s) : Zhou P , Zhang G , Chen S , Jiang Z , Tang Y , Henrissat B , Yan Q , Yang S , Chen CF , Zhang B , Du Z
Ref : BMC Genomics , 15 :294 , 2014
Abstract : BACKGROUND: The zygomycete fungi like Rhizomucor miehei have been extensively exploited for the production of various enzymes. As a thermophilic fungus, R. miehei is capable of growing at temperatures that approach the upper limits for all eukaryotes. To date, over hundreds of fungal genomes are publicly available. However, Zygomycetes have been rarely investigated both genetically and genomically.
RESULTS: Here, we report the genome of R. miehei CAU432 to explore the thermostable enzymatic repertoire of this fungus. The assembled genome size is 27.6-million-base (Mb) with 10,345 predicted protein-coding genes. Even being thermophilic, the G + C contents of fungal whole genome (43.8%) and coding genes (47.4%) are less than 50%. Phylogenetically, R. miehei is more closerly related to Phycomyces blakesleeanus than to Mucor circinelloides and Rhizopus oryzae. The genome of R. miehei harbors a large number of genes encoding secreted proteases, which is consistent with the characteristics of R. miehei being a rich producer of proteases. The transcriptome profile of R. miehei showed that the genes responsible for degrading starch, glucan, protein and lipid were highly expressed.
CONCLUSIONS: The genome information of R. miehei will facilitate future studies to better understand the mechanisms of fungal thermophilic adaptation and the exploring of the potential of R. miehei in industrial-scale production of thermostable enzymes. Based on the existence of a large repertoire of amylolytic, proteolytic and lipolytic genes in the genome, R. miehei has potential in the production of a variety of such enzymes.
ESTHER : Zhou_2014_BMC.Genomics_15_294
PubMedSearch : Zhou_2014_BMC.Genomics_15_294
PubMedID: 24746234

Title : Determination of Meserine, a new candidate for Alzheimer's disease in mice brain by liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic and tissue distribution study - Zheng_2014_Anal.Bioanal.Chem_406_3451
Author(s) : Zheng Z , Tang Y , Lv H , Xu J , Zhao H , Xie Q , Qiu Z , Chen H , Wang H
Ref : Anal Bioanal Chem , 406 :3451 , 2014
Abstract : A rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determination of Meserine ((-)-meptazinol phenylcarbamate), a novel potent inhibitor of acetylcholinesterase (AChE), was developed, validated, and applied to a pharmacokinetic study in mice brain. The lower limit of quantification (LLOQ) was 1 ng mL(-1) and the linear range was 1-1,000 ng mL(-1). The analyte was eluted on a Zorbax SB-Aq column (2.1 x 100 mm, 3.5 mum) with the mobile phase composed of methanol and water (70:30, v/v, aqueous phase contained 10 mM ammonium formate and 0.3% formic acid) using isocratic elution, and monitored by positive electrospray ionization in multiple reaction monitoring (MRM) mode. The flow rate was 0.25 mL min(-1). The injection volume was 5 muL and total run time was 4 min. The relative standard deviation (RSD) of intraday and interday variation was 2.49-7.81 and 3.01-7.67%, respectively. All analytes were stable after 4 h at room temperature and 6 h in autosampler. The extraction recoveries of Meserine in brain homogenate were over 90%. The main brain pharmacokinetic parameters obtained after intranasal administration were T max = 0.05 h, C max = 462.0 +/- 39.7 ng g(-1), T 1/2 = 0.4 h, and AUC(0-infinity) = 283.1 +/- 9.1 ng h g(-1). Moreover, Meserine was distributed rapidly and widely into brain, heart, liver, spleen, lung, and kidney tissue. The method is validated and could be applied to the pharmacokinetic and tissue distribution study of Meserine in mice.
ESTHER : Zheng_2014_Anal.Bioanal.Chem_406_3451
PubMedSearch : Zheng_2014_Anal.Bioanal.Chem_406_3451
PubMedID: 24756818

Title : Fungal polyketide synthase product chain-length control by partnering thiohydrolase - Zabala_2014_ACS.Chem.Biol_9_1576
Author(s) : Zabala AO , Chooi YH , Choi MS , Lin HC , Tang Y
Ref : ACS Chemical Biology , 9 :1576 , 2014
Abstract : Fungal highly reducing polyketide synthases (HRPKSs) are an enigmatic group of multidomain enzymes that catalyze the biosynthesis of structurally diverse compounds. This variety stems from their intrinsic programming rules, which permutate the use of tailoring domains and determine the overall number of iterative cycles. From genome sequencing and mining of the producing strain Eupenicillium brefeldianum ATCC 58665, we identified an HRPKS involved in the biosynthesis of an important protein transport-inhibitor Brefeldin A (BFA), followed by reconstitution of its activity in Saccharomyces cerevisiae and in vitro. Bref-PKS demonstrated an NADPH-dependent reductive tailoring specificity that led to the synthesis of four different octaketide products with varying degrees of reduction. Furthermore, contrary to what is expected from the structure of BFA, Bref-PKS is found to be a nonaketide synthase in the absence of an associated thiohydrolase Bref-TH. Such chain-length control by the partner thiohydrolase was found to be present in other HRPKS systems and highlights the importance of including tailoring enzyme activities in predicting fungal HRPKS functions and their products.
ESTHER : Zabala_2014_ACS.Chem.Biol_9_1576
PubMedSearch : Zabala_2014_ACS.Chem.Biol_9_1576
PubMedID: 24845309
Gene_locus related to this paper: eupbr-bref2

Title : Generation of complexity in fungal terpene biosynthesis: discovery of a multifunctional cytochrome P450 in the fumagillin pathway - Lin_2014_J.Am.Chem.Soc_136_4426
Author(s) : Lin HC , Tsunematsu Y , Dhingra S , Xu W , Fukutomi M , Chooi YH , Cane DE , Calvo AM , Watanabe K , Tang Y
Ref : Journal of the American Chemical Society , 136 :4426 , 2014
Abstract : Fumagillin (1), a meroterpenoid from Aspergillus fumigatus, is known for its antiangiogenic activity due to binding to human methionine aminopeptidase 2. 1 has a highly oxygenated structure containing a penta-substituted cyclohexane that is generated by oxidative cleavage of the bicyclic sesquiterpene beta-trans-bergamotene. The chemical nature, order, and biochemical mechanism of all the oxygenative tailoring reactions has remained enigmatic despite the identification of the biosynthetic gene cluster and the use of targeted-gene deletion experiments. Here, we report the identification and characterization of three oxygenases from the fumagillin biosynthetic pathway, including a multifunctional cytochrome P450 monooxygenase, a hydroxylating nonheme-iron-dependent dioxygenase, and an ABM family monooxygenase for oxidative cleavage of the polyketide moiety. Most significantly, the P450 monooxygenase is shown to catalyze successive hydroxylation, bicyclic ring-opening, and two epoxidations that generate the sesquiterpenoid core skeleton of 1. We also characterized a truncated polyketide synthase with a ketoreductase function that controls the configuration at C-5 of hydroxylated intermediates.
ESTHER : Lin_2014_J.Am.Chem.Soc_136_4426
PubMedSearch : Lin_2014_J.Am.Chem.Soc_136_4426
PubMedID: 24568283
Gene_locus related to this paper: aspfu-fmac

Title : Elucidation of pseurotin biosynthetic pathway points to trans-acting C-methyltransferase: generation of chemical diversity - Tsunematsu_2014_Angew.Chem.Int.Ed.Engl_53_8475
Author(s) : Tsunematsu Y , Fukutomi M , Saruwatari T , Noguchi H , Hotta K , Tang Y , Watanabe K
Ref : Angew Chem Int Ed Engl , 53 :8475 , 2014
Abstract : Pseurotins comprise a family of structurally related Aspergillal natural products having interesting bioactivity. However, little is known about the biosynthetic steps involved in the formation of their complex chemical features. Systematic deletion of the pseurotin biosynthetic genes in A. fumigatus and invivo and invitro characterization of the tailoring enzymes to determine the biosynthetic intermediates, and the gene products responsible for the formation of each intermediate, are described. Thus, the main biosynthetic steps leading to the formation of pseurotinA from the predominant precursor, azaspirene, were elucidated. The study revealed the combinatorial nature of the biosynthesis of the pseurotin family of compounds and the intermediates. Most interestingly, we report the first identification of an epoxidase C-methyltransferase bifunctional fusion protein PsoF which appears to methylate the nascent polyketide backbone carbon atom in trans.
ESTHER : Tsunematsu_2014_Angew.Chem.Int.Ed.Engl_53_8475
PubMedSearch : Tsunematsu_2014_Angew.Chem.Int.Ed.Engl_53_8475
PubMedID: 24939566
Gene_locus related to this paper: aspfu-psoB

Title : Nanoparticle-based immunochromatographic test strip with fluorescent detector for quantification of phosphorylated acetylcholinesterase: an exposure biomarker of organophosphorus agents - Zhang_2013_Analyst_138_5431
Author(s) : Zhang W , Ge X , Tang Y , Du D , Liu D , Lin Y
Ref : Analyst , 138 :5431 , 2013
Abstract : A nanoparticle-based fluorescence immunochromatographic test strip (FITS) coupled with a hand-held detector for highly selective and sensitive detection of phosphorylated acetylcholinesterase (AChE), an exposure biomarker of organophosphate (OP) pesticides and nerve agents, is reported. In this approach, OP-AChE adducts were selectively captured by quantum dot-tagged anti-AChE antibodies (Qdot-anti-AChE) and zirconia nanoparticles (ZrO2 NPs). The sandwich-like immunoreactions were performed among the Qdot-anti-AChE, OP-AChE and ZrO2 NPs to form a Qdot-anti-AChE-OP-AChE-ZrO2 complex, which was detected by recording the fluorescence intensity of Qdots captured during the test line. Paraoxon was used as the model OP pesticide. Under optimal conditions, this portable FITS immunosensor demonstrates a highly linear absorption response over the range of 0.01 nM to 10 nM OP-AChE, with a detection limit of 4 pM, coupled with good reproducibility. Moreover, the FITS immunosensor has been validated with OP-AChE spiked human plasma samples. This is the first report on the development of ZrO2 NP-based FITS for the detection of the OP-AChE adduct. The FITS immunosensor provides a sensitive and low-cost sensing platform for on-site screening/evaluating OP pesticides and nerve agents poisoning.
ESTHER : Zhang_2013_Analyst_138_5431
PubMedSearch : Zhang_2013_Analyst_138_5431
PubMedID: 23885349

Title : Association of lipoprotein lipase polymorphism rs2197089 with serum lipid concentrations and LPL gene expression - Mo_2013_J.Hum.Genet_58_160
Author(s) : Mo X , Liu X , Wang L , Lu X , Chen S , Li H , Huang J , Chen J , Cao J , Li J , Tang Y , Gu D
Ref : J Hum Genet , 58 :160 , 2013
Abstract : Many single-nucleotide polymorphisms (SNPs) have been reported to be associated with lipid concentrations in recent genome-wide association studies. The aim of this study was to validate the associations of rs2197089 in the lipoprotein lipase (LPL) gene with serum lipid concentrations and gene expression levels in the Chinese Han population and examine the potential interactions. A total of 9339 participants were recruited and genotyped for rs2197089. Gene expression levels of LPL in blood cells of 309 participants were evaluated by real-time PCR. We observed significant associations between rs2197089 and decreased triglycerides (TG) (P=0.0006), but not high-density lipoprotein cholesterol (HDL-C) concentration (P=0.0881). However, weak evidence of interaction between cigarette smoking and rs2197089 was detected (P=0.0362). In smokers, significant association between rs2197089 and increased HDL-C concentration was found (P=0.0068). Participants with the minor allele A had higher expression levels of LPL (P=0.0243). The results of our study indicated that rs2197089 was significantly associated with TG but it was associated with HDL-C only in smokers. This SNP seemed to have influence on the expression level of LPL.
ESTHER : Mo_2013_J.Hum.Genet_58_160
PubMedSearch : Mo_2013_J.Hum.Genet_58_160
PubMedID: 23344322

Title : The fumagillin biosynthetic gene cluster in Aspergillus fumigatus encodes a cryptic terpene cyclase involved in the formation of beta-trans-bergamotene - Lin_2013_J.Am.Chem.Soc_135_4616
Author(s) : Lin HC , Chooi YH , Dhingra S , Xu W , Calvo AM , Tang Y
Ref : Journal of the American Chemical Society , 135 :4616 , 2013
Abstract : Fumagillin 1 is a meroterpenoid from Aspergillus fumigatus that is known for its anti-angiogenic activity by binding to human methionine aminopeptidase 2. The genetic and molecular basis for biosynthesis of 1 had been an enigma despite the availability of the A. fumigatus genome sequence. Here, we report the identification and verification of the fma gene cluster, followed by characterization of the polyketide synthase and acyltransferase involved in biosynthesis of the dioic acid portion of 1. More significantly, we uncovered the elusive beta-trans-bergamotene synthase in A. fumigatus as a membrane-bound terpene cyclase.
ESTHER : Lin_2013_J.Am.Chem.Soc_135_4616
PubMedSearch : Lin_2013_J.Am.Chem.Soc_135_4616
PubMedID: 23488861
Gene_locus related to this paper: aspfu-fmac

Title : The fumagillin gene cluster, an example of hundreds of genes under veA control in Aspergillus fumigatus - Dhingra_2013_PLoS.One_8_e77147
Author(s) : Dhingra S , Lind AL , Lin HC , Tang Y , Rokas A , Calvo AM
Ref : PLoS ONE , 8 :e77147 , 2013
Abstract : Aspergillus fumigatus is the causative agent of invasive aspergillosis, leading to infection-related mortality in immunocompromised patients. We previously showed that the conserved and unique-to-fungi veA gene affects different cell processes such as morphological development, gliotoxin biosynthesis and protease activity, suggesting a global regulatory effect on the genome of this medically relevant fungus. In this study, RNA sequencing analysis revealed that veA controls the expression of hundreds of genes in A. fumigatus, including those comprising more than a dozen known secondary metabolite gene clusters. Chemical analysis confirmed that veA controls the synthesis of other secondary metabolites in this organism in addition to gliotoxin. Among the secondary metabolite gene clusters regulated by veA is the elusive but recently identified gene cluster responsible for the biosynthesis of fumagillin, a meroterpenoid known for its anti-angiogenic activity by binding to human methionine aminopeptidase 2. The fumagillin gene cluster contains a veA-dependent regulatory gene, fumR (Afu8g00420), encoding a putative C6 type transcription factor. Deletion of fumR results in silencing of the gene cluster and elimination of fumagillin biosynthesis. We found expression of fumR to also be dependent on laeA, a gene encoding another component of the fungal velvet complex. The results in this study argue that veA is a global regulator of secondary metabolism in A. fumigatus, and that veA may be a conduit via which chemical development is coupled to morphological development and other cellular processes.
ESTHER : Dhingra_2013_PLoS.One_8_e77147
PubMedSearch : Dhingra_2013_PLoS.One_8_e77147
PubMedID: 24116213
Gene_locus related to this paper: aspfu-fmac

Title : LovG: the thioesterase required for dihydromonacolin L release and lovastatin nonaketide synthase turnover in lovastatin biosynthesis -
Author(s) : Xu W , Chooi YH , Choi JW , Li S , Vederas JC , Da Silva NA , Tang Y
Ref : Angew Chem Int Ed Engl , 52 :6472 , 2013
PubMedID: 23653178
Gene_locus related to this paper: asptn-LOVG

Title : Basic fibroblast growth factor attenuates the degeneration of injured spinal cord motor endplates - Wang_2013_Neural.Regen.Res_8_2213
Author(s) : Wang J , Sun J , Tang Y , Guo G , Zhou X , Chen Y , Shen M
Ref : Neural Regen Res , 8 :2213 , 2013
Abstract : The distal end of the spinal cord and neuromuscular junction may develop secondary degeneration and damage following spinal cord injury because of the loss of neural connections. In this study, a rat model of spinal cord injury, established using a modified Allen's method, was injected with basic fibroblast growth factor solution via subarachnoid catheter. After injection, rats with spinal cord injury displayed higher scores on the Basso, Beattie and Bresnahan locomotor scale. Motor function was also well recovered and hematoxylin-eosin staining showed that spinal glial scar hyperplasia was not apparent. Additionally, anterior tibial muscle fibers slowly, but progressively, atrophied. nohistochemical staining showed that the absorbance values of calcitonin gene related peptide and acetylcholinesterase in anterior tibial muscle and spinal cord were similar, and injection of basic broblast growth factor increased this absorbance. Results showed that after spinal cord injury, the distal motor neurons and motor endplate degenerated. Changes in calcitonin gene related peptide and acetylcholinesterase in the spinal cord anterior horn motor neurons and motor endplate then occurred that were consistent with this regeneration. Our findings indicate that basic fibroblast growth factor can protect the endplate through attenuating the decreased expression of calcitonin gene related peptide and acetylcholinesterase in anterior horn motor neurons of the injured spinal cord.
ESTHER : Wang_2013_Neural.Regen.Res_8_2213
PubMedSearch : Wang_2013_Neural.Regen.Res_8_2213
PubMedID: 25206531

Title : Casuarinines A-J, Lycodine-Type Alkaloids from Lycopodiastrum casuarinoides - Tang_2013_J.Nat.Prod_76_1475
Author(s) : Tang Y , Fu Y , Xiong J , Li M , Ma GL , Yang GX , Wei BG , Zhao Y , Zhang HY , Hu JF
Ref : Journal of Natural Products , 76 :1475 , 2013
Abstract : Ten new lycodine-type alkaloids, named casuarinines A-J (1-10), along with eight known analogues (11-18), were isolated from the whole plant of Lycopodiastrum casuarinoides . The new structures were established by spectroscopic methods and chemical transformations. Casuarinines A-D (1-4) and J (10) are common lycodine alkaloids possessing four connected six-membered rings, while tricyclic casuarinines E-H (5-8) are the piperidine ring cleavage products. In particular, casuarinine I (9) has an unprecedented five-membered tetrahydropyrrole ring instead of the piperidine ring. A plausible biosynthetic pathway to 9 is proposed. Among the compounds reported, casuarinine H (8) exhibited significant neuroprotective effect against hydrogen peroxide (H2O2)-induced neuronal cell damage in human neuroblastoma SH-SY5Y cells, while casuarinines C (3) and I (9) showed moderate inhibitory activity against acetylcholinesterase (AChE).
ESTHER : Tang_2013_J.Nat.Prod_76_1475
PubMedSearch : Tang_2013_J.Nat.Prod_76_1475
PubMedID: 23941108

Title : Design, synthesis and biological evaluation of organophosphorous-homodimers as dual binding site acetylcholinesterase inhibitors - Xie_2013_Bioorg.Med.Chem_21_278
Author(s) : Xie R , Zhao Q , Zhang T , Fang J , Mei X , Ning J , Tang Y
Ref : Bioorganic & Medicinal Chemistry , 21 :278 , 2013
Abstract : The cluster effect is an effective strategy to explore new lead compounds, and has been successfully applied in rational drug design and screening. A series of novel organophosphorous-homodimers were designed and synthesized based on the dual-site structure characteristics of acetylcholinesterase (AChE). The compounds were evaluated in vitro for their inhibitory activity to AChE extracted from Drosophila melanogaster and Musca domestic. Compound 4H showed an excellent inhibitor activity to both Drosophila melanogaster and Musca domestic with the corresponding IC(50) values of 23 and 168nM, respectively. Meanwhile, its activities against Drosophila melanogaster and Musca domestic AChE were more than 10,00,000 and 100,000-fold higher compared with the parent compound (MH), and was up to 245 and 107-fold higher than those of the positive control omethoate. The molecular docking study revealed that 4H possessed an optimal spacer length and can perfectly fit into the central pocket, active gorge, and peripheral site of DmAChE, and consequently exhibited highly improved inhibitor potency to DmAChE. The bioassay tests showed that 4 series compounds showed prominent insecticidal activities against both Lipaphser erysimi and Tetranychus cinnbarinus at a concentration of 200mg/L. The insecticide activity of compound 4H was particularly significant that can cause 96% mortality to Tetranychus cinnbarinus after 24h of treatment.
ESTHER : Xie_2013_Bioorg.Med.Chem_21_278
PubMedSearch : Xie_2013_Bioorg.Med.Chem_21_278
PubMedID: 23200223

Title : Synthesis, structure-activity relationship, and pharmacophore modeling studies of pyrazole-3-carbohydrazone derivatives as dipeptidyl peptidase IV inhibitors - Wu_2012_Chem.Biol.Drug.Des_79_897
Author(s) : Wu D , Jin F , Lu W , Zhu J , Li C , Wang W , Tang Y , Jiang H , Huang J , Liu G , Li J
Ref : Chemical Biology Drug Des , 79 :897 , 2012
Abstract : Type 2 diabetes mellitus (T2DM) is a metabolic disease and a major challenge to healthcare systems around the world. Dipeptidyl peptidase IV (DPP-4), a serine protease, has been rapidly emerging as an effective therapeutic target for the treatment for T2DM. In this study, a series of novel DPP-4 inhibitors, featuring the pyrazole-3-carbohydrazone scaffold, have been discovered using an integrated approach of structure-based virtual screening, chemical synthesis, and bioassay. Virtual screening of SPECS Database, followed by enzymatic activity assay, resulted in five micromolar or low-to-mid-micromolar inhibitory level compounds (1-5) with different scaffold. Compound 1 was selected for the further structure modifications in considering inhibitory activity, structural variability, and synthetic accessibility. Seventeen new compounds were synthesized and tested with biological assays. Nine compounds (6e, 6g, 6k-l, and 7a-e) were found to show inhibitory effects against DPP-4. Molecular docking models give rational explanation about structure-activity relationships. Based on eight DPP-4 inhibitors (1-5, 6e, 6k, and 7d), the best pharmacophore model hypo1 was obtained, consisting of one hydrogen bond donor (HBD), one hydrogen bond acceptor (HBA), and two hydrophobic (HY) features. Both docking models and pharmacophore mapping results are in agreement with pharmacological results. The present studies give some guiding information for further structural optimization and are helpful for future DPP-4 inhibitors design.
ESTHER : Wu_2012_Chem.Biol.Drug.Des_79_897
PubMedSearch : Wu_2012_Chem.Biol.Drug.Des_79_897
PubMedID: 22381062

Title : Characterization of a silent azaphilone gene cluster from Aspergillus niger ATCC 1015 reveals a hydroxylation-mediated pyran-ring formation - Zabala_2012_Chem.Biol_19_1049
Author(s) : Zabala AO , Xu W , Chooi YH , Tang Y
Ref : Chemical Biology , 19 :1049 , 2012
Abstract : Azaphilones are a class of fungal metabolites characterized by a highly oxygenated pyrano-quinone bicyclic core and exhibiting a broad range of bioactivities. Although widespread among various fungi, their biosynthesis has not been thoroughly elucidated. By activation of a silent (aza) gene cluster in Aspergillus niger ATCC 1015, we discovered six azaphilone compounds, azanigerones A-F (1, 3-7). Transcriptional analysis and deletion of a key polyketide synthase (PKS) gene further confirmed the involvement of the aza gene cluster. The biosynthetic pathway was shown to involve the convergent actions of a highly reducing PKS and a non-reducing PKS. Most significantly, in vitro reaction of a key flavin-dependent monooxygenase encoded in the cluster with an early benzaldehyde intermediate revealed its roles in hydroxylation and pyran-ring formation to afford the characteristic bicylic core shared by azaphilones.
ESTHER : Zabala_2012_Chem.Biol_19_1049
PubMedSearch : Zabala_2012_Chem.Biol_19_1049
PubMedID: 22921072
Gene_locus related to this paper: aspna-azac

Title : Possible ligand release pathway of dipeptidyl peptidase IV investigated by molecular dynamics simulations - Li_2011_Proteins_79_1800
Author(s) : Li C , Shen J , Li W , Lu C , Liu G , Tang Y
Ref : Proteins , 79 :1800 , 2011
Abstract : Dipeptidyl peptidase IV (DPP4) is an important target for the treatment of Type II diabetes mellitus. The crystal structure of DPP4 demonstrates that there are two possible pathways to the active site, a side opening and a beta propeller opening. However, it still lacks quantitative evidence to illustrate which pathway is more favorable for inhibitor to enter into or release from the active site. In this study, conventional and steered molecular dynamics simulations were performed to explore the details of inhibitor Q448 release from the active site of DPP4 via the two potential pathways. The comparisons of force and work together with potentials of mean force results suggested that the side opening might be more favorable for the inhibitor to pass through. Moreover, Glu205-Glu206 and Phe357 were recognized as two "key residues" in the active site for inhibitor binding. Accordingly, suggestions for further inhibitor design were provided.
ESTHER : Li_2011_Proteins_79_1800
PubMedSearch : Li_2011_Proteins_79_1800
PubMedID: 21465558

Title : Structural and biochemical characterization of the salicylyl-acyltranferase SsfX3 from a tetracycline biosynthetic pathway - Pickens_2011_J.Biol.Chem_286_41539
Author(s) : Pickens LB , Sawaya MR , Rasool H , Pashkov I , Yeates TO , Tang Y
Ref : Journal of Biological Chemistry , 286 :41539 , 2011
Abstract : SsfX3 is a GDSL family acyltransferase that transfers salicylate to the C-4 hydroxyl of a tetracycline intermediate in the penultimate step during biosynthesis of the anticancer natural product SF2575. The C-4 salicylate takes the place of the more common C-4 dimethylamine functionality, making SsfX3 the first acyltransferase identified to act on a tetracycline substrate. The crystal structure of SsfX3 was determined at 2.5 A, revealing two distinct domains as follows: an N-terminal beta-sandwich domain that resembles a carbohydrate-binding module, and a C-terminal catalytic domain that contains the atypical alpha/beta-hydrolase fold found in the GDSL hydrolase family of enzymes. The active site lies at one end of a large open binding pocket, which is spatially defined by structural elements from both the N- and C-terminal domains. Mutational analysis in the putative substrate binding pocket identified residues from both domains that are important for binding the acyl donor and acceptor. Furthermore, removal of the N-terminal carbohydrate-binding module-like domain rendered the stand-alone alpha/beta-hydrolase domain inactive. The additional noncatalytic module is therefore proposed to be required to define the binding pocket and provide sufficient interactions with the spatially extended tetracyclic substrate. SsfX3 was also demonstrated to accept a variety of non-native acyl groups. This relaxed substrate specificity toward the acyl donor allowed the chemoenzymatic biosynthesis of C-4-modified analogs of the immediate precursor to the bioactive SF2575; these were used to assay the structure activity relationships at the C-4 position.
ESTHER : Pickens_2011_J.Biol.Chem_286_41539
PubMedSearch : Pickens_2011_J.Biol.Chem_286_41539
PubMedID: 21965680

Title : Effects of subchronic exposure to benzo[a]pyrene (B[a]P) on learning and memory, and neurotransmitters in male Sprague-Dawley rat - Xia_2011_Neurotoxicol_32_188
Author(s) : Xia Y , Cheng S , He J , Liu X , Tang Y , Yuan H , He L , Lu T , Tu B , Wang Y
Ref : Neurotoxicology , 32 :188 , 2011
Abstract : The harmful effects of the environmental carcinogen, benzo[a]pyrene (B[a]P), on mammalian neurodevelopment and behavior as yet remain unclear. Several studies have suggested that B[a]P impairs learning and memory. In the present investigation, we investigated the effects of subchronic exposure to B[a]P on rats. Male rats received daily injection of B[a]P (0, 1.0, 2.5, and 6.25 mg/kg, i.p.) or vehicle for 13 weeks. Employing the Morris water maze (MWM) test, we observed that rats exposed to either 2.5 mg/kg or 6.25 mg/kg B[a]P had modified behavior compared to controls as indicated by the increased mean latencies, the decreased number of crossing platform and the decreased swimming time in the target area. B[a]P treatment decreased the levels of malondialdehyde (MDA), nitric oxide (NO), nitric oxide synthase (NOS), superoxide dismutase (SOD), acetylcholine (ACh), choline acetyltransferase (ChAT), and increased the activity of acetylcholinesterase (AChE). Endogenous monoamine levels, norepinephrine (NE), adrenaline (A), dopamine (DA) and 5-hydroxytryptamine (5-HT) and their selected metabolites dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) in hippocampus were measured using high performance liquid chromatography (HPLC). B[a]P at both doses, 2.5 and 6.25 mg/kg, increased NE, DA, DOPAC and 5-HT content in the hippocampus. Our results suggested a close link between the modified levels of neurotransmitters in the hippocampus and the impaired behavioral performance, indicating that B[a]P is a potential neurotoxic pollutant.
ESTHER : Xia_2011_Neurotoxicol_32_188
PubMedSearch : Xia_2011_Neurotoxicol_32_188
PubMedID: 21216261

Title : Identification and engineering of the cytochalasin gene cluster from Aspergillus clavatus NRRL 1 - Qiao_2011_Metab.Eng_13_723
Author(s) : Qiao K , Chooi YH , Tang Y
Ref : Metab Eng , 13 :723 , 2011
Abstract : Cytochalasins are a group of fungal secondary metabolites with diverse structures and bioactivities, including cytochalasin E produced by Aspergillus clavatus, which is a potent anti-angiogenic agent. Here, we report the identification and characterization of the cytochalasin gene cluster from A. clavatus NRRL 1. As a producer of cytochalasin E and K, the genome of A. clavatus was analyzed and the -30 kb ccs gene cluster was identified based on the presence of a polyketide synthase-nonribosomal peptide synthetases (PKS-NRPS) and a putative Baeyer-Villiger monooxygenase (BVMO). Deletion of the central PKS-NRPS gene, ccsA, abolished the production of cytochalasin E and K, confirming the association between the natural products and the gene cluster. Based on bioinformatic analysis, a putative biosynthetic pathway is proposed. Furthermore, overexpression of the pathway specific regulator ccsR elevated the titer of cytochalasin E from 25mg/L to 175 mg/L. Our results not only shed light on the biosynthesis of cytochalasins, but also provided genetic tools for increasing and engineering the production.
ESTHER : Qiao_2011_Metab.Eng_13_723
PubMedSearch : Qiao_2011_Metab.Eng_13_723
PubMedID: 21983160
Gene_locus related to this paper: aspcl-CCSE

Title : Homo- and hetero-dimers of inactive organophosphorous group binding at dual sites of AChE - Zhao_2011_Bioorg.Med.Chem.Lett_21_6404
Author(s) : Zhao Q , Xie R , Zhang T , Fang J , Mei X , Ning J , Tang Y
Ref : Bioorganic & Medicinal Chemistry Lett , 21 :6404 , 2011
Abstract : Homo- and hetero-dimers of inactive organophosphorous group(s) dramatically enhanced the acetylcholinesterase (AChE; EC inhibiting potency, with the highest potency observed at a tether length of 6 methylene groups (6d) for the homodimers, and 7 methylene groups (8e) for the heterodimers. The docking model of Drosophila melanogaster AChE suggested that 6d and 8e bound at the catalytic and peripheral sites of AChE, in which two organophosphorous groups of 6d individually oriented towards TRP83 of catalytic sites and TRP321 of peripheral sites, and phthalicimide group of 8e was appropriately arranged for a pi-pi interaction with the phenyl ring of TYR330, furthermore, the organophosphorous group introduced hydrophobic interaction with TRP83. The compounds prepared in this work demonstrated high insecticidal activity to Lipaphis erysimi and Tetranychus cinnbarinus at the concentration 300mg/L.
ESTHER : Zhao_2011_Bioorg.Med.Chem.Lett_21_6404
PubMedSearch : Zhao_2011_Bioorg.Med.Chem.Lett_21_6404
PubMedID: 21940169

Title : Enzymatic synthesis of resorcylic acid lactones by cooperation of fungal iterative polyketide synthases involved in hypothemycin biosynthesis - Zhou_2010_J.Am.Chem.Soc_132_4530
Author(s) : Zhou H , Qiao K , Gao Z , Meehan MJ , Li JW , Zhao X , Dorrestein PC , Vederas JC , Tang Y
Ref : Journal of the American Chemical Society , 132 :4530 , 2010
Abstract : Hypothemycin is a macrolide protein kinase inhibitor from the fungus Hypomyces subiculosus. During biosynthesis, its carbon framework is assembled by two iterative polyketide synthases (PKSs), Hpm8 (highly reducing) and Hpm3 (nonreducing). These were heterologously expressed in Saccharomyces cerevisiae BJ5464-NpgA, purified to near homogeneity, and reconstituted in vitro to produce (6'S,10'S)-trans-7',8'-dehydrozearalenol (1) from malonyl-CoA and NADPH. The structure of 1 was determined by X-ray crystallographic analysis. In the absence of functional Hpm3, the reducing PKS Hpm8 produces and offloads truncated pyrone products instead of the expected hexaketide. The nonreducing Hpm3 is able to accept an N-acetylcysteamine thioester of a correctly functionalized hexaketide to form 1, but it is unable to initiate polyketide formation from malonyl-CoA. We show that the starter-unit:ACP transacylase (SAT) of Hpm3 is critical for crosstalk between the two enzymes and that the rate of biosynthesis of 1 is determined by the rate of hexaketide formation by Hpm8.
ESTHER : Zhou_2010_J.Am.Chem.Soc_132_4530
PubMedSearch : Zhou_2010_J.Am.Chem.Soc_132_4530
PubMedID: 20222707
Gene_locus related to this paper: hypsb-hpm3

Title : Cloning, sequence analysis and expression of bacterial lipase-coding DNA fragments from environment in Escherichia coli - Fan_2009_Mol.Biol.Rep_36_1515
Author(s) : Fan Z , Yue C , Tang Y , Zhang Y
Ref : Mol Biol Rep , 36 :1515 , 2009
Abstract : Thirteen pairs of primers were designed, synthesized and used to clone the whole coding sequences or mature peptide-coding sequences of lipases. Bacteria producing extracellular lipases were enriched for the extraction of total DNAs. Eight fragments with 500-1,200 bp in length were obtained by using touchdown PCR and sequenced. Five of them were found to be lipase-coding DNAs. One fragment called BL9 that was 95.9% similar to a coding sequence of putative lipase. This lipase contained a Gly-His-Ser-Met-Gly motif which is matched to the consensus Gly-X-Ser-X-Gly conserved among lipolytic enzymes. The BL9 DNA fragment was inserted into the expression vector pET32a(+) of Escherichia coli. A functional product was yielded in the supernatant and produced a hydrolyzed zone on the tributyrin agar.
ESTHER : Fan_2009_Mol.Biol.Rep_36_1515
PubMedSearch : Fan_2009_Mol.Biol.Rep_36_1515
PubMedID: 18773306

Title : Berberine and total base from rhizoma coptis chinensis attenuate brain injury in an aluminum-induced rat model of neurodegenerative disease - Zhang_2009_Saudi.Med.J_30_760
Author(s) : Zhang J , Yang JQ , He BC , Zhou QX , Yu HR , Tang Y , Liu BZ
Ref : Saudi Med J , 30 :760 , 2009
Abstract : OBJECTIVE: To investigate the protective effects of the total base from rhizoma coptis chinensis (CTB) and berberine (Ber) on neurodegeneration induced by aluminum overload in rats. METHODS: The study took place in the Department of Pharmacology, Chongqing Medical University, Chongqing, China, between February 2005 and May 2007. Wistar rats were divided into control group, model group, Ber-treated group, CTB (55 mg/kg and 110 mg/kg)-treated group, and nimodipine-treated group (n=20). A rat brain damage model was established via intragastric administration of 400 mg/kg element aluminum once a day, 5 days a week for 12 weeks. The CTB, Ber, and nimodipine were intragastrically administered 4 hours after each aluminum administration for 12 weeks. The morphological changes of the neurons of the rat hippocampus and the changes of rat learning and memory functions were observed. The superoxide dismutase (SOD), choline acetyltransferase (ChAT), acetylcholinesterase (AchE), and monoamine oxidase-B (MAO-B) activities and malondialdehyde (MDA) content, as well as the MAO-B expression in the rat brain were examined. RESULTS: The CTB, Ber, and nimodipine significantly improved the learning and memory ability impairment and hippocampal neuronal death. The CTB, Ber, and nimodipine also significantly blunted the decrease of SOD and ChAT activities, and the increase of MDA content, AchE activities, and MAO-B expressions and activity in the aluminum-overload rats. CONCLUSION: The CTB and Ber have protective effects on neurodegeneration induced by aluminum overload. The CTB (110 mg/kg) has more powerful neuroprotection than Ber.
ESTHER : Zhang_2009_Saudi.Med.J_30_760
PubMedSearch : Zhang_2009_Saudi.Med.J_30_760
PubMedID: 19526156

Title : A butterfly effect: highly insecticidal resistance caused by only a conservative residue mutated of drosophila melanogaster acetylcholinesterase - Fan_2009_J.Mol.Model_15_1229
Author(s) : Fan F , You Z , Li Z , Cheng J , Tang Y , Tang Z
Ref : J Mol Model , 15 :1229 , 2009
Abstract : Acetylcholinesterase (AChE) and its mutation recently emerged as a significant research area, due to its resistance against organophosphate and carbamate insecticides. Residue G265, which is always a conservative residue, mutated to A265 is the most frequent mutant of AChE in Drosophila populations. However, only this mutation caused a 'butterfly effect' that gives high insecticidal resistance. Herein, the models of sensitive strain (Dm-S) and the resistance strain (Dm-R) were constructed, to give a total of 2000 ps molecular dynamics simulation and to reveal the insecticidal resistance mechanism, with implied, the active gorge of Dm-R was much less flexible than that of Dm-S. The "back door" channel was widened to accelerate the detoxication against insecticides by the conformation changing of W83 and I161. All the distances (S238-H480, S238-G150, S238-G151, Y71-M153) in Dm-R became smaller than those in Dm-S, which may deeply influence the binding between the insecticides and DmAChE.
ESTHER : Fan_2009_J.Mol.Model_15_1229
PubMedSearch : Fan_2009_J.Mol.Model_15_1229
PubMedID: 19263097

Title : Physostigmine-induced hypothermic response in rats and its relationship with endogenous arginine vasopressin - Yang_2009_Life.Sci_85_586
Author(s) : Yang YL , Shen ZL , Zou Q , Tang Y , Huang T
Ref : Life Sciences , 85 :586 , 2009
Abstract : AIMS: It is well known that physostigmine (PHY) and other anticholinesterase (anti-ChE) agents induce hypothermia in rodents but little is known about the mechanism of action. Because arginine vasopressin (AVP) has been found to be an endogenous antipyretic molecule in the CNS, we determined if PHY-induced hypothermia is linked to the endogenous release of AVP. MAIN METHODS: Core temperature and motor activity were monitored by telemetry in rats maintained at an ambient temperature of 25 degrees C. Tail skin temperature was also measured at 30min intervals to estimate nonevaporative heat loss. The central cholinergic antagonist, scopolamine (1mg/kg; ip) and an AVP V(1) receptor antagonist (30microg/kg; ip) were administered during the period of PHY (200microg/kg; sc) induced hypothermia at 10am. Plasma AVP concentration and plasma cholinesterase (ChE) activity were measured at 50min after administration of PHY or scopolamine, respectively. KEY FINDINGS: PHY led to a rapid reduction in core temperature concomitant with a marked increase in heat loss from the tail. The hypothermic response of PHY was blocked by the AVP V(1) receptor antagonist. Administration of scopolamine also reversed the hypothermic responses and led to marked elevations in motor activity. Plasma AVP levels increased markedly at 50min after PHY and plasma ChE activity was significantly reduced by PHY. SIGNIFICANCE: The results clearly demonstrate that PHY-induced hypothermia was blocked by the AVP V(1) antagonist and associated with elevations in plasma AVP, suggesting a novel role for AVP in the mechanism of action of anti-ChE agents.
ESTHER : Yang_2009_Life.Sci_85_586
PubMedSearch : Yang_2009_Life.Sci_85_586
PubMedID: 19723529

Title : The crystal structure of a complex of acetylcholinesterase with a bis-(-)-nor-meptazinol derivative reveals disruption of the catalytic triad - Paz_2009_J.Med.Chem_52_2543
Author(s) : Paz A , Xie Q , Greenblatt HM , Fu W , Tang Y , Silman I , Qiu Z , Sussman JL
Ref : Journal of Medicinal Chemistry , 52 :2543 , 2009
Abstract : A bis-(-)-nor-meptazinol derivative in which the two meptazinol rings are linked by a nonamethylene spacer is a novel acetylcholinesterase inhibitor that inhibits both catalytic activity and Abeta peptide aggregation. The crystal structure of its complex with Torpedo californica acetylcholinesterase was determined to 2.7 A resolution. The ligand spans the active-site gorge, with one nor-meptazinol moiety bound at the "anionic" subsite of the active site, disrupting the catalytic triad by forming a hydrogen bond with His440N(epsilon2), which is hydrogen-bonded to Ser200O(gamma) in the native enzyme. The second nor-meptazinol binds at the peripheral "anionic" site at the gorge entrance. A number of GOLD models of the complex, using both native TcAChE and the protein template from the crystal structure of the bis-(-)-nor-meptazinol/TcAChE complex, bear higher similarity to the X-ray structure than a previous model obtained using the mouse enzyme structure. These findings may facilitate rational design of new meptazinol-based acetylcholinesterase inhibitors.
ESTHER : Paz_2009_J.Med.Chem_52_2543
PubMedSearch : Paz_2009_J.Med.Chem_52_2543
PubMedID: 19326912
Gene_locus related to this paper: torca-ACHE

Title : [Changes in plasma endotoxin content due to cholinesterase inhibitor VX intoxication and therapeutic effect of benthiaczine in mice] - Song_2008_Zhongguo.Wei.Zhong.Bing.Ji.Jiu.Yi.Xue_20_558
Author(s) : Song LX , Tang Y , Wang H
Ref : Zhongguo Wei Zhong Bing Ji Jiu Yi Xue , 20 :558 , 2008
Abstract : OBJECTIVE: To investigate the therapeutic effect and its mechanisms of benthiaczine on cholinesterase inhibitor VX poisoning by observing on the changes in plasma endotoxin content in mice.
METHODS: Three hundred and six male Kunming mice were randomly assigned to five groups: normal group, VX poisoning (model) group, benthiaczine, atropine or 654-2 pretreatment group. The above mentioned drugs were respectively given 10 minutes before hypodermic injection of VX in a dose of 0.02 mg/kg. The plasma concentration of endotoxin was measured at 1.5, 3, 6, 24, 48 and 72 hours after VX poisoning.
RESULTS: After VX injection, the endotoxin concentration in model group was significantly increased compared with normal group (all P < 0.01). The endotoxin concentration in model group was (5.36+/-1.62) kEU/L at 1.5 hours, which was almost twice of that of normal group [(1.90+/-0.41) kEU/L]. It increased gradually to (11.47+/-3.90) kEU/L at 24 hours, which was 5 fold of that of the normal group (all P < 0.01), and it maintained on the abnormally high level until 48 hours, then declined to the level of normal group after 72 hours. The endotoxin concentration of benthiaczine pretreatment group was significantly lower than that of model group at 1.5 hours and 3 hours after VX injection [(3.73+/-0.71) kEU/L, (3.95+/-1.26) kEU/L, respectively, P < 0.01 and P < 0.05], but there was no significant difference between two groups at 6 hours [(8.77+/-1.85) kEU/L] and 24 hours [(11.47+/-2.51) kEU/L], though it was significantly higher than normal group (both P < 0.01). It lowered to the normal level at 48 hours. The endotoxin concentration in atropine pretreatment group was significantly higher than model group at 1.5-24 hours after VX injection (P < 0.05 or P < 0.01), while that of 654-2 pretreatment group reached a peak at 6 hours, which was significantly higher than that of the model group (P < 0.01). CONCLUSION: The increased endotoxin concentration induced by VX in mice 1.5-48 hours after poisoning can be reversed by pretreatment of benthiaczine, but aggravated by pretreatment of atropine or 654-2. The administration of benthiaczine could alleviate the injury to the gut barrier function thus delay translocation of endotoxin into blood, and also shorten the time of endotoxemia.
ESTHER : Song_2008_Zhongguo.Wei.Zhong.Bing.Ji.Jiu.Yi.Xue_20_558
PubMedSearch : Song_2008_Zhongguo.Wei.Zhong.Bing.Ji.Jiu.Yi.Xue_20_558
PubMedID: 18786321

Title : Bis-(-)-nor-meptazinols as novel nanomolar cholinesterase inhibitors with high inhibitory potency on amyloid-beta aggregation - Xie_2008_J.Med.Chem_51_2027
Author(s) : Xie Q , Wang H , Xia Z , Lu M , Zhang W , Wang X , Fu W , Tang Y , Sheng W , Li W , Zhou W , Zhu X , Qiu Z , Chen H
Ref : Journal of Medicinal Chemistry , 51 :2027 , 2008
Abstract : Bis-(-)-nor-meptazinols (bis-(-)-nor-MEPs) 5 were designed and synthesized by connecting two (-)-nor-MEP monomers with alkylene linkers of different lengths via the secondary amino groups. Their acetylcholinesterase (AChE) inhibitory activities were more greatly influenced by the length of the alkylene chain than butyrylcholinesterase (BChE) inhibition. The most potent nonamethylene-tethered dimer 5h exhibited low-nanomolar IC 50 values for both ChEs, having a 10 000-fold and 1500-fold increase in inhibition of AChE and BChE compared with (-)-MEP. Molecular docking elucidated that 5h simultaneously bound to the catalytic and peripheral sites in AChE via hydrophobic interactions with Trp86 and Trp286. In comparison, it folded in the large aliphatic cavity of BChE because of the absence of peripheral site and the enlargement of the active site. Furthermore, 5h and 5i markedly prevented the AChE-induced Abeta aggregation with IC 50 values of 16.6 and 5.8 microM, similar to that of propidium (IC 50 = 12.8 microM), which suggests promising disease-modifying agents for the treatment of AD patients.
ESTHER : Xie_2008_J.Med.Chem_51_2027
PubMedSearch : Xie_2008_J.Med.Chem_51_2027
PubMedID: 18333606

Title : Enzymatic synthesis of aromatic polyketides using PKS4 from Gibberella fujikuroi - Ma_2007_J.Am.Chem.Soc_129_10642
Author(s) : Ma SM , Zhan J , Watanabe K , Xie X , Zhang W , Wang CC , Tang Y
Ref : Journal of the American Chemical Society , 129 :10642 , 2007
Abstract : Iterative fungal polyketide synthases (PKSs) use a unique set of biochemical rules in the synthesis of complex polyketides. These rules dictate polyketide starter unit selection, chain length control, and post-PKS processing. We have demonstrated the E. coli expression and reconstitution of an iterative, unreduced fungal PKS. The Gibberella fujikuroi PKS4 was expressed at high levels, purified to homogeneity and functionally characterized. In the presence of malonyl-CoA, PKS4 was able to synthesize the nonaketide 3,8,10,11-tetrahydroxy-1-methyl-12H-benzo[b]xanthen-12-one (2) as the predominant product. PKS4 selectively used octanoyl-CoA as the starter unit and synthesized two novel benzopyrone-containing polyketides. Our work sets the stage for a comprehensive characterization of the intact PKS and its domains, and offers significant opportunity towards the enzymatic synthesis of additional compounds.
ESTHER : Ma_2007_J.Am.Chem.Soc_129_10642
PubMedSearch : Ma_2007_J.Am.Chem.Soc_129_10642
PubMedID: 17696354
Gene_locus related to this paper: gibf5-bik1

Title : Continuous fluorometric assays for acetylcholinesterase activity and inhibition with conjugated polyelectrolytes -
Author(s) : Feng F , Tang Y , Wang S , Li Y , Zhu D
Ref : Angew Chem Int Ed Engl , 46 :7882 , 2007
PubMedID: 17768745

Title : Molecular docking and 3D-QSAR studies of 2-substituted 1-indanone derivatives as acetylcholinesterase inhibitors - Shen_2007_Acta.Pharmacol.Sin_28_2053
Author(s) : Shen LL , Liu GX , Tang Y
Ref : Acta Pharmacol Sin , 28 :2053 , 2007
Abstract : AIM: To explore the binding mode of 2-substituted 1-indanone derivatives with acetylcholinesterase (AChE) and provide hints for the future design of new derivatives with higher potency and specificity.
METHODS: The GOLD-docking conformations of the compounds in the active site of the enzyme were used in subsequent studies. The highly reliable and predictive three-dimensional quantitative structure-activity relationship (3D-QSAR) models were achieved by comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) methods. The predictive capabilities of the models were validated by an external test set. Moreover, the stabilities of the 3D-QSAR models were verified by the leave-4-out cross-validation method.
RESULTS: The CoMFA and CoMSIA models were constructed successfully with a good cross-validated coefficient (q(2)) and a non-cross-validated coefficient (r(2)). The q(2)and r(2)obtained from the leave-1-out cross validation method were 0.784 and 0.974 in the CoMFA model and 0.736 and 0.947 in the CoMSIA model, respectively. The coefficient isocontour maps obtained from these models were compatible with the geometrical and physicochemical properties of AChE. CONCLUSION: The contour map demonstrated that the binding affinity could be enhanced when the small protonated nitrogen moiety was replaced by a more hydrophobic and bulky group with a highly partial positive charge. The present study provides a better understanding of the interaction between the inhibitors and AChE, which is helpful for the discovery of new compounds with more potency and selective activity.
ESTHER : Shen_2007_Acta.Pharmacol.Sin_28_2053
PubMedSearch : Shen_2007_Acta.Pharmacol.Sin_28_2053
PubMedID: 18031622

Title : Improving simvastatin bioconversion in Escherichia coli by deletion of bioH - Xie_2007_Metab.Eng_9_379
Author(s) : Xie X , Wong WW , Tang Y
Ref : Metab Eng , 9 :379 , 2007
Abstract : Simvastatin is an important cholesterol lowering compound and is currently synthesized from the natural product lovastatin via multistep chemical synthesis. We have previously reported the use of an Escherichia coli strain BL21(DE3)/pAW31 as the host for whole-cell biocatalytic conversion of monacolin J acid to simvastatin acid. During fermentation and bioconversion, unknown E. coli enzyme(s) hydrolyzed the membrane permeable thioester substrate dimethylbutyryl-S-methyl mercaptopropionate (DMB-S-MMP) to the free acid, significantly decreased the efficiencies of the whole-cell bioconversion and the downstream purification steps. Using the Keio K-12 Singe-Gene Knockout collection, we identified BioH as the sole enzyme responsible for the observed substrate hydrolysis. Purification and reconstitution of E. coli BioH activity in vitro confirmed its function. BioH catalyzed the rapid hydrolysis of DMB-S-MMP with kcat and Km values of 260+/-45 s(-1) and 229+/-26 microM, respectively. This is in agreement with previous reports that BioH can function as a carboxylesterase towards fatty acid esters. YT2, which is a delta bioH mutant of BL21(DE3), did not hydrolyze DMB-S-MMP during prolonged fermentation and was used as an alternative host for whole-cell biocatalysis. The rate of simvastatin acid synthesis in YT2 was significantly faster than in BL21(DE3) and 99% conversion of 15 mM simvastatin acid in less than 12 h was achieved. Furthermore, the engineered host required significantly less DMB-S-MMP to be added to accomplish complete conversion. Finally, simvastatin acid synthesized using YT2 can be readily purified from fermentation broth and no additional steps to remove the hydrolyzed dimethylbutyryl-S-mercaptopropionic acid is required. Together, the proteomic and metabolic engineering approaches render the whole-cell biocatalytic process more robust and economically attractive.
ESTHER : Xie_2007_Metab.Eng_9_379
PubMedSearch : Xie_2007_Metab.Eng_9_379
PubMedID: 17625941

Title : 3D-QSAR studies on fluoropyrrolidine amides as dipeptidyl peptidase IV inhibitors by CoMFA and CoMSIA - Zeng_2007_J.Mol.Model_13_993
Author(s) : Zeng J , Liu G , Tang Y , Jiang H
Ref : J Mol Model , 13 :993 , 2007
Abstract : Three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses using CoMFA and CoMSIA methods were conducted on a series of fluoropyrrolidine amides as dipeptidyl peptidase IV (DP-IV) inhibitors. The selected ligands were docked into the binding site of the 3D model of DP-IV using the GOLD software, and the possible interaction models between DP-IV and the inhibitors were obtained. Based on the binding conformations of these fluoropyrrolidine amides and their alignment inside the binding pocket of DP-IV, predictive 3D-QSAR models were established by CoMFA and CoMSIA analyses, which had conventional r2 and cross-validated coefficient values ([Formula: see text]) up to 0.982 and 0.555 for CoMFA and 0.953 and 0.613 for CoMSIA, respectively. The predictive ability of these models was validated by six compounds that were in the testing set. Structure-based investigations and the final 3D-QSAR results provide the guide for designing new potent inhibitors.
ESTHER : Zeng_2007_J.Mol.Model_13_993
PubMedSearch : Zeng_2007_J.Mol.Model_13_993
PubMedID: 17618469

Title : Genome and proteome of long-chain alkane degrading Geobacillus thermodenitrificans NG80-2 isolated from a deep-subsurface oil reservoir - Feng_2007_Proc.Natl.Acad.Sci.U.S.A_104_5602
Author(s) : Feng L , Wang W , Cheng J , Ren Y , Zhao G , Gao C , Tang Y , Liu X , Han W , Peng X , Liu R , Wang L
Ref : Proc Natl Acad Sci U S A , 104 :5602 , 2007
Abstract : The complete genome sequence of Geobacillus thermodenitrificans NG80-2, a thermophilic bacillus isolated from a deep oil reservoir in Northern China, consists of a 3,550,319-bp chromosome and a 57,693-bp plasmid. The genome reveals that NG80-2 is well equipped for adaptation into a wide variety of environmental niches, including oil reservoirs, by possessing genes for utilization of a broad range of energy sources, genes encoding various transporters for efficient nutrient uptake and detoxification, and genes for a flexible respiration system including an aerobic branch comprising five terminal oxidases and an anaerobic branch comprising a complete denitrification pathway for quick response to dissolved oxygen fluctuation. The identification of a nitrous oxide reductase gene has not been previously described in Gram-positive bacteria. The proteome further reveals the presence of a long-chain alkane degradation pathway; and the function of the key enzyme in the pathway, the long-chain alkane monooxygenase LadA, is confirmed by in vivo and in vitro experiments. The thermophilic soluble monomeric LadA is an ideal candidate for treatment of environmental oil pollutions and biosynthesis of complex molecules.
ESTHER : Feng_2007_Proc.Natl.Acad.Sci.U.S.A_104_5602
PubMedSearch : Feng_2007_Proc.Natl.Acad.Sci.U.S.A_104_5602
PubMedID: 17372208
Gene_locus related to this paper: geotd-g3jwz2 , geoka-q5l1n0 , geotn-a4ijt0 , geotn-a4ilq0 , geotn-a4is13 , geotn-a4isp0 , geotn-a4isp3

Title : Investigation of the binding mode of (-)-meptazinol and bis-meptazinol derivatives on acetylcholinesterase using a molecular docking method - Xie_2006_J.Mol.Model_12_390
Author(s) : Xie Q , Tang Y , Li W , Wang XH , Qiu ZB
Ref : J Mol Model , 12 :390 , 2006
Abstract : Molecular docking has been performed to investigate the binding mode of (-)-meptazinol (MEP) with acetylcholinesterase (AChE) and to screen bis-meptazinol (bis-MEP) derivatives for preferable synthetic candidates virtually. A reliable and practical docking method for investigation of AChE ligands was established by the comparison of two widely used docking programs, FlexX and GOLD. In our hands, we had more luck using GOLD than FlexX in reproducing the experimental poses of known ligands (RMSD<1.5 A). GOLD fitness values of known ligands were also in good agreement with their activities. In the present GOLD docking protocol, (-)-MEP seemed to bind with the enzyme catalytic site in an open-gate conformation through strong hydrophobic interactions and a hydrogen bond. Virtual screening of a potential candidate compound library suggested that the most promising 15 bis-MEP derivatives on the list were mainly derived from (-)-MEP with conformations of (S,S) and (SR,RS) and with a 2- to 7-carbon linkage. Although there are still no biological results to confirm the predictive power of this method, the current study could provide an alternate tool for structural optimization of (-)-MEP as new AChE inhibitors. [Figure: see text].
ESTHER : Xie_2006_J.Mol.Model_12_390
PubMedSearch : Xie_2006_J.Mol.Model_12_390
PubMedID: 16404617

Title : Mating factor linkage and genome evolution in basidiomycetous pathogens of cereals - Bakkeren_2006_Fungal.Genet.Biol_43_655
Author(s) : Bakkeren G , Jiang G , Warren RL , Butterfield Y , Shin H , Chiu R , Linning R , Schein J , Lee N , Hu G , Kupfer DM , Tang Y , Roe BA , Jones S , Marra M , Kronstad JW
Ref : Fungal Genet Biol , 43 :655 , 2006
Abstract : Sex in basidiomycete fungi is controlled by tetrapolar mating systems in which two unlinked gene complexes determine up to thousands of mating specificities, or by bipolar systems in which a single locus (MAT) specifies different sexes. The genus Ustilago contains bipolar (Ustilago hordei) and tetrapolar (Ustilago maydis) species and sexual development is associated with infection of cereal hosts. The U. hordei MAT-1 locus is unusually large (approximately 500 kb) and recombination is suppressed in this region. We mapped the genome of U. hordei and sequenced the MAT-1 region to allow a comparison with mating-type regions in U. maydis. Additionally the rDNA cluster in the U. hordei genome was identified and characterized. At MAT-1, we found 47 genes along with a striking accumulation of retrotransposons and repetitive DNA; the latter features were notably absent from the corresponding U. maydis regions. The tetrapolar mating system may be ancestral and differences in pathogenic life style and potential for inbreeding may have contributed to genome evolution.
ESTHER : Bakkeren_2006_Fungal.Genet.Biol_43_655
PubMedSearch : Bakkeren_2006_Fungal.Genet.Biol_43_655
PubMedID: 16793293
Gene_locus related to this paper: ustho-q2a721

Title : Neurotoxicity of polycyclic aromatic hydrocarbons and simple chemical mixtures - Tang_2003_J.Toxicol.Environ.Health.A_66_919
Author(s) : Tang Y , Donnelly KC , Tiffany-Castiglioni E , Mumtaz MM
Ref : J Toxicol Environ Health A , 66 :919 , 2003
Abstract : Polycyclic aromatic hydrocarbons (PAHs) are a major class of environmental pollutants. These chemicals are the products of incomplete combustion and are present in every compartment of the environment. While the carcinogenic potential of these chemicals has been investigated in numerous studies, very little is known about the potential of these chemicals to produce damage to neural cells. The objective of this study was to investigate the toxicity of several model PAHs and binary mixtures of these chemicals in neural cells. Chemicals tested included benzo[a]pyrene (BaP), chrysene, anthracene, and pentachlorophenol (PCP). Four end points, including amino acid incorporation, total protein, total cell count, and viable cells (trypan dye exclusion), were measured in SY5Y human neuroblastoma cells and C6 rat glioma cells. The most sensitive measure of PAH toxicity in neural cells was amino acid incorporation into proteins. BaP was the most toxic of all PAHs tested, and anthracene failed to produce a toxic response at any concentration tested. Without metabolic activation, BaP induced a significant cytotoxic response at a concentration of 30 microM. With activation (0.25% S9), BaP induced a response at concentration levels of 3 microM and 30 microM. Minimal toxicity was observed with chrysene at the highest concentration tested, and anthracene failed to produce a toxic response at any concentration tested. With mixtures of PAHs the majority of samples induced additive responses. The minimum concentration required to induce a significant response was reduced for the mixture of chrysene and BaP when compared to BaP alone. In addition, PCP appeared to increase the inhibition of acetylcholinesterase by mipafox. The data suggest that PAHs are capable of producing damage to neural cells only at concentrations that are near their solubility limits.
ESTHER : Tang_2003_J.Toxicol.Environ.Health.A_66_919
PubMedSearch : Tang_2003_J.Toxicol.Environ.Health.A_66_919
PubMedID: 12825237

Title : The effect of oxidation on the enzyme-catalyzed hydrolytic biodegradation of poly(urethane)s - Labow_2002_J.Biomater.Sci.Polym.Ed_13_651
Author(s) : Labow RS , Tang Y , McCloskey CB , Santerre JP
Ref : J Biomater Sci Polym Ed , 13 :651 , 2002
Abstract : Although the biodegradation of polyurethanes (PU) by oxidative and hydrolytic agents has been studied extensively, few investigations have reported on the combination of their effects. Since neutrophils (PMN) arrive at an implanted device first and release HOCl, followed by monocyte-derived macrophages (MDM) which have potent esterase activities and oxidants of their own, the combined effect of oxidative and hydrolytic degradation on radiolabeled polycarbonate-polyurethanes (PCNU)s was investigated and compared to that of a polyester-PU (PESU) and a polyether-PU (PEU). The PCNUs were synthesized with PCN (MW = 1,000), and butanediol (14C-BD) and one of two diisocyanates, hexane-1,6-diisocyanate (14C-HDI) or methylene bis-p-phenyl diisocyanate (MDI). The PESU and PEU were synthesized using toluene-diisocyanate (14C-TDI), with polycaprolactone and polytetramethylene oxide as soft segments respectively, and ethylene diamine as the chain extender. The effect of pre-treatment with 0.1 mM HOC1 for 1 week on the HDI-based PCNUs and both TDI-based PUs resulted in a significant inhibition of radiolabel release (RR) elicited by cholesterol esterase (CE), when compared to buffer alone, whereas the MDI-based PCNU showed a small but significant increase. When PMN were activated on the HDI-based PCNU surface with phorbol myristate acetate (PMA), HOCl was released for 3 h, and was almost completely abolished by sodium azide (AZ). Simultaneously, the PMN-elicited RR, shown previously to be due to the esterolytic cleavage by serine proteases, was inhibited approximately 75% by PMA-activation of the cells, but significantly increased relative to the latter when AZ was added. Both in vitro oxidation by HOCl and the release of HOCI by PMN were associated with the inhibition of RR and suggest perturbations between oxidative and hydrolytic mechanisms of biodegradation.
ESTHER : Labow_2002_J.Biomater.Sci.Polym.Ed_13_651
PubMedSearch : Labow_2002_J.Biomater.Sci.Polym.Ed_13_651
PubMedID: 12182550

Title : Sequence and analysis of rice chromosome 4 - Feng_2002_Nature_420_316
Author(s) : Feng Q , Zhang Y , Hao P , Wang S , Fu G , Huang Y , Li Y , Zhu J , Liu Y , Hu X , Jia P , Zhao Q , Ying K , Yu S , Tang Y , Weng Q , Zhang L , Lu Y , Mu J , Zhang LS , Yu Z , Fan D , Liu X , Lu T , Li C , Wu Y , Sun T , Lei H , Li T , Hu H , Guan J , Wu M , Zhang R , Zhou B , Chen Z , Chen L , Jin Z , Wang R , Yin H , Cai Z , Ren S , Lv G , Gu W , Zhu G , Tu Y , Jia J , Chen J , Kang H , Chen X , Shao C , Sun Y , Hu Q , Zhang X , Zhang W , Wang L , Ding C , Sheng H , Gu J , Chen S , Ni L , Zhu F , Chen W , Lan L , Lai Y , Cheng Z , Gu M , Jiang J , Li J , Hong G , Xue Y , Han B
Ref : Nature , 420 :316 , 2002
Abstract : Rice is the principal food for over half of the population of the world. With its genome size of 430 megabase pairs (Mb), the cultivated rice species Oryza sativa is a model plant for genome research. Here we report the sequence analysis of chromosome 4 of O. sativa, one of the first two rice chromosomes to be sequenced completely. The finished sequence spans 34.6 Mb and represents 97.3% of the chromosome. In addition, we report the longest known sequence for a plant centromere, a completely sequenced contig of 1.16 Mb corresponding to the centromeric region of chromosome 4. We predict 4,658 protein coding genes and 70 transfer RNA genes. A total of 1,681 predicted genes match available unique rice expressed sequence tags. Transposable elements have a pronounced bias towards the euchromatic regions, indicating a close correlation of their distributions to genes along the chromosome. Comparative genome analysis between cultivated rice subspecies shows that there is an overall syntenic relationship between the chromosomes and divergence at the level of single-nucleotide polymorphisms and insertions and deletions. By contrast, there is little conservation in gene order between rice and Arabidopsis.
ESTHER : Feng_2002_Nature_420_316
PubMedSearch : Feng_2002_Nature_420_316
PubMedID: 12447439
Gene_locus related to this paper: orysa-Q7XTC5 , orysa-Q7F959 , orysa-q7f9i3 , orysa-q7x7y5 , orysa-q7xkj9 , orysa-q7xr62 , orysa-q7xr63 , orysa-q7xr64 , orysa-q7xsg1 , orysa-q7xsq2 , orysa-Q7XTM8 , orysa-q7xts6 , orysa-q7xue7 , orysa-q7xv53 , orysa-Q7XVB5 , orysa-Q7XVG5 , orysj-q0jaf0 , orysj-q7f8x1

Title : Effects of mobile buffers on facilitation: experimental and computational studies - Tang_2000_Biophys.J_78_2735
Author(s) : Tang Y , Schlumpberger T , Kim T , Lueker M , Zucker RS
Ref : Biophysical Journal , 78 :2735 , 2000
Abstract : Facilitation is an important form of short-term plasticity that occurs in most synapses. At crayfish neuromuscular junctions, basal transmission and facilitation were significantly reduced after presynaptic introduction of "fast" high-affinity calcium buffers, and the decay of facilitation was accelerated. The existence of residual calcium during facilitation was also demonstrated. Computational modeling of three-dimensional buffered Ca(2+) diffusion and binding to secretory and facilitation targets suggest that the facilitation site is located away from a secretory trigger mediating exocytosis; otherwise, the facilitation site would be saturated by each action potential. Our simulations account for many characteristics of facilitation and effects of exogenous buffer, and suggest that facilitation is caused by residual calcium gaining access to a site distinct from the secretory trigger through restricted diffusion.
ESTHER : Tang_2000_Biophys.J_78_2735
PubMedSearch : Tang_2000_Biophys.J_78_2735
PubMedID: 10827959

Title : Mitochondrial involvement in post-tetanic potentiation of synaptic transmission - Tang_1997_Neuron_18_483
Author(s) : Tang Y , Zucker RS
Ref : Neuron , 18 :483 , 1997
Abstract : Posttetanic potentiation (PTP) is an essential aspect of synaptic transmission that arises from a persistent presynaptic [Ca2+]i following tetanic stimulation. At crayfish neuromuscular junctions, several inhibitors of mitochondrial Ca2+ uptake and release (tetraphenylphosphonium or TPP+, carbonyl cyanide m-chlorophenylhydrazone or CCCP, and ruthenium red) blocked PTP and the persistence of presynaptic residual [Ca2+]i, while endoplasmic reticulum (ER) Ca2+ pump inhibitors and release channel activators (thapsigargin, 2,5-di-(tert-butyl)-1,4-benzohydroquinone or BHQ, and caffeine) had no effects. PTP apparently results from the slow efflux of tetanically accumulated mitochondrial Ca2+.
ESTHER : Tang_1997_Neuron_18_483
PubMedSearch : Tang_1997_Neuron_18_483
PubMedID: 9115741

Title : Synthesis and cholinergic properties of N-aryl-2-[[[5- [(dimethylamino)methyl]-2-furanyl]methyl]thio]ethylamino analogs of ranitidine - Valli_1992_J.Med.Chem_35_3141
Author(s) : Valli MJ , Tang Y , Kosh JW , Chapman JM, Jr. , Sowell JW, Sr.
Ref : Journal of Medicinal Chemistry , 35 :3141 , 1992
Abstract : A series of N-aryl-2-[[[5-[(dimethylamino)methyl]-2- furanyl]methyl]thio]ethylamino analogs of the H2-antagonist, ranitidine, was synthesized and the abilities of the compounds to alleviate the cholinergic deficit characteristic of Alzheimer's disease evaluated. The compounds were initially tested for their ability to inhibit human erythrocyte acetylcholinesterase activity in vitro. Selected compounds were further evaluated for butyrylcholinesterase inhibition, M1 and M2 cholinergic receptor binding, potentiation of ileal contractions, and the ability to elevate brain acetylcholine levels in mice. The analogs were compared to tetrahydroaminoacridine and to a recently reported series of bis-[[(dimethylamino)methyl]furans]. The N-aryl-2-[[[5-[(dimethylamino)methyl]-2- furanyl]methyl]thio]ethylamine derivatives were generally comparable to tetrahydroaminoacridine and the bis[[(dimethylamino)methyl]furans] in acetylcholinesterase inhibition, M1/M2 receptor binding, and the potentiation of ileal contractions, while being more potent inhibitors of acetylcholinesterase than butyrylcholinesterase. The 4-nitro-3-pyridazinyl analog, 26, was notable in demonstrating a potent and selective binding to the M2 receptor, with an M2 IC50/M1 IC50 of 0.060. Compounds in which the substituents on the dinitro-N-aryl moiety were relatively small were the best at inhibiting acetylcholinesterase in vitro. The N-aryl-2-[[[5-[(dimethylamino)methyl]-2- furanyl]methyl]thio]ethylamines in general, and those with small N-aryl substituents in particular, were superior to the bis[[(dimethylamino)methyl]furans] in elevating brain ACh levels in mice, probably due to enhanced distribution into the CNS. The 1,5-difluoro-2,4-dinitrophenyl analog, 8, resulted in the largest elevation in brain acetylcholine levels, affording a 53% increase at 88 mg/kg.
ESTHER : Valli_1992_J.Med.Chem_35_3141
PubMedSearch : Valli_1992_J.Med.Chem_35_3141
PubMedID: 1507203

Title : Synthesis and cholinergic properties of bis[[(dimethylamino)methyl]furanyl] analogues of ranitidine - Sowell_1992_J.Med.Chem_35_1102
Author(s) : Sowell JW, Sr. , Tang Y , Valli MJ , Chapman JM, Jr. , Usher LA , Vaughan CM , Kosh JW
Ref : Journal of Medicinal Chemistry , 35 :1102 , 1992
Abstract : The histaminergic H2 antagonist, ranitidine, has also been found to significantly inhibit acetylcholinesterase (AChE) in vitro. In an effort to develop novel, nonquaternary AChE inhibitors capable of penetrating into the CNS and alleviating the cholinergic deficit characteristic of Alzheimer's disease, a series of bis[[(dimethylamino)methyl]furanyl] analogues of ranitidine has been synthesized. All compounds were evaluated for human erythrocyte AChE inhibitory activity and compared to ranitidine, physostigmine, and tetrahydro-9-aminoacridine (THA). The most active AChE inhibitors were N,N'-disubstituted derivatives of 2-nitro-1,1-ethenediamine and 4,6-dinitro-1,3-benzenediamine, with compound 8 demonstrating activity greater than physostigmine. Deletion of the diaminonitroethene group in a series of alkyl and aryl bis-thioethers, yielded a number of slightly less active compounds, comparable in potency to THA. The 13 most active AChE inhibitors all demonstrated a more selective inhibition of AChE, as opposed to butyrylcholinesterase inhibition, than did THA. Compounds 3 and 22 were equally active to THA in potentiating rat ileal contractions. Binding studies demonstrated M1 and M2 cholinergic receptor affinities slightly greater than or equal to THA. Differential receptor binding studies showed compound 12 resembled THA in agonist/antagonist activity. Compounds 11-13 significantly elevated mouse brain acetylcholine levels, when administered at 80% of their approximate lethal doses, but were less active than THA or physostigmine.
ESTHER : Sowell_1992_J.Med.Chem_35_1102
PubMedSearch : Sowell_1992_J.Med.Chem_35_1102
PubMedID: 1552502