Wang A

References (43)

Title : A Pralidoxime Nanocomplex Formulation Targeting Transferrin Receptors for Reactivation of Brain Acetylcholinesterase After Exposure of Mice to an Anticholinesterase Organophosphate - Pirollo_2024_Int.J.Nanomedicine_19_307
Author(s) : Pirollo KF , Moghe M , Guan M , Rait AS , Wang A , Kim SS , Chang EH , Harford JB
Ref : Int J Nanomedicine , 19 :307 , 2024
Abstract : INTRODUCTION: Organophosphates are among the deadliest of known chemicals based on their ability to inactivate acetylcholinesterase in neuromuscular junctions and synapses of the central and peripheral nervous systems. The consequent accumulation of acetylcholine can produce severe acute toxicities and death. Oxime antidotes act by reactivating acetylcholinesterase with the only such reactivator approved for use in the United States being 2-pyridine aldoxime methyl chloride (a.k.a., pralidoxime or 2-PAM). However, this compound does not cross the blood-brain barrier readily and so is limited in its ability to reactivate acetylcholinesterase in the brain. METHODS: We have developed a novel formulation of 2-PAM by encapsulating it within a nanocomplex designed to cross the blood-brain barrier via transferrin receptor-mediated transcytosis. This nanocomplex (termed scL-2PAM) has been subjected to head-to-head comparisons with unencapsulated 2-PAM in mice exposed to paraoxon, an organophosphate with anticholinesterase activity. RESULTS AND DISCUSSION: In mice exposed to a sublethal dose of paraoxon, scL-2PAM reduced the extent and duration of cholinergic symptoms more effectively than did unencapsulated 2-PAM. The scL-2PAM formulation was also more effective than unencapsulated 2-PAM in rescuing mice from death after exposure to otherwise-lethal levels of paraoxon. Improved survival rates in paraoxon-exposed mice were accompanied by a higher degree of reactivation of brain acetylcholinesterase. CONCLUSION: Our data indicate that scL-2PAM is superior to the currently used form of 2-PAM in terms of both mitigating paraoxon toxicity in mice and reactivating acetylcholinesterase in their brains.
ESTHER : Pirollo_2024_Int.J.Nanomedicine_19_307
PubMedSearch : Pirollo_2024_Int.J.Nanomedicine_19_307
PubMedID: 38229703

Title : Donepezil promotes skin flap survival through activation of the HIF-1alpha\/VEGF signalling pathway - Lin_2024_Wound.Repair.Regen__
Author(s) : Lin H , Wang K , Yang J , Wang A , Deng J , Lin D
Ref : Wound Repair Regen , : , 2024
Abstract : Flaps are mainly used to repair wounds in the clinical setting but can sometimes experience ischaemic necrosis postoperatively. This study investigated whether donepezil, an acetylcholinesterase inhibitor, can enhance the survival rate of flaps. We randomly allocated 36 rats into control, low-dose (3 mg/kg/day), and high-dose (5 mg/kg/day) groups. On Postoperative day 7, we assessed flap viability and calculated the mean area of viable flap. After euthanizing the rats, we employed immunological and molecular biology techniques to examine the changes in flap tissue vascularization, apoptosis, autophagy, and inflammation. Donepezil enhanced the expression of hypoxia-inducible factor and vascular endothelial growth factor to facilitate angiogenesis. In addition, it elevated the expression of LC3B, p62, and beclin to stimulate autophagy. Furthermore, it increased the expression of Bcl-2 while reducing the expression of Bax, thus inhibiting apoptosis. Finally, it had anti-inflammatory effects by reducing the levels of IL-1beta, IL-6, and TNF-alpha. The results suggest that donepezil can enhance the viability of randomly generated skin flaps by upregulating HIF-1alpha/VEGF signalling pathway, facilitating vascularization, inducing autophagy, suppressing cell apoptosis, and mitigating inflammation within the flap tissue.
ESTHER : Lin_2024_Wound.Repair.Regen__
PubMedSearch : Lin_2024_Wound.Repair.Regen__
PubMedID: 38551210

Title : Toxic effects of isofenphos-methyl on zebrafish embryonic development - Wu_2023_Ecotoxicol.Environ.Saf_254_114723
Author(s) : Wu Y , Wang J , Xia Y , Tang K , Xu J , Wang A , Hu S , Wen L , Wang B , Yao W
Ref : Ecotoxicology & Environmental Safety , 254 :114723 , 2023
Abstract : Isofenphos-methyl (IFP) is widely used as an organophosphorus for controlling underground insects and nematodes. However, excessive use of IFP may pose potential risks to the environment and humans, but little information is available on its sublethal toxicity to aquatic organisms. To address this knowledge gap, the current study exposed zebrafish embryos to 2, 4, and 8 mg/L IFP within 6-96 h past fertilization (hpf) and measured mortality, hatching, developmental abnormalities, oxidative stress, gene expressions, and locomotor activity. The results showed that IFP exposure reduced the rates of heart and survival rate, hatchability, and body length of embryos and induced uninflated swim bladder and developmental malformations. Reduction in locomotive behavior and inhibition of AChE activity indicated that IFP exposure may induce behavioral defects and neurotoxicity in zebrafish larvae. IFP exposure also led to pericardial edema, longer venous sinus-arterial bulb (SV-BA) distance, and apoptosis of the heart cells. Moreover, IFP exposure increased the accumulation of reactive oxygen species (ROS) and the content of malonaldehyde (MDA), also elevated the levels of antioxidant enzymes of superoxide dismutase (SOD) and catalase (CAT), but decreased glutathione (GSH) levels in zebrafish embryos. The relative expressions of heart development-related genes (nkx2.5, nppa, gata4, and tbx2b), apoptosis-related genes (bcl2, p53, bax, and puma), and swim bladder development-related genes (foxA3, anxa5b, mnx1, and has2) were significantly altered by IFP exposure. Collectively, our results indicated that IFP induced developmental toxicity and neurotoxicity to zebrafish embryos and the mechanisms may be relevant to the activation of oxidative stress and reduction of acetylcholinesterase (AChE) content.
ESTHER : Wu_2023_Ecotoxicol.Environ.Saf_254_114723
PubMedSearch : Wu_2023_Ecotoxicol.Environ.Saf_254_114723
PubMedID: 36871354

Title : Genome-wide identification of CXE and PuCXE15 functions in the catabolism of volatile ester in 'Nanguo' pear fruit - Qi_2023_Plant.Physiol.Biochem_203_107996
Author(s) : Qi L , Li X , Zang N , Zhang Z , Yang Y , Du Y , Sun J , Mostafa I , Yin Z , Wang A
Ref : Plant Physiol Biochem , 203 :107996 , 2023
Abstract : Volatile esters are the main aromatic components that affect consumer sensory preferences. Aroma is a crucial characteristic of the 'Nanguo' pear (Pyrus ussriensis Maxim). Carboxylesterases (CXEs) are positively correlated with the catabolism of volatile esters in peaches; however, the mechanism of action of CXE family members in 'Nanguo' pear is poorly understood. In this study, 40 PuCXEs were identified in the 'Nanguo' pear and assigned into seven groups. In addition, we found that most PuCXEs were relatively conserved and contained cytoplasmic proteins. This hypothesis was supported by phylogenetic analysis, investigation of conserved domains and gene structures, and prediction of subcellular localization. Based on the content of volatile esters and expression levels of PuCXEs analysis, four PuCXEs, including PuCXE7, PuCXE15, PuCXE20, and PuCXE25, had a significant negative correlation with volatile ester accumulation. Particularly, the correlation of PuCXE15 far exceeded that of the other PuCXEs. The results of the transient expression assay showed that PuCXE15 promoted the degradation of ester in vivo. Subcellular localization experiment revealed that PuCXE15 is located in the plasma membrane and nucleus. These results show that PuCXE15 functions in the catabolism of volatile ester in 'Nanguo' pear fruit, and provides a foundation for enhancing aroma quality by artificial control in pear.
ESTHER : Qi_2023_Plant.Physiol.Biochem_203_107996
PubMedSearch : Qi_2023_Plant.Physiol.Biochem_203_107996
PubMedID: 37688900

Title : Molecular, morphological and behavioral alterations of zebrafish (Danio rerio) embryos\/larvae after clorprenaline hydrochloride exposure - Wang_2023_Food.Chem.Toxicol_176_113776
Author(s) : Wang B , Wang A , Xu C , Tong Z , Wang Y , Zhuo X , Fu L , Yao W , Wang J , Wu Y
Ref : Food & Chemical Toxicology , 176 :113776 , 2023
Abstract : Chlorprenaline hydrochloride (CLOR) is a typical representative of beta-adrenergic agonists that may be used illegally as a livestock feed additive and may have adverse impacts on the environment. In the present study, zebrafish embryos were exposed to CLOR to investigate its developmental toxicity and neurotoxicity. The results demonstrated that CLOR exposure led to adverse effects on developing zebrafish, such as morphological changes, a high heart rate, and increased body length, resulting in developmental toxicity. Moreover, the up-regulation of activities of superoxide dismutase (SOD) and catalase (CAT) and the enhancement of malondialdehyde (MDA) content illustrated that CLOR exposure activated oxidative stress in exposed zebrafish embryos. Meanwhile, CLOR exposure also caused alterations in locomotive behavior in zebrafish embryos, including an increase in acetylcholinesterase (AChE) activity. Quantitative polymerase chain reaction (QPCR) results showed that the transcription of genes related to the central nervous system (CNS) development, namely, mbp, syn2a, alpha1-tubulin, gap43, shha, and elavl3, indicated that CLOR exposure could lead to neurotoxicity in zebrafish embryos. These results showed that CLOR exposure could cause developmental neurotoxicity in the early stages of zebrafish development and that CLOR might induce neurotoxicity by altering the expression of neuro-developmental genes, elevating AChE activity, and activating oxidative stress.
ESTHER : Wang_2023_Food.Chem.Toxicol_176_113776
PubMedSearch : Wang_2023_Food.Chem.Toxicol_176_113776
PubMedID: 37059383

Title : Catalytically active inclusion bodies (CatIBs) induced by terminally attached self-assembling coiled-coil domains: To enhance the stability of (R)-hydroxynitrile lyase - Pei_2022_Enzyme.Microb.Technol_153_109915
Author(s) : Pei X , Wang J , Zheng H , Xiao Q , Wang A , Su W
Ref : Enzyme Microb Technol , 153 :109915 , 2022
Abstract : The catalytically-active inclusion bodies (CatIBs) represent a promising strategy for immobilizing enzyme without additional carriers and chemicals, which has aroused great attention in academic and industrial communities. In this work, we discovered two natural parallel right-handed coiled-coil tetramer peptides from PDB database by a structural mining strategy. The two self-assembling peptides, NSPdoT from rotavirus and HVdoT from human Vasodilator-stimulated phosphoprotein, efficiently induced the CatIBs formation of a (R)-Hydroxynitrile lyase from Arabidopsis thaliana (AtHNL) in Escherichia coli cells. This is convenient to simultaneously purify and immobilize the target proteins as biocatalysts. As expected, HVdoT-AtHNL and NSPdoT-AtHNL possessed drastically increased tolerance toward lower pH values, which will be very critical to synthesize cyanohydrins under acidic condition for suppressing the non-enzymatic side reaction. In addition. AtHNL-CatIBs are produced at high yield in host cells as bioactive microparticles, which exhibited high thermal and pH stabilities. Therefore, the CatIBs method represent a promising application for the immobilization of enzymes in the biocatalysis field.
ESTHER : Pei_2022_Enzyme.Microb.Technol_153_109915
PubMedSearch : Pei_2022_Enzyme.Microb.Technol_153_109915
PubMedID: 34670185
Gene_locus related to this paper: arath-HNL

Title : QSSR Modeling of Bacillus Subtilis Lipase A Peptide Collision Cross-Sections in Ion Mobility Spectrometry: Local Descriptor Versus Global Descriptor - Ni_2021_Protein.J__
Author(s) : Ni Z , Wang A , Kang L , Zhang T
Ref : Protein J , : , 2021
Abstract : To investigate the structure-dependent peptide mobility behavior in ion mobility spectrometry (IMS), quantitative structure-spectrum relationship (QSSR) is systematically modeled and predicted for the collision cross section values of totally 162 single-protonated tripeptide fragments extracted from the Bacillus subtilis lipase A. Two different types of structure characterization methods, namely, local and global descriptor as well as three machine learning methods, namely, partial least squares (PLS), support vector machine (SVM) and Gaussian process (GP), are employed to parameterize and correlate the structures and values of these peptide samples. In this procedure, the local descriptor is derived from the principal component analysis (PCA) of 516 physicochemical properties for 20 standard amino acids, which can be used to sequentially characterize the three amino acid residues composing a tripeptide. The global descriptor is calculated using CODESSA method, which can generate > 200 statistically significant variables to characterize the whole molecular structure of a tripeptide. The obtained QSSR models are evaluated rigorously via tenfold cross-validation and Monte Carlo cross-validation (MCCV). A comprehensive comparison is performed on the resulting statistics arising from the systematic combination of different descriptor types and machine learning methods. It is revealed that the local descriptor-based QSSR models have a better fitting ability and predictive power, but worse interpretability, than those based on the global descriptor. In addition, since the QSSR modeling using local descriptor does not consider the three-dimensional conformation of tripeptide samples, the method would be largely efficient as compared to the global descriptor.
ESTHER : Ni_2021_Protein.J__
PubMedSearch : Ni_2021_Protein.J__
PubMedID: 33454893

Title : Mechanisms of Congenital Myasthenia Caused by Three Mutations in the COLQ Gene - Luo_2021_Front.Pediatr_9_679342
Author(s) : Luo X , Wang C , Lin L , Yuan F , Wang S , Wang Y , Wang A , Wu S , Lan X , Xu Q , Yin R , Cheng H , Zhang Y , Xi J , Zhang J , Sun X , Yan J , Zeng F , Chen Y
Ref : Front Pediatr , 9 :679342 , 2021
Abstract : The gene encoding collagen like tail subunit of asymmetric acetylcholinesterase (COLQ) is responsible for the transcription of three strands of collagen of acetylcholinesterase, which is attached to the endplate of neuromuscular junctions. Mutations in the COLQ gene are inherited in an autosomal-recessive manner and can lead to type V congenital myasthenia syndrome (CMS), which manifests as decreased muscle strength at birth or shortly after birth, respiratory failure, restricted eye movements, drooping of eyelids, and difficulty swallowing. Here we reported three variants within COLQ in two unrelated children with CMS. An intronic variant (c.393+1G>A) and a novel missense variant (p.Q381P) were identified as compound heterozygous in a 13-month-old boy, with the parents being carriers of each. An intragenic deletion including exons 14 and 15 was found in a homozygous state in a 12-year-old boy. We studied the relative expression of the COLQ and AChE gene in the probands' families, performed three-dimensional protein structural analysis, and analyzed the conservation of the missense mutation c.1142A>C (p.Q381P). The splicing mutation c.393+1G>A was found to affect the normal splicing of COLQ exon 5, resulting in a 27-bp deletion. The missense mutation c.1142A>C (p.Q381P) was located in a conserved position in different species. We found that homozygous deletion of COLQ exons 14-15 resulted in a 241-bp deletion, which decreased the number of amino acids and caused a frameshift translation. COLQ expression was significantly lower in the probands than in the probands' parents and siblings, while AChE expression was significantly higher. Moreover, the mutations were found to cause significant differences in the predicted three-dimensional structure of the protein. The splicing mutation c.393+1G>A, missense mutation c.1A>C (p.Q381P), and COLQ exon 14-15 deletion could cause CMS.
ESTHER : Luo_2021_Front.Pediatr_9_679342
PubMedSearch : Luo_2021_Front.Pediatr_9_679342
PubMedID: 34912755

Title : Characterization of a carboxylesterase with hyper-thermostability and alkali-stability from Streptomyces lividans TK24 - Chang_2021_Extremophiles__
Author(s) : Chang X , Wu S , Chen J , Xiong S , Wang P , Shi X , Wang A , Wang B
Ref : Extremophiles , : , 2021
Abstract : A gene (estA', 804 bp) from Streptomyces lividans TK24 was artificially synthesized and successfully overexpressed as a 6His-tagged fusion protein in Escherichia coli. It encoded a carboxylesterase (EstA) that composed of 267 amino acids with a predicted molecular weight of 28.56 kDa. Multiple sequence alignment indicated that EstA has typical characteristics of esterases, including a catalytic triad (Ser93-Asp194-His224) and a conserved pentapeptide motif (Gly91-Leu92-Ser93-Met94-Gly95). Simultaneously, phylogenetic analysis indicated that EstA belongs to family VI. Biochemical characterization displayed its optimum enzyme activity was at 55 and pH 8.5. Additionally, EstA exhibited higher activity towards short carbon substrates and showed the outstanding catalytic efficiency for pNPA2 with k(cat)/K(m) of 2296.14 +/- 10.35 s(-1) mM(-1). Notably, EstA has hyper-thermostability and good alkali stability. The activity of EstA did not change obviously when incubated at 50 and 100 for 337 and 1 h, independently. Besides, by incubating at 100 for 6 h, EstA remained about half of its initial activity. Moreover, EstA showed stability at pH ranging from 8.0 to 11.0, and about 90% residual enzyme activity was reserved by being treated at pH 8.0 or 9.0 for 80 h, especially. Such multiple features prepare EstA for a potential candidate in the field of biological catalysis of some industrial applications under harsh conditions.
ESTHER : Chang_2021_Extremophiles__
PubMedSearch : Chang_2021_Extremophiles__
PubMedID: 33515353
Gene_locus related to this paper: strco-SCO2123

Title : The cholinergic system, intelligence, and dental fluorosis in school-aged children with low-to-moderate fluoride exposure - Wang_2021_Ecotoxicol.Environ.Saf_228_112959
Author(s) : Wang S , Zhao Q , Li G , Wang M , Liu H , Yu X , Chen J , Li P , Dong L , Zhou G , Cui Y , Liu L , Wang A
Ref : Ecotoxicology & Environmental Safety , 228 :112959 , 2021
Abstract : Disruption of cholinergic neurotransmission can affect cognition, but little is known about whether low-to-moderate fluoride exposure affects cholinergic system and its effect on the prevalence of dental fluorosis (DF) and intelligence quotient (IQ). A cross-sectional study was conducted to explore the associations of moderate fluoride exposure and cholinergic system in relation to children's DF and IQ. We recruited 709 resident children in Tianjin, China. Ion selective electrode method was used to detect fluoride concentrations in water and urine. Cholinergic system was assessed by the detection of choline acetyltransferase (ChAT), acetylcholinesterase (AChE) and acetylcholine (ACh) levels in serum. Compared with children in the first quartile, those in fourth quartile the risk of either developing DF or IQ < 120 increased by 19% and 20% for water and urinary fluoride. The risk of having both increased by 58% and 62% in third and fourth quartile for water fluoride, 52% and 65% for urinary fluoride. Water fluoride concentrations were positively associated with AChE and negatively associated with ChAT and ACh, trends were same for urinary fluoride except for ACh. The risk of either developing DF or having non-high intelligence rose by 22% (95%CI: 1.07%, 1.38%) for the fourth quartile than those in the first quartile of AChE, for having the both, the risk was 1.27 (95%CI: 1.07, 1.50), 1.37 (95%CI: 1.17, 1.62) and 1.44 (95%CI: 1.23, 1.68) in second, third and fourth quartiles. The mediation proportion by AChE between water fluoride and either developing DF or IQ < 120 was 15.7%. For both to exist, the proportion was 6.7% and 7.2% for water and urinary fluoride. Our findings suggest low-to-moderate fluoride exposure was associated with dysfunction of cholinergic system for children. AChE may partly mediate the prevalence of DF and lower probability of having superior and above intelligence.
ESTHER : Wang_2021_Ecotoxicol.Environ.Saf_228_112959
PubMedSearch : Wang_2021_Ecotoxicol.Environ.Saf_228_112959
PubMedID: 34808511

Title : Effects of nucleo(s)tide analogs therapy on chronic hepatitis B as evaluated by hepatosplenic radionuclide angiography - Wang_2020_Nucl.Med.Commun__
Author(s) : Wang L , Wu Z , Wang A , Jin X , Qiu Y
Ref : Nucl Med Commun , : , 2020
Abstract : OBJECTIVES: Hepatosplenic radionuclide angiography is a relatively noninvasive method for evaluating hepatic portal perfusion. We used hepatosplenic radionuclide angiography to assess the effects of nucleo(s)tide analogs therapy on patients with chronic hepatitis B (CHB). PATIENTS AND METHODS: A retrospective analysis was performed on patients who underwent hepatosplenic radionuclide angiography from January 2012 to May 2017 at the First Affiliated Hospital, College of Medicine, Zhejiang University. The correlations between the results of routine laboratory tests and hepatic perfusion index (HPI) were evaluated. The Wilcoxon signed-rank test and one-way ANOVA of repeated measures were used to compare the HPIs of patients who received nucleo(s)tide analogs therapy. RESULTS: There is a positive correlation between HPI and cholinesterase and serum albumin (ALB) and a negative correlation between HPI and aspartate aminotransferase-to-platelet ratio index and bilirubin (TBiL). An improvement in HPI was observed in patients with an initial HPI <61% after nucleo(s)tide analogs therapy. CONCLUSIONS: Hepatosplenic radionuclide angiography can reflect the functional reserve of the liver and monitor liver fibrosis indirectly. It can also comprehensively assess the effects of antiviral therapy on patients with CHB, and antiviral therapy is critical for the treatment of hepatitis.
ESTHER : Wang_2020_Nucl.Med.Commun__
PubMedSearch : Wang_2020_Nucl.Med.Commun__
PubMedID: 31939901

Title : Neurexin-1alpha regulates neurite growth of rat hippocampal neurons - Wang_2019_Int.J.Physiol.Pathophysiol.Pharmacol_11_115
Author(s) : Wang A , Xiang YY , Yang BB , Lu WY
Ref : Int Journal de Physiologie Pathophysiol Pharmacol , 11 :115 , 2019
Abstract : The growth of neurites underlies the axonal pathfinding and synaptic formation during neuronal development and regeneration. Neurite growth is regulated by specific interactions between growth cone receptors and their ligands that function as molecular cues existing in microenvironments. Neurexins (NRXNs) are concentrated on growth cones and they may function to constrain axonal branches of invertebrate neurons. The present study explored the role of NRXN-1alpha in regulating neurite growth of mammalian neurons. Results showed that transfecting an effective NRXN-1alpha siRNA to cultured rat hippocampal neurons significantly increased neurite length. Adding NRXN-1alpha ligands including neuroligin (NLGN) peptide and/or alpha-latrotoxin (alpha-LTX) to the culture media largely decreased neurite growth of naive neurons in a Ca(2+)-dependent manner, but had no effect on neurite growth of neurons transfected with NRXN-1alpha siRNA. Our results suggest that NRXN-1alpha regulates neurite development of mammalian neurons.
ESTHER : Wang_2019_Int.J.Physiol.Pathophysiol.Pharmacol_11_115
PubMedSearch : Wang_2019_Int.J.Physiol.Pathophysiol.Pharmacol_11_115
PubMedID: 31523359

Title : Electrocardiogram Changes of Donepezil Administration in Elderly Patients with Ischemic Heart Disease - Wang_2018_Cardiol.Res.Pract_2018_9141320
Author(s) : Wang D , Wu Y , Wang A , Chen Y , Zhang T , Hu N
Ref : Cardiol Res Pract , 2018 :9141320 , 2018
Abstract : Objective: Donepezil, a widely used cholinesterase inhibitor for treating Alzheimer's disease, has been reported to induce bradyarrhythmias and torsade de pointes. In this study, we aimed at determining electrocardiogram changes of donepezil administration in elderly patients with ischemic heart disease, who tend to suffer from cognitive disorders. Methods: Sixty patients with ischemic heart disease and mild cognitive impairment were treated with donepezil (5 mg/day) and followed up for at least four weeks. A twenty-four-hour ambulatory electrocardiogram was performed for the analysis of heart rate variability. The ECG parameters including heart rate (HR), PR and RR intervals, QT interval, and QRS duration were recorded at the baseline and after donepezil administration. Results: Donepezil administration resulted in significant reduction in mean HR and the lowest HR and prolongation of PR and RR intervals, whereas it had no significant effects on QRS duration and QT parameters including QT, corrected QT interval, QT dispersion, and Tpeak-end interval. HRV analysis showed that donepezil administration significantly improved parasympathetic function, indicated by decreased low/high frequency (LF/HF) ratio and high frequency (HF) components and oscillation of RR intervals. Conclusions: These data demonstrated that donepezil administration decreased HR, prolonged PR interval, and increased parasympathetic function without affecting QRS duration and QT intervals, suggesting that it can be used safely in elderly patients with ischemic heart disease.
ESTHER : Wang_2018_Cardiol.Res.Pract_2018_9141320
PubMedSearch : Wang_2018_Cardiol.Res.Pract_2018_9141320
PubMedID: 29850230

Title : Nuclear envelope localization of LEMD2 is developmentally dynamic and lamin A\/C dependent yet insufficient for heterochromatin tethering - Thanisch_2017_Differentiation_94_58
Author(s) : Thanisch K , Song C , Engelkamp D , Koch J , Wang A , Hallberg E , Foisner R , Leonhardt H , Stewart CL , Joffe B , Solovei I
Ref : Differentiation , 94 :58 , 2017
Abstract : Peripheral heterochromatin in mammalian nuclei is tethered to the nuclear envelope by at least two mechanisms here referred to as the A- and B-tethers. The A-tether includes lamins A/C and additional unknown components presumably INM protein(s) interacting with both lamins A/C and chromatin. The B-tether includes the inner nuclear membrane (INM) protein Lamin B-receptor, which binds B-type lamins and chromatin. Generally, at least one of the tethers is always present in the nuclear envelope of mammalian cells. Deletion of both causes the loss of peripheral heterochromatin and consequently inversion of the entire nuclear architecture, with this occurring naturally in rod photoreceptors of nocturnal mammals. The tethers are differentially utilized during development, regulate gene expression in opposite manners, and play an important role during cell differentiation. Here we aimed to identify the unknown chromatin binding component(s) of the A-tether. We analyzed 10 mouse tissues by immunostaining with antibodies against 7 INM proteins and found that every cell type has specific, although differentially and developmentally regulated, sets of these proteins. In particular, we found that INM protein LEMD2 is concomitantly expressed with A-type lamins in various cell types but is lacking in inverted nuclei of rod cells. Truncation or deletion of Lmna resulted in the downregulation and mislocalization of LEMD2, suggesting that the two proteins interact and pointing at LEMD2 as a potential chromatin binding mediator of the A-tether. Using nuclei of mouse rods as an experimental model lacking peripheral heterochromatin, we expressed a LEMD2 transgene alone or in combination with lamin C in these cells and observed no restoration of peripheral heterochromatin in either case. We conclude that in contrary to the B-tether, the A-tether has a more intricate composition and consists of multiple components that presumably vary, at differing degrees of redundancy, between cell types and differentiation stages.
ESTHER : Thanisch_2017_Differentiation_94_58
PubMedSearch : Thanisch_2017_Differentiation_94_58
PubMedID: 28056360

Title : Dibenzo-alpha-pyrones: a new class of larvicidal metabolites against Aedes aegypti from the endophytic fungus Hyalodendriella sp. Ponipodef12 - Mao_2017_Pest.Manag.Sci_73_1478
Author(s) : Mao Z , Lai D , Liu X , Fu X , Meng J , Wang A , Wang X , Sun W , Liu ZL , Zhou L , Liu Y
Ref : Pest Manag Sci , 73 :1478 , 2017
Abstract : BACKGROUND: In our search for new agrochemicals from endophytic fungi, the crude extract of the endophytic Hyalodendriella sp. Ponipodef12 associated with the hybrid 'Neva' of Populus deltoides Marsh x P. nigra L. was found to possess larvicidal activity against Aedes aegypti.
RESULTS: Fractionation of the extract has led to the isolation of 11 dibenzo-alpha-pyrones (1-11), including three new congeners: hyalodendriols A-C (1-3). The structures of the new compounds were elucidated by comprehensive spectroscopic analyses, including the modified Mosher's method for the assignment of the absolute configuration. Compounds 2-7 showed potent larvicidal activities against the fourth-instar larvae of A. aegypti with IC50 values ranging from 7.21 to 120.81 microg mL-1 . Among them, penicilliumolide D (6) displayed the strongest activity (IC50 = 7.21 microg mL-1 ). A structure-larvicidal activity relationship was discussed. The possible mode of action of these compounds was assessed for their acetylcholinesterase inhibitory activities. In addition, hyalodendriol C (3) displayed antibacterial activity against Bacillus subtilis and Xanthomonas vesicatoria, and exhibited strong inhibition against the spore germination of Magnaporthe oryzae. CONCLUSION: Our study revealed dibenzo-alpha-pyrones to be a new class of larvicidal metabolites against A. aegypti. (c) 2016 Society of Chemical Industry.
ESTHER : Mao_2017_Pest.Manag.Sci_73_1478
PubMedSearch : Mao_2017_Pest.Manag.Sci_73_1478
PubMedID: 27862895

Title : Characterization of a novel highly thermostable esterase from the Gram-positive soil bacterium Streptomyces lividans TK64 - Wang_2016_Biotechnol.Appl.Biochem_63_334
Author(s) : Wang B , Wang A , Cao Z , Zhu G
Ref : Biotechnol Appl Biochem , 63 :334 , 2016
Abstract : A novel esterase gene (estW) from soil bacterium Streptomyces lividans TK64 was successfully cloned using a pair of homologous primers. The estW gene encoded a protein (EstW) of 289 amino acid residues with a predicted molecular weight of 31.43 kDa. Sequence alignment revealed that EstW show relatively high levels of homology to other lipolytic enzymes characterized from Streptomyces and phylogenetic analysis suggested EstW belongs to the bacterial lipase/esterase family I. The estW gene was expressed at a high level in Escherichia coli and the recombinant enzyme was purified to homogeneity. The purified EstW was characterized via hydrolysis of various p-nitrophenyl esters and the best substrate was found to be p-nitrophenyl acetate (pNPA). Maximal activity of the recombinant protein was observed at pH 8.0 and 50 degrees C with pNPA as the substrate. The calculated activation energy (Ea ) of the esterase reaction was 9.12 kcal/mol. Half-life of EstW at 95 degrees C was approximately 12.5 H, making it the most thermostable esterase among all of the known lipolytic enzymes from Streptomyces, and the thermostability of EstW was similar to those of some enzymes characterized from the thermophilic bacteria. EstW exhibited relatively high tolerance to several detergents and required no cations for its maximal activity. The unique properties of EstW, namely its high thermostability and stability in the presence of organic solvents, may render it a potential candidate for industrial applications.
ESTHER : Wang_2016_Biotechnol.Appl.Biochem_63_334
PubMedSearch : Wang_2016_Biotechnol.Appl.Biochem_63_334
PubMedID: 26621184
Gene_locus related to this paper: strco-SCO1265

Title : The association between ambient exposure to organophosphates and Parkinson's disease risk - Wang_2014_Occup.Environ.Med_71_275
Author(s) : Wang A , Cockburn M , Ly TT , Bronstein JM , Ritz B
Ref : Occup Environ Med , 71 :275 , 2014
Abstract : OBJECTIVES: There is a general consensus that pesticides are involved in the aetiology of Parkinson's disease (PD), although associations between specific pesticides and the risk of developing PD have not been well studied. This study examines the risk of developing PD associated with specific organophosphate (OP) pesticides and their mechanisms of toxicity.
METHODS: This case-control study uses a geographic information system-based exposure assessment tool to estimate ambient exposure to 36 commonly used OPs from 1974 to 1999. All selected OPs were analysed individually and also in groups formed according to their presumed mechanisms of toxicity.
RESULTS: The study included 357 incident PD cases and 752 population controls living in the Central Valley of California. Ambient exposure to each OP evaluated separately increased the risk of developing PD. However, most participants were exposed to combinations of OPs rather than a single pesticide. Risk estimates for OPs grouped according to different presumed functionalities and toxicities were similar and did not allow us to distinguish between them. However, we observed exposure-response patterns with exposure to an increasing number of OPs.
CONCLUSIONS: This study adds strong evidence that OPs are implicated in the aetiology of idiopathic PD. However, studies of OPs at low doses reflective of real-world ambient exposure are needed to determine the mechanisms of neurotoxicity.
ESTHER : Wang_2014_Occup.Environ.Med_71_275
PubMedSearch : Wang_2014_Occup.Environ.Med_71_275
PubMedID: 24436061

Title : Substituted piperidinyl glycinyl 2-cyano-4,5-methano pyrrolidines as potent and stable dipeptidyl peptidase IV inhibitors - Zhao_2013_Bioorg.Med.Chem.Lett_23_1622
Author(s) : Zhao G , Kwon C , Wang A , Robertson JG , Marcinkeviciene J , Parker RA , Kirby MS , Hamann LG
Ref : Bioorganic & Medicinal Chemistry Lett , 23 :1622 , 2013
Abstract : Synthesis and structure-activity relationship of a series of substituted piperidinyl glycine 2-cyano-4,5-methano pyrroline DPP-IV inhibitors are described. Improvement of the inhibitory activity and chemical stability of this series of compounds was respectively achieved by the introduction of bulky groups at the 4-position and 1-position of the piperidinyl glycine, leading to a series of potent and stable DPP-IV inhibitors.
ESTHER : Zhao_2013_Bioorg.Med.Chem.Lett_23_1622
PubMedSearch : Zhao_2013_Bioorg.Med.Chem.Lett_23_1622
PubMedID: 23416006

Title : Optimization of Activity, Selectivity, and Liability Profiles in 5-Oxopyrrolopyridine DPP4 Inhibitors Leading to Clinical Candidate (Sa)-2-(3-(Aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-5-oxo-5H-pyrrolo[3,4-b]py ridin-6(7H)-yl)-N,N-dimethylacetamide (BMS-767778) - Devasthale_2013_J.Med.Chem_56_7343
Author(s) : Devasthale P , Wang Y , Wang W , Fevig J , Feng J , Wang A , Harrity T , Egan D , Morgan N , Cap M , Fura A , Klei HE , Kish K , Weigelt C , Sun L , Levesque P , Moulin F , Li YX , Zahler R , Kirby MS , Hamann LG
Ref : Journal of Medicinal Chemistry , 56 :7343 , 2013
Abstract : Optimization of a 5-oxopyrrolopyridine series based upon structure-activity relationships (SARs) developed from our previous efforts on a number of related bicyclic series yielded compound 2s (BMS-767778) with an overall activity, selectivity, efficacy, PK, and developability profile suitable for progression into the clinic. SAR in the series and characterization of 2s are described.
ESTHER : Devasthale_2013_J.Med.Chem_56_7343
PubMedSearch : Devasthale_2013_J.Med.Chem_56_7343
PubMedID: 23964740
Gene_locus related to this paper: human-DPP4

Title : On-line immobilized acetylcholinesterase microreactor for screening of inhibitors from natural extracts by capillary electrophoresis - Min_2012_Anal.Bioanal.Chem_404_2397
Author(s) : Min W , Wang W , Chen J , Wang A , Hu Z
Ref : Anal Bioanal Chem , 404 :2397 , 2012
Abstract : In this study we developed a simple capillary electrophoresis (CE) method with an on-line acetylcholinesterase (AChE) microreactor at the inlet of capillary for inhibitor screening. The fused-silica capillary surface was modified with a polycationic polyethylenimine coating. Solutions of the enzyme and chitosan were then injected to immobilize the enzyme in approximately 2.9 cm of the capillary inlet (total length of capillary 60.2 cm) by electrostatic interaction and the film overlay technique. Separation of enzyme reaction product (thiocholine, ThCh) and unreacted substrate (acetylthiocholine, AThCh) was achieved within 3.0 min. The conditions affecting the efficiency of reaction of the enzyme were optimized by measuring the peak area of ThCh. Under the optimum conditions, using Huperzine-A as model inhibitor, K (i) and IC (50) were 0.551 mumol L(-1) and 1.52 mumol L(-1), respectively, for immobilized AChE. Finally, screening of a small compound library containing two known AChE inhibitors and 30 natural extracts was conducted, and species with inhibition activity were directly identified. Compared with previous publications on screening for AChE inhibitors in natural products based on CE methods, the method developed in this work has the advantages of lower cost per analysis, less leakage, and better bioaffinity for the immobilized enzyme because of the unique properties of sodium alginate and chitosan.
ESTHER : Min_2012_Anal.Bioanal.Chem_404_2397
PubMedSearch : Min_2012_Anal.Bioanal.Chem_404_2397
PubMedID: 22932810

Title : Potency, selectivity and prolonged binding of saxagliptin to DPP4: maintenance of DPP4 inhibition by saxagliptin in vitro and ex vivo when compared to a rapidly-dissociating DPP4 inhibitor - Wang_2012_BMC.Pharmacol_12_2
Author(s) : Wang A , Dorso C , Kopcho L , Locke G , Langish R , Harstad E , Shipkova P , Marcinkeviciene J , Hamann L , Kirby MS
Ref : BMC Pharmacol , 12 :2 , 2012
Abstract : BACKGROUND: Dipeptidylpeptidase 4 (DPP4) inhibitors have clinical benefit in patients with type 2 diabetes mellitus by increasing levels of glucose-lowering incretin hormones, such as glucagon-like peptide -1 (GLP-1), a peptide with a short half life that is secreted for approximately 1 hour following a meal. Since drugs with prolonged binding to their target have been shown to maximize pharmacodynamic effects while minimizing drug levels, we developed a time-dependent inhibitor that has a half-life for dissociation from DPP4 close to the duration of the first phase of GLP-1 release. RESULTS: Saxagliptin and its active metabolite (5-hydroxysaxagliptin) are potent inhibitors of human DPP4 with prolonged dissociation from its active site (Ki = 1.3 nM and 2.6 nM, t1/2 = 50 and 23 minutes respectively at 37 degrees C). In comparison, both vildagliptin (3.5 minutes) and sitagliptin ( < 2 minutes) rapidly dissociated from DPP4 at 37 degrees C. Saxagliptin and 5-hydroxysaxagliptin are selective for inhibition of DPP4 versus other DPP family members and a large panel of other proteases, and have similar potency and efficacy across multiple species.Inhibition of plasma DPP activity is used as a biomarker in animal models and clinical trials. However, most DPP4 inhibitors are competitive with substrate and rapidly dissociate from DPP4; therefore, the type of substrate, volume of addition and final concentration of substrate in these assays can change measured inhibition. We show that unlike a rapidly dissociating DPP4 inhibitor, inhibition of plasma DPP activity by saxagliptin and 5-hydroxysaxagliptin in an ex vivo assay was not dependent on substrate concentration when substrate was added rapidly because saxagliptin and 5-hydroxysaxagliptin dissociate slowly from DPP4, once bound. We also show that substrate concentration was important for rapidly dissociating DPP4 inhibitors. CONCLUSIONS: Saxagliptin and its active metabolite are potent, selective inhibitors of DPP4, with prolonged dissociation from its active site. They also demonstrate prolonged inhibition of plasma DPP4 ex vivo in animal models, which implies that saxagliptin and 5-hydroxysaxagliptin would continue to inhibit DPP4 during rapid increases in substrates in vivo.
ESTHER : Wang_2012_BMC.Pharmacol_12_2
PubMedSearch : Wang_2012_BMC.Pharmacol_12_2
PubMedID: 22475049

Title : Genome sequence of Enterobacter cloacae subsp. dissolvens SDM, an efficient biomass-utilizing producer of platform chemical 2,3-butanediol - Xu_2012_J.Bacteriol_194_897
Author(s) : Xu Y , Wang A , Tao F , Su F , Tang H , Ma C , Xu P
Ref : Journal of Bacteriology , 194 :897 , 2012
Abstract : Enterobacter cloacae subsp. dissolvens SDM has an extraordinary characteristic of biomass utilization for 2,3-butanediol production. Here we present a 4.9-Mb assembly of its genome. The key genes for regulation and metabolism of 2,3-butanediol production were annotated, which could provide further insights into the molecular mechanism of high-yield production of 2,3-butanediol.
ESTHER : Xu_2012_J.Bacteriol_194_897
PubMedSearch : Xu_2012_J.Bacteriol_194_897
PubMedID: 22275097
Gene_locus related to this paper: entcl-i6s5g2 , entcl-y1bd05 , entcl-g8lek8

Title : 7-Oxopyrrolopyridine-derived DPP4 inhibitors-mitigation of CYP and hERG liabilities via introduction of polar functionalities in the active site - Wang_2011_Bioorg.Med.Chem.Lett_21_6646
Author(s) : Wang W , Devasthale P , Wang A , Harrity T , Egan D , Morgan N , Cap M , Fura A , Klei HE , Kish K , Weigelt C , Sun L , Levesque P , Li YX , Zahler R , Kirby MS , Hamann LG
Ref : Bioorganic & Medicinal Chemistry Lett , 21 :6646 , 2011
Abstract : Design, synthesis, and SAR of 7-oxopyrrolopyridine-derived DPP4 inhibitors are described. The preferred stereochemistry of these atropisomeric biaryl analogs has been identified as Sa. Compound (+)-3t, with a K(i) against DPP4, DPP8, and DPP9 of 0.37 nM, 2.2, and 5.7 muM, respectively, showed a significant improvement in insulin response after single doses of 3 and 10 mumol/kg in ob/ob mice.
ESTHER : Wang_2011_Bioorg.Med.Chem.Lett_21_6646
PubMedSearch : Wang_2011_Bioorg.Med.Chem.Lett_21_6646
PubMedID: 21996520
Gene_locus related to this paper: human-DPP4

Title : Synthesis and SAR of azolopyrimidines as potent and selective dipeptidyl peptidase-4 (DPP4) inhibitors for type 2 diabetes - Brigance_2010_Bioorg.Med.Chem.Lett_20_4395
Author(s) : Brigance RP , Meng W , Fura A , Harrity T , Wang A , Zahler R , Kirby MS , Hamann LG
Ref : Bioorganic & Medicinal Chemistry Lett , 20 :4395 , 2010
Abstract : Several pyrazolo-, triazolo-, and imidazolopyrimidines were synthesized and evaluated as inhibitors of DPP4. Of these three classes of compounds, the imidazolopyrimidines displayed the greatest potency and demonstrated excellent selectivity over the other dipeptidyl peptidases. SAR evaluation for these scaffolds was described as they may represent potential treatments for type 2 diabetes.
ESTHER : Brigance_2010_Bioorg.Med.Chem.Lett_20_4395
PubMedSearch : Brigance_2010_Bioorg.Med.Chem.Lett_20_4395
PubMedID: 20598534

Title : Prospecting metagenomic enzyme subfamily genes for DNA family shuffling by a novel PCR-based approach - Wang_2010_J.Biol.Chem_285_41509
Author(s) : Wang Q , Wu H , Wang A , Du P , Pei X , Li H , Yin X , Huang L , Xiong X
Ref : Journal of Biological Chemistry , 285 :41509 , 2010
Abstract : DNA family shuffling is a powerful method for enzyme engineering, which utilizes recombination of naturally occurring functional diversity to accelerate laboratory-directed evolution. However, the use of this technique has been hindered by the scarcity of family genes with the required level of sequence identity in the genome database. We describe here a strategy for collecting metagenomic homologous genes for DNA shuffling from environmental samples by truncated metagenomic gene-specific PCR (TMGS-PCR). Using identified metagenomic gene-specific primers, twenty-three 921-bp truncated lipase gene fragments, which shared 64-99% identity with each other and formed a distinct subfamily of lipases, were retrieved from 60 metagenomic samples. These lipase genes were shuffled, and selected active clones were characterized. The chimeric clones show extensive functional and genetic diversity, as demonstrated by functional characterization and sequence analysis. Our results indicate that homologous sequences of genes captured by TMGS-PCR can be used as suitable genetic material for DNA family shuffling with broad applications in enzyme engineering.
ESTHER : Wang_2010_J.Biol.Chem_285_41509
PubMedSearch : Wang_2010_J.Biol.Chem_285_41509
PubMedID: 20962349

Title : Synthesis, SAR, and atropisomerism of imidazolopyrimidine DPP4 inhibitors - O'Connor_2010_Bioorg.Med.Chem.Lett_20_6273
Author(s) : O'Connor SP , Wang Y , Simpkins LM , Brigance RP , Meng W , Wang A , Kirby MS , Weigelt CA , Hamann LG
Ref : Bioorganic & Medicinal Chemistry Lett , 20 :6273 , 2010
Abstract : The synthesis and SAR of aminomethyl-substituted imidazolopyrimidine DPP4 inhibitors bearing varied pendant aryl groups is described. Compound 1, which exists as a separable mixture of non-interconvertible atropisomers was used as the starting point for investigation. The effects of substituent pattern and type as well as stereochemical effects on inhibitor potency are discussed.
ESTHER : O'Connor_2010_Bioorg.Med.Chem.Lett_20_6273
PubMedSearch : O'Connor_2010_Bioorg.Med.Chem.Lett_20_6273
PubMedID: 20833042

Title : Discovery of 6-(Aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxa mides as Potent, Selective Dipeptidyl Peptidase-4 (DPP4) Inhibitors - Meng_2010_J.Med.Chem_53_5620
Author(s) : Meng W , Brigance RP , Chao HJ , Fura A , Harrity T , Marcinkeviciene J , O'Connor SP , Tamura JK , Xie D , Zhang Y , Klei HE , Kish K , Weigelt CA , Turdi H , Wang A , Zahler R , Kirby MS , Hamann LG
Ref : Journal of Medicinal Chemistry , 53 :5620 , 2010
Abstract : Continued structure-activity relationship (SAR) exploration within our previously disclosed azolopyrimidine containing dipeptidyl peptidase-4 (DPP4) inhibitors led us to focus on an imidazolopyrimidine series in particular. Further study revealed that by replacing the aryl substitution on the imidazole ring with a more polar carboxylic ester or amide, these compounds displayed not only increased DPP4 binding activity but also significantly reduced human ether-a-go-go related gene (hERG) and sodium channel inhibitory activities. Additional incremental adjustment of polarity led to permeable molecules which exhibited favorable pharmacokinetic (PK) profiles in preclinical animal species. The active site binding mode of these compounds was determined by X-ray crystallography as exemplified by amide 24c. A subsequent lead molecule from this series, (+)-6-(aminomethyl)-5-(2,4-dichlorophenyl)-N-(1-ethyl-1H-pyrazol-5-yl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamide (24s), emerged as a potent, selective DPP4 inhibitor that displayed excellent PK profiles and in vivo efficacy in ob/ob mice.
ESTHER : Meng_2010_J.Med.Chem_53_5620
PubMedSearch : Meng_2010_J.Med.Chem_53_5620
PubMedID: 20684603
Gene_locus related to this paper: human-DPP4

Title : Effect of a single cyclosporine dose on the single-dose pharmacokinetics of sitagliptin (MK-0431), a dipeptidyl peptidase-4 inhibitor, in healthy male subjects - Krishna_2007_J.Clin.Pharmacol_47_165
Author(s) : Krishna R , Bergman A , Larson P , Cote J , Lasseter K , Dilzer S , Wang A , Zeng W , Chen L , Wagner J , Herman G
Ref : Journal of Clinical Pharmacology , 47 :165 , 2007
Abstract : Sitagliptin (MK-0431) is an orally active, potent, and selective dipeptidyl peptidase-4 inhibitor used for the treatment of patients with type 2 diabetes mellitus. Sitagliptin has been shown to be a substrate for P-glycoprotein in preclinical studies. Cyclosporine was used as a probe P-glycoprotein inhibitor at a high dose to evaluate the potential effect of potent P-glycoprotein inhibition on single-dose sitagliptin pharmacokinetics in healthy male subjects. Eight healthy young men received a single oral 600-mg dose of cyclosporine with a single 100-mg oral sitagliptin dose and a single oral 100-mg sitagliptin dose alone in an open-label, randomized, 2-period, crossover study. Single doses of sitagliptin with or without single doses of cyclosporine were generally well tolerated. The sitagliptin AUC(0-infinity) geometric mean ratio was 1.29 with a 90% confidence interval of (1.24, 1.34). The sitagliptin Cmax geometric mean ratio was 1.68 with a 90% confidence interval of (1.35, 2.08). Cyclosporine coadministration did not appear to affect apparent sitagliptin renal clearance, t(1/2), or C(24 h), suggesting that effects of these high doses of cyclosporine are more likely due to enhanced absorption of sitagliptin, potentially through inhibition of intestinal P-glycoprotein. These results rationalize the use of a single high-dose cyclosporine as a probe inhibitor of P-glycoprotein for compound candidates whose elimination is less dependent on CYP3A4-mediated metabolism.
ESTHER : Krishna_2007_J.Clin.Pharmacol_47_165
PubMedSearch : Krishna_2007_J.Clin.Pharmacol_47_165
PubMedID: 17244767

Title : Complete genomic characterization of a pathogenic A.II strain of Francisella tularensis subspecies tularensis - Beckstrom-Sternberg_2007_PLoS.One_2_e947
Author(s) : Beckstrom-Sternberg SM , Auerbach RK , Godbole S , Pearson JV , Beckstrom-Sternberg JS , Deng Z , Munk C , Kubota K , Zhou Y , Bruce D , Noronha J , Scheuermann RH , Wang A , Wei X , Wang J , Hao J , Wagner DM , Brettin TS , Brown N , Gilna P , Keim PS
Ref : PLoS ONE , 2 :e947 , 2007
Abstract : Francisella tularensis is the causative agent of tularemia, which is a highly lethal disease from nature and potentially from a biological weapon. This species contains four recognized subspecies including the North American endemic F. tularensis subsp. tularensis (type A), whose genetic diversity is correlated with its geographic distribution including a major population subdivision referred to as A.I and A.II. The biological significance of the A.I - A.II genetic differentiation is unknown, though there are suggestive ecological and epidemiological correlations. In order to understand the differentiation at the genomic level, we have determined the complete sequence of an A.II strain (WY96-3418) and compared it to the genome of Schu S4 from the A.I population. We find that this A.II genome is 1,898,476 bp in size with 1,820 genes, 1,303 of which code for proteins. While extensive genomic variation exists between "WY96" and Schu S4, there is only one whole gene difference. This one gene difference is a hypothetical protein of unknown function. In contrast, there are numerous SNPs (3,367), small indels (1,015), IS element differences (7) and large chromosomal rearrangements (31), including both inversions and translocations. The rearrangement borders are frequently associated with IS elements, which would facilitate intragenomic recombination events. The pathogenicity island duplicated regions (DR1 and DR2) are essentially identical in WY96 but vary relative to Schu S4 at 60 nucleotide positions. Other potential virulence-associated genes (231) varied at 559 nucleotide positions, including 357 non-synonymous changes. Molecular clock estimates for the divergence time between A.I and A.II genomes for different chromosomal regions ranged from 866 to 2131 years before present. This paper is the first complete genomic characterization of a member of the A.II clade of Francisella tularensis subsp. tularensis.
ESTHER : Beckstrom-Sternberg_2007_PLoS.One_2_e947
PubMedSearch : Beckstrom-Sternberg_2007_PLoS.One_2_e947
PubMedID: 17895988
Gene_locus related to this paper: fratt-q5ngu5

Title : Curated genome annotation of Oryza sativa ssp. japonica and comparative genome analysis with Arabidopsis thaliana - Itoh_2007_Genome.Res_17_175
Author(s) : Itoh T , Tanaka T , Barrero RA , Yamasaki C , Fujii Y , Hilton PB , Antonio BA , Aono H , Apweiler R , Bruskiewich R , Bureau T , Burr F , Costa de Oliveira A , Fuks G , Habara T , Haberer G , Han B , Harada E , Hiraki AT , Hirochika H , Hoen D , Hokari H , Hosokawa S , Hsing YI , Ikawa H , Ikeo K , Imanishi T , Ito Y , Jaiswal P , Kanno M , Kawahara Y , Kawamura T , Kawashima H , Khurana JP , Kikuchi S , Komatsu S , Koyanagi KO , Kubooka H , Lieberherr D , Lin YC , Lonsdale D , Matsumoto T , Matsuya A , McCombie WR , Messing J , Miyao A , Mulder N , Nagamura Y , Nam J , Namiki N , Numa H , Nurimoto S , O'Donovan C , Ohyanagi H , Okido T , Oota S , Osato N , Palmer LE , Quetier F , Raghuvanshi S , Saichi N , Sakai H , Sakai Y , Sakata K , Sakurai T , Sato F , Sato Y , Schoof H , Seki M , Shibata M , Shimizu Y , Shinozaki K , Shinso Y , Singh NK , Smith-White B , Takeda J , Tanino M , Tatusova T , Thongjuea S , Todokoro F , Tsugane M , Tyagi AK , Vanavichit A , Wang A , Wing RA , Yamaguchi K , Yamamoto M , Yamamoto N , Yu Y , Zhang H , Zhao Q , Higo K , Burr B , Gojobori T , Sasaki T
Ref : Genome Res , 17 :175 , 2007
Abstract : We present here the annotation of the complete genome of rice Oryza sativa L. ssp. japonica cultivar Nipponbare. All functional annotations for proteins and non-protein-coding RNA (npRNA) candidates were manually curated. Functions were identified or inferred in 19,969 (70%) of the proteins, and 131 possible npRNAs (including 58 antisense transcripts) were found. Almost 5000 annotated protein-coding genes were found to be disrupted in insertional mutant lines, which will accelerate future experimental validation of the annotations. The rice loci were determined by using cDNA sequences obtained from rice and other representative cereals. Our conservative estimate based on these loci and an extrapolation suggested that the gene number of rice is approximately 32,000, which is smaller than previous estimates. We conducted comparative analyses between rice and Arabidopsis thaliana and found that both genomes possessed several lineage-specific genes, which might account for the observed differences between these species, while they had similar sets of predicted functional domains among the protein sequences. A system to control translational efficiency seems to be conserved across large evolutionary distances. Moreover, the evolutionary process of protein-coding genes was examined. Our results suggest that natural selection may have played a role for duplicated genes in both species, so that duplication was suppressed or favored in a manner that depended on the function of a gene.
ESTHER : Itoh_2007_Genome.Res_17_175
PubMedSearch : Itoh_2007_Genome.Res_17_175
PubMedID: 17210932
Gene_locus related to this paper: orysa-Q7XTC5 , orysa-Q852M6 , orysa-Q8GSE8 , orysa-Q9FYP7 , orysa-Q5ZA26 , orysa-Q5JLP6 , orysa-Q8H5P5 , orysa-Q7F1Y5 , orysa-cbp3 , orysa-cbpx , orysa-Q6YSZ8 , orysa-Q9FW17 , orysa-Q84QZ6 , orysa-Q0JK71 , orysa-B9EWJ8 , orysa-Q6ZDG6 , orysa-Q6ZDG5 , orysa-Q658B2 , orysa-Q5N7L1 , orysa-Q8RYV9 , orysa-Q8H3R3 , orysa-Q5SNH3 , orysa-pir7a , orysa-q2qnj4 , orysa-q2qyj1 , orysa-q2r077 , orysa-Q4VWY7 , orysa-q5smv5 , orysa-q5z901 , orysa-Q5ZBI5 , orysa-q6atz0 , orysa-q6i5q3 , orysa-q6j657 , orysa-q6k4q2 , orysj-q6yse8 , orysa-q6yy42 , orysa-q6yzk1 , orysa-q6z8b1 , orysa-q6z995 , orysa-q6zjq6 , orysa-q7x7y5 , orysa-Q7XC50 , orysa-q7xr62 , orysa-q7xr63 , orysa-q7xsg1 , orysa-q7xsq2 , orysa-q7xts6 , orysa-q7xv53 , orysa-Q8LQS5 , orysa-Q8RZ79 , orysa-Q8S0U8 , orysa-Q8W3C6 , orysa-Q9LHX5 , orysa-q53m20 , orysa-q53nd8 , orysa-q60e79 , orysa-q67iz2 , orysa-q67iz3 , orysa-q67iz7 , orysa-q67iz8 , orysa-q67j02 , orysa-q67j05 , orysa-q67j09 , orysa-q67j10 , orysa-q67tr6 , orysa-q67tv0 , orysa-q69j38 , orysa-q69y21 , orysa-q75hy1 , orysa-q75hy2 , orysa-Q0J0A4 , orysa-q651a8 , orysa-q652g4 , orysa-q688m8 , orysa-Q6H8G1 , orysi-a2z179 , orysi-a2zef2 , orysi-b8a7e6 , orysi-b8a7e7 , orysi-b8bfe5 , orysi-b8bhp9 , orysj-b9fi05 , orysj-q0djj0 , orysj-q0jaf0 , orysj-q0jga1 , orysj-q0jhi5 , orysj-q5jl22 , orysj-q5jlw7 , orysj-q6h7q9 , orysj-q6yvk6 , orysj-q7f8x1 , orysj-q7xcx3 , orysj-q9fwm6 , orysj-q10j20 , orysj-q10ss2 , orysj-q69uw6 , orysj-q94d71 , orysj-q0iq98 , orysj-b9gbs4 , orysj-b9gbs1

Title : Potent non-nitrile dipeptidic dipeptidyl peptidase IV inhibitors - Simpkins_2007_Bioorg.Med.Chem.Lett_17_6476
Author(s) : Simpkins LM , Bolton S , Pi Z , Sutton JC , Kwon C , Zhao G , Magnin DR , Augeri DJ , Gungor T , Rotella DP , Sun Z , Liu Y , Slusarchyk WS , Marcinkeviciene J , Robertson JG , Wang A , Robl JA , Atwal KS , Zahler RL , Parker RA , Kirby MS , Hamann LG
Ref : Bioorganic & Medicinal Chemistry Lett , 17 :6476 , 2007
Abstract : The synthesis and structure-activity relationships of novel dipeptidyl peptidase IV inhibitors replacing the classical cyanopyrrolidine P1 group with other small nitrogen heterocycles are described. A unique potency enhancement was achieved with beta-branched natural and unnatural amino acids, particularly adamantylglycines, linked to a (2S,3R)-2,3-methanopyrrolidine based scaffold.
ESTHER : Simpkins_2007_Bioorg.Med.Chem.Lett_17_6476
PubMedSearch : Simpkins_2007_Bioorg.Med.Chem.Lett_17_6476
PubMedID: 17937986

Title : Seco-prolinenitrile inhibitors of dipeptidyl peptidase IV define minimal pharmacophore requirements at P1 - Magnin_2006_Bioorg.Med.Chem.Lett_16_1731
Author(s) : Magnin DR , Taunk PC , Robertson JG , Wang A , Marcinkeviciene J , Kirby MS , Hamann LG
Ref : Bioorganic & Medicinal Chemistry Lett , 16 :1731 , 2006
Abstract : A series of seco-prolinenitrile-containing dipeptides were synthesized and assayed as inhibitors of the N-terminal sequence-specific serine protease dipeptidyl peptidase IV, a promising new target for treatment of type 2 diabetes. The inhibitors described herein assess the minimum structural requirements at P1 for this enzyme, resulting in the identification of inhibitors with low nM potency.
ESTHER : Magnin_2006_Bioorg.Med.Chem.Lett_16_1731
PubMedSearch : Magnin_2006_Bioorg.Med.Chem.Lett_16_1731
PubMedID: 16376077

Title : Discovery and preclinical profile of Saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes - Augeri_2005_J.Med.Chem_48_5025
Author(s) : Augeri DJ , Robl JA , Betebenner DA , Magnin DR , Khanna A , Robertson JG , Wang A , Simpkins LM , Taunk P , Huang Q , Han SP , Abboa-Offei B , Cap M , Xin L , Tao L , Tozzo E , Welzel GE , Egan DM , Marcinkeviciene J , Chang SY , Biller SA , Kirby MS , Parker RA , Hamann LG
Ref : Journal of Medicinal Chemistry , 48 :5025 , 2005
Abstract : Efforts to further elucidate structure-activity relationships (SAR) within our previously disclosed series of beta-quaternary amino acid linked l-cis-4,5-methanoprolinenitrile dipeptidyl peptidase IV (DPP-IV) inhibitors led to the investigation of vinyl substitution at the beta-position of alpha-cycloalkyl-substituted glycines. Despite poor systemic exposure, vinyl-substituted compounds showed extended duration of action in acute rat ex vivo plasma DPP-IV inhibition models. Oxygenated putative metabolites were prepared and were shown to exhibit the potency and extended duration of action of their precursors in efficacy models measuring glucose clearance in Zucker(fa/fa) rats. Extension of this approach to adamantylglycine-derived inhibitors led to the discovery of highly potent inhibitors, including hydroxyadamantyl compound BMS-477118 (saxagliptin), a highly efficacious, stable, and long-acting DPP-IV inhibitor, which is currently undergoing clinical trials for treatment of type 2 diabetes.
ESTHER : Augeri_2005_J.Med.Chem_48_5025
PubMedSearch : Augeri_2005_J.Med.Chem_48_5025
PubMedID: 16033281

Title : Probing prime substrate binding sites of human dipeptidyl peptidase-IV using competitive substrate approach - Kopcho_2005_Arch.Biochem.Biophys_436_367
Author(s) : Kopcho LM , Kim YB , Wang A , Liu MA , Kirby MS , Marcinkeviciene J
Ref : Archives of Biochemistry & Biophysics , 436 :367 , 2005
Abstract : Dipeptidyl peptidase-IV is a cell surface protease which plays an important role in glucose homeostasis through proteolytic inactivation of incretin hormones, primarily glucagon like peptide-1 (GLP-1). Substrate N-terminal amino acid (S2-S1) specificity is rather clearly defined, while no substantial information is available on the significance of amino acid interactions towards the C-terminus after the scissile bond (so called prime S1'-S4' or distant S5'-S28' sites). In the present study the increasing length of the peptide towards prime sites (S1'-S4') resulted in approximately 7-fold decrease in Km. Moreover, the Km for GLP-1 cleavage was comparable to that of an S2-S4' peptide, suggesting that few, if any, important enzyme-substrate interactions occur beyond the active site. Effect of substrate length on kcat was less obvious, but kcat/Km showed an increasing trend when His-Ala-pNA (representing the natural two N-terminal residues) was compared to GLP-1. To probe the impact of increasing substrate length on the free energy of activation (as has been suggested for elastase and chymotrypsin) we performed temperature studies. To adequately interpret thermodynamic data we sought to understand what steps limit the kcat expression. Steady-state parameters of the reactions catalyzed by serine proteases are composed of microscopic constants describing binding, acylation, and deacylation steps. Viscosity and pre-steady-state studies suggested that His-Ala-pNA cleavage is limited in the deacylation half-reaction, most likely the product release step. Thus, the free energy of activation, as calculated from the Eyring equation, is underestimated (at least for His-Ala-pNA) and the effect of substrate length on the acylation step (and transition-state stabilization) could not be unambiguously assessed.
ESTHER : Kopcho_2005_Arch.Biochem.Biophys_436_367
PubMedSearch : Kopcho_2005_Arch.Biochem.Biophys_436_367
PubMedID: 15797249

Title : Diprolyl nitriles as potent dipeptidyl peptidase IV inhibitors - Zhao_2005_Bioorg.Med.Chem.Lett_15_3992
Author(s) : Zhao G , Taunk PC , Magnin DR , Simpkins LM , Robl JA , Wang A , Robertson JG , Marcinkeviciene J , Sitkoff DF , Parker RA , Kirby MS , Hamann LG
Ref : Bioorganic & Medicinal Chemistry Lett , 15 :3992 , 2005
Abstract : Dipeptidyl peptidase IV (DPP4) is a multifunctional type II transmembrane serine peptidase which regulates various physiological processes, most notably plasma glucose homeostasis by cleaving peptide hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. Inhibition of DPP4 is a potentially valuable therapy for type 2 diabetes. Synthesis and structure-activity relationships of a series of substituted diprolyl nitriles are described, leading to the identification of compound 1 with a measured DPP4 K(i) of 3.6 nM.
ESTHER : Zhao_2005_Bioorg.Med.Chem.Lett_15_3992
PubMedSearch : Zhao_2005_Bioorg.Med.Chem.Lett_15_3992
PubMedID: 16046120

Title : Sequence, annotation, and analysis of synteny between rice chromosome 3 and diverged grass species - Buell_2005_Genome.Res_15_1284
Author(s) : Buell CR , Yuan Q , Ouyang S , Liu J , Zhu W , Wang A , Maiti R , Haas B , Wortman J , Pertea M , Jones KM , Kim M , Overton L , Tsitrin T , Fadrosh D , Bera J , Weaver B , Jin S , Johri S , Reardon M , Webb K , Hill J , Moffat K , Tallon L , Van Aken S , Lewis M , Utterback T , Feldblyum T , Zismann V , Iobst S , Hsiao J , de Vazeille AR , Salzberg SL , White O , Fraser C , Yu Y , Kim H , Rambo T , Currie J , Collura K , Kernodle-Thompson S , Wei F , Kudrna K , Ammiraju JS , Luo M , Goicoechea JL , Wing RA , Henry D , Oates R , Palmer M , Pries G , Saski C , Simmons J , Soderlund C , Nelson W , de la Bastide M , Spiegel L , Nascimento L , Huang E , Preston R , Zutavern T , Palmer LE , O'Shaughnessy A , Dike S , McCombie WR , Minx P , Cordum H , Wilson R , Jin W , Lee HR , Jiang J , Jackson S
Ref : Genome Res , 15 :1284 , 2005
Abstract : Rice (Oryza sativa L.) chromosome 3 is evolutionarily conserved across the cultivated cereals and shares large blocks of synteny with maize and sorghum, which diverged from rice more than 50 million years ago. To begin to completely understand this chromosome, we sequenced, finished, and annotated 36.1 Mb ( approximately 97%) from O. sativa subsp. japonica cv Nipponbare. Annotation features of the chromosome include 5915 genes, of which 913 are related to transposable elements. A putative function could be assigned to 3064 genes, with another 757 genes annotated as expressed, leaving 2094 that encode hypothetical proteins. Similarity searches against the proteome of Arabidopsis thaliana revealed putative homologs for 67% of the chromosome 3 proteins. Further searches of a nonredundant amino acid database, the Pfam domain database, plant Expressed Sequence Tags, and genomic assemblies from sorghum and maize revealed only 853 nontransposable element related proteins from chromosome 3 that lacked similarity to other known sequences. Interestingly, 426 of these have a paralog within the rice genome. A comparative physical map of the wild progenitor species, Oryza nivara, with japonica chromosome 3 revealed a high degree of sequence identity and synteny between these two species, which diverged approximately 10,000 years ago. Although no major rearrangements were detected, the deduced size of the O. nivara chromosome 3 was 21% smaller than that of japonica. Synteny between rice and other cereals using an integrated maize physical map and wheat genetic map was strikingly high, further supporting the use of rice and, in particular, chromosome 3, as a model for comparative studies among the cereals.
ESTHER : Buell_2005_Genome.Res_15_1284
PubMedSearch : Buell_2005_Genome.Res_15_1284
PubMedID: 16109971
Gene_locus related to this paper: orysa-Q852M6 , orysa-Q8S5X5 , orysa-Q84QZ6 , orysa-Q84QY7 , orysa-Q851E3 , orysa-q6ave2 , orysj-cgep , orysj-q0dud7 , orysj-q10j20 , orysj-q10ss2

Title : Synthesis of novel potent dipeptidyl peptidase IV inhibitors with enhanced chemical stability: interplay between the N-terminal amino acid alkyl side chain and the cyclopropyl group of alpha-aminoacyl-l-cis-4,5-methanoprolinenitrile-based inhibitors - Magnin_2004_J.Med.Chem_47_2587
Author(s) : Magnin DR , Robl JA , Sulsky RB , Augeri DJ , Huang Y , Simpkins LM , Taunk PC , Betebenner DA , Robertson JG , Abboa-Offei BE , Wang A , Cap M , Xin L , Tao L , Sitkoff DF , Malley MF , Gougoutas JZ , Khanna A , Huang Q , Han SP , Parker RA , Hamann LG
Ref : Journal of Medicinal Chemistry , 47 :2587 , 2004
Abstract : A series of methanoprolinenitrile-containing dipeptide mimetics were synthesized and assayed as inhibitors of the N-terminal sequence-specific serine protease dipeptidyl peptidase IV (DPP-IV). The catalytic action of DPP-IV is the principle means of degradation of glucagon-like peptide-1, a key mediator of glucose-stimulated insulin secretion, and DPP-IV inhibition shows clinical benefit as a novel mechanism for treatment of type 2 diabetes. However, many of the reversible inhibitors to date suffer from chemical instability stemming from an amine to nitrile intramolecular cyclization. Installation of a cyclopropyl moiety at either the 3,4- or 4,5-position of traditional 2-cyanopyrrolidide proline mimetics led to compounds with potent inhibitory activity against the enzyme. Additionally, cis-4,5-methanoprolinenitriles with beta-branching in the N-terminal amino acid provided enhanced chemical stability and high inhibitory potency. This class of inhibitors also exhibited the ability to suppress prandial glucose elevations after an oral glucose challenge in male Zucker rats.
ESTHER : Magnin_2004_J.Med.Chem_47_2587
PubMedSearch : Magnin_2004_J.Med.Chem_47_2587
PubMedID: 15115400

Title : The genome sequence of the malaria mosquito Anopheles gambiae - Holt_2002_Science_298_129
Author(s) : Holt RA , Subramanian GM , Halpern A , Sutton GG , Charlab R , Nusskern DR , Wincker P , Clark AG , Ribeiro JM , Wides R , Salzberg SL , Loftus B , Yandell M , Majoros WH , Rusch DB , Lai Z , Kraft CL , Abril JF , Anthouard V , Arensburger P , Atkinson PW , Baden H , de Berardinis V , Baldwin D , Benes V , Biedler J , Blass C , Bolanos R , Boscus D , Barnstead M , Cai S , Center A , Chaturverdi K , Christophides GK , Chrystal MA , Clamp M , Cravchik A , Curwen V , Dana A , Delcher A , Dew I , Evans CA , Flanigan M , Grundschober-Freimoser A , Friedli L , Gu Z , Guan P , Guigo R , Hillenmeyer ME , Hladun SL , Hogan JR , Hong YS , Hoover J , Jaillon O , Ke Z , Kodira C , Kokoza E , Koutsos A , Letunic I , Levitsky A , Liang Y , Lin JJ , Lobo NF , Lopez JR , Malek JA , McIntosh TC , Meister S , Miller J , Mobarry C , Mongin E , Murphy SD , O'Brochta DA , Pfannkoch C , Qi R , Regier MA , Remington K , Shao H , Sharakhova MV , Sitter CD , Shetty J , Smith TJ , Strong R , Sun J , Thomasova D , Ton LQ , Topalis P , Tu Z , Unger MF , Walenz B , Wang A , Wang J , Wang M , Wang X , Woodford KJ , Wortman JR , Wu M , Yao A , Zdobnov EM , Zhang H , Zhao Q , Zhao S , Zhu SC , Zhimulev I , Coluzzi M , della Torre A , Roth CW , Louis C , Kalush F , Mural RJ , Myers EW , Adams MD , Smith HO , Broder S , Gardner MJ , Fraser CM , Birney E , Bork P , Brey PT , Venter JC , Weissenbach J , Kafatos FC , Collins FH , Hoffman SL
Ref : Science , 298 :129 , 2002
Abstract : Anopheles gambiae is the principal vector of malaria, a disease that afflicts more than 500 million people and causes more than 1 million deaths each year. Tenfold shotgun sequence coverage was obtained from the PEST strain of A. gambiae and assembled into scaffolds that span 278 million base pairs. A total of 91% of the genome was organized in 303 scaffolds; the largest scaffold was 23.1 million base pairs. There was substantial genetic variation within this strain, and the apparent existence of two haplotypes of approximately equal frequency ("dual haplotypes") in a substantial fraction of the genome likely reflects the outbred nature of the PEST strain. The sequence produced a conservative inference of more than 400,000 single-nucleotide polymorphisms that showed a markedly bimodal density distribution. Analysis of the genome sequence revealed strong evidence for about 14,000 protein-encoding transcripts. Prominent expansions in specific families of proteins likely involved in cell adhesion and immunity were noted. An expressed sequence tag analysis of genes regulated by blood feeding provided insights into the physiological adaptations of a hematophagous insect.
ESTHER : Holt_2002_Science_298_129
PubMedSearch : Holt_2002_Science_298_129
PubMedID: 12364791
Gene_locus related to this paper: anoga-a0nb77 , anoga-a0nbp6 , anoga-a0neb7 , anoga-a0nei9 , anoga-a0nej0 , anoga-a0ngj1 , anoga-a7ut12 , anoga-a7uuz9 , anoga-ACHE1 , anoga-ACHE2 , anoga-agCG44620 , anoga-agCG44666 , anoga-agCG45273 , anoga-agCG45279 , anoga-agCG45511 , anoga-agCG46741 , anoga-agCG47651 , anoga-agCG47655 , anoga-agCG47661 , anoga-agCG47690 , anoga-agCG48797 , anoga-AGCG49362 , anoga-agCG49462 , anoga-agCG49870 , anoga-agCG49872 , anoga-agCG49876 , anoga-agCG50851 , anoga-agCG51879 , anoga-agCG52383 , anoga-agCG54954 , anoga-AGCG55021 , anoga-agCG55401 , anoga-agCG55408 , anoga-agCG56978 , anoga-ebiG239 , anoga-ebiG2660 , anoga-ebiG5718 , anoga-ebiG5974 , anoga-ebiG8504 , anoga-ebiG8742 , anoga-glita , anoga-nrtac , anoga-q5tpv0 , anoga-Q5TVS6 , anoga-q7pm39 , anoga-q7ppw9 , anoga-q7pq17 , anoga-Q7PQT0 , anoga-q7q8m4 , anoga-q7q626 , anoga-q7qa14 , anoga-q7qa52 , anoga-q7qal7 , anoga-q7qbj0 , anoga-f5hl20 , anoga-q7qkh2 , anoga-a0a1s4h1y7 , anoga-q7q887

Title : A comparison of whole-genome shotgun-derived mouse chromosome 16 and the human genome - Mural_2002_Science_296_1661
Author(s) : Mural RJ , Adams MD , Myers EW , Smith HO , Miklos GL , Wides R , Halpern A , Li PW , Sutton GG , Nadeau J , Salzberg SL , Holt RA , Kodira CD , Lu F , Chen L , Deng Z , Evangelista CC , Gan W , Heiman TJ , Li J , Li Z , Merkulov GV , Milshina NV , Naik AK , Qi R , Shue BC , Wang A , Wang J , Wang X , Yan X , Ye J , Yooseph S , Zhao Q , Zheng L , Zhu SC , Biddick K , Bolanos R , Delcher AL , Dew IM , Fasulo D , Flanigan MJ , Huson DH , Kravitz SA , Miller JR , Mobarry CM , Reinert K , Remington KA , Zhang Q , Zheng XH , Nusskern DR , Lai Z , Lei Y , Zhong W , Yao A , Guan P , Ji RR , Gu Z , Wang ZY , Zhong F , Xiao C , Chiang CC , Yandell M , Wortman JR , Amanatides PG , Hladun SL , Pratts EC , Johnson JE , Dodson KL , Woodford KJ , Evans CA , Gropman B , Rusch DB , Venter E , Wang M , Smith TJ , Houck JT , Tompkins DE , Haynes C , Jacob D , Chin SH , Allen DR , Dahlke CE , Sanders R , Li K , Liu X , Levitsky AA , Majoros WH , Chen Q , Xia AC , Lopez JR , Donnelly MT , Newman MH , Glodek A , Kraft CL , Nodell M , Ali F , An HJ , Baldwin-Pitts D , Beeson KY , Cai S , Carnes M , Carver A , Caulk PM , Center A , Chen YH , Cheng ML , Coyne MD , Crowder M , Danaher S , Davenport LB , Desilets R , Dietz SM , Doup L , Dullaghan P , Ferriera S , Fosler CR , Gire HC , Gluecksmann A , Gocayne JD , Gray J , Hart B , Haynes J , Hoover J , Howland T , Ibegwam C , Jalali M , Johns D , Kline L , Ma DS , MacCawley S , Magoon A , Mann F , May D , McIntosh TC , Mehta S , Moy L , Moy MC , Murphy BJ , Murphy SD , Nelson KA , Nuri Z , Parker KA , Prudhomme AC , Puri VN , Qureshi H , Raley JC , Reardon MS , Regier MA , Rogers YH , Romblad DL , Schutz J , Scott JL , Scott R , Sitter CD , Smallwood M , Sprague AC , Stewart E , Strong RV , Suh E , Sylvester K , Thomas R , Tint NN , Tsonis C , Wang G , Williams MS , Williams SM , Windsor SM , Wolfe K , Wu MM , Zaveri J , Chaturvedi K , Gabrielian AE , Ke Z , Sun J , Subramanian G , Venter JC , Pfannkoch CM , Barnstead M , Stephenson LD
Ref : Science , 296 :1661 , 2002
Abstract : The high degree of similarity between the mouse and human genomes is demonstrated through analysis of the sequence of mouse chromosome 16 (Mmu 16), which was obtained as part of a whole-genome shotgun assembly of the mouse genome. The mouse genome is about 10% smaller than the human genome, owing to a lower repetitive DNA content. Comparison of the structure and protein-coding potential of Mmu 16 with that of the homologous segments of the human genome identifies regions of conserved synteny with human chromosomes (Hsa) 3, 8, 12, 16, 21, and 22. Gene content and order are highly conserved between Mmu 16 and the syntenic blocks of the human genome. Of the 731 predicted genes on Mmu 16, 509 align with orthologs on the corresponding portions of the human genome, 44 are likely paralogous to these genes, and 164 genes have homologs elsewhere in the human genome; there are 14 genes for which we could find no human counterpart.
ESTHER : Mural_2002_Science_296_1661
PubMedSearch : Mural_2002_Science_296_1661
PubMedID: 12040188
Gene_locus related to this paper: mouse-ABH15 , mouse-Ces3b , mouse-Ces4a , mouse-dpp4 , mouse-FAP , mouse-Lipg , mouse-Q8C1A9 , mouse-rbbp9 , mouse-SERHL , mouse-SPG21 , mouse-w4vsp6

Title : The sequence of the human genome - Venter_2001_Science_291_1304
Author(s) : Venter JC , Adams MD , Myers EW , Li PW , Mural RJ , Sutton GG , Smith HO , Yandell M , Evans CA , Holt RA , Gocayne JD , Amanatides P , Ballew RM , Huson DH , Wortman JR , Zhang Q , Kodira CD , Zheng XH , Chen L , Skupski M , Subramanian G , Thomas PD , Zhang J , Gabor Miklos GL , Nelson C , Broder S , Clark AG , Nadeau J , McKusick VA , Zinder N , Levine AJ , Roberts RJ , Simon M , Slayman C , Hunkapiller M , Bolanos R , Delcher A , Dew I , Fasulo D , Flanigan M , Florea L , Halpern A , Hannenhalli S , Kravitz S , Levy S , Mobarry C , Reinert K , Remington K , Abu-Threideh J , Beasley E , Biddick K , Bonazzi V , Brandon R , Cargill M , Chandramouliswaran I , Charlab R , Chaturvedi K , Deng Z , Di Francesco V , Dunn P , Eilbeck K , Evangelista C , Gabrielian AE , Gan W , Ge W , Gong F , Gu Z , Guan P , Heiman TJ , Higgins ME , Ji RR , Ke Z , Ketchum KA , Lai Z , Lei Y , Li Z , Li J , Liang Y , Lin X , Lu F , Merkulov GV , Milshina N , Moore HM , Naik AK , Narayan VA , Neelam B , Nusskern D , Rusch DB , Salzberg S , Shao W , Shue B , Sun J , Wang Z , Wang A , Wang X , Wang J , Wei M , Wides R , Xiao C , Yan C , Yao A , Ye J , Zhan M , Zhang W , Zhang H , Zhao Q , Zheng L , Zhong F , Zhong W , Zhu S , Zhao S , Gilbert D , Baumhueter S , Spier G , Carter C , Cravchik A , Woodage T , Ali F , An H , Awe A , Baldwin D , Baden H , Barnstead M , Barrow I , Beeson K , Busam D , Carver A , Center A , Cheng ML , Curry L , Danaher S , Davenport L , Desilets R , Dietz S , Dodson K , Doup L , Ferriera S , Garg N , Gluecksmann A , Hart B , Haynes J , Haynes C , Heiner C , Hladun S , Hostin D , Houck J , Howland T , Ibegwam C , Johnson J , Kalush F , Kline L , Koduru S , Love A , Mann F , May D , McCawley S , McIntosh T , McMullen I , Moy M , Moy L , Murphy B , Nelson K , Pfannkoch C , Pratts E , Puri V , Qureshi H , Reardon M , Rodriguez R , Rogers YH , Romblad D , Ruhfel B , Scott R , Sitter C , Smallwood M , Stewart E , Strong R , Suh E , Thomas R , Tint NN , Tse S , Vech C , Wang G , Wetter J , Williams S , Williams M , Windsor S , Winn-Deen E , Wolfe K , Zaveri J , Zaveri K , Abril JF , Guigo R , Campbell MJ , Sjolander KV , Karlak B , Kejariwal A , Mi H , Lazareva B , Hatton T , Narechania A , Diemer K , Muruganujan A , Guo N , Sato S , Bafna V , Istrail S , Lippert R , Schwartz R , Walenz B , Yooseph S , Allen D , Basu A , Baxendale J , Blick L , Caminha M , Carnes-Stine J , Caulk P , Chiang YH , Coyne M , Dahlke C , Mays A , Dombroski M , Donnelly M , Ely D , Esparham S , Fosler C , Gire H , Glanowski S , Glasser K , Glodek A , Gorokhov M , Graham K , Gropman B , Harris M , Heil J , Henderson S , Hoover J , Jennings D , Jordan C , Jordan J , Kasha J , Kagan L , Kraft C , Levitsky A , Lewis M , Liu X , Lopez J , Ma D , Majoros W , McDaniel J , Murphy S , Newman M , Nguyen T , Nguyen N , Nodell M , Pan S , Peck J , Peterson M , Rowe W , Sanders R , Scott J , Simpson M , Smith T , Sprague A , Stockwell T , Turner R , Venter E , Wang M , Wen M , Wu D , Wu M , Xia A , Zandieh A , Zhu X
Ref : Science , 291 :1304 , 2001
Abstract : A 2.91-billion base pair (bp) consensus sequence of the euchromatic portion of the human genome was generated by the whole-genome shotgun sequencing method. The 14.8-billion bp DNA sequence was generated over 9 months from 27,271,853 high-quality sequence reads (5.11-fold coverage of the genome) from both ends of plasmid clones made from the DNA of five individuals. Two assembly strategies-a whole-genome assembly and a regional chromosome assembly-were used, each combining sequence data from Celera and the publicly funded genome effort. The public data were shredded into 550-bp segments to create a 2.9-fold coverage of those genome regions that had been sequenced, without including biases inherent in the cloning and assembly procedure used by the publicly funded group. This brought the effective coverage in the assemblies to eightfold, reducing the number and size of gaps in the final assembly over what would be obtained with 5.11-fold coverage. The two assembly strategies yielded very similar results that largely agree with independent mapping data. The assemblies effectively cover the euchromatic regions of the human chromosomes. More than 90% of the genome is in scaffold assemblies of 100,000 bp or more, and 25% of the genome is in scaffolds of 10 million bp or larger. Analysis of the genome sequence revealed 26,588 protein-encoding transcripts for which there was strong corroborating evidence and an additional approximately 12,000 computationally derived genes with mouse matches or other weak supporting evidence. Although gene-dense clusters are obvious, almost half the genes are dispersed in low G+C sequence separated by large tracts of apparently noncoding sequence. Only 1.1% of the genome is spanned by exons, whereas 24% is in introns, with 75% of the genome being intergenic DNA. Duplications of segmental blocks, ranging in size up to chromosomal lengths, are abundant throughout the genome and reveal a complex evolutionary history. Comparative genomic analysis indicates vertebrate expansions of genes associated with neuronal function, with tissue-specific developmental regulation, and with the hemostasis and immune systems. DNA sequence comparisons between the consensus sequence and publicly funded genome data provided locations of 2.1 million single-nucleotide polymorphisms (SNPs). A random pair of human haploid genomes differed at a rate of 1 bp per 1250 on average, but there was marked heterogeneity in the level of polymorphism across the genome. Less than 1% of all SNPs resulted in variation in proteins, but the task of determining which SNPs have functional consequences remains an open challenge.
ESTHER : Venter_2001_Science_291_1304
PubMedSearch : Venter_2001_Science_291_1304
PubMedID: 11181995
Gene_locus related to this paper: human-AADAC , human-ABHD1 , human-ABHD10 , human-ABHD11 , human-ACHE , human-BCHE , human-LDAH , human-ABHD18 , human-CMBL , human-ABHD17A , human-KANSL3 , human-LIPA , human-LYPLAL1 , human-NDRG2 , human-NLGN3 , human-NLGN4X , human-NLGN4Y , human-PAFAH2 , human-PREPL , human-RBBP9 , human-SPG21

Title : A specific human lysophospholipase: cDNA cloning, tissue distribution and kinetic characterization - Wang_1999_Biochim.Biophys.Acta_1437_157
Author(s) : Wang A , Yang HC , Friedman P , Johnson CA , Dennis EA
Ref : Biochimica & Biophysica Acta , 1437 :157 , 1999
Abstract : Lysophospholipases are critical enzymes that act on biological membranes to regulate the multifunctional lysophospholipids; increased levels of lysophospholipids are associated with a host of diseases. Herein we report the cDNA cloning of a human brain 25 kDa lysophospholipid-specific lysophospholipase (hLysoPLA). The enzyme (at both mRNA and protein levels) is widely distributed in tissues, but with quite different abundances. The hLysoPLA hydrolyzes lysophosphatidylcholine in both monomeric and micellar forms, and exhibits apparent cooperativity and surface dilution kinetics, but not interfacial activation. Detailed kinetic analysis indicates that the hLysoPLA binds first to the micellar surface and then to the substrate presented on the surface. The kinetic parameters associated with this surface dilution kinetic model are reported, and it is concluded that hLysoPLA has a single substrate binding site and a surface recognition site. The apparent cooperativity observed is likely due to the change of substrate presentation. In contrast to many non-specific lipolytic enzymes that exhibit lysophospholipase activity, hLysoPLA hydrolyzes only lysophospholipids and has no other significant enzymatic activity. Of special interest, hLysoPLA does not act on plasmenylcholine. Of the several inhibitors tested, only methyl arachidonyl fluorophosphonate (MAFP) potently and irreversibly inhibits the enzymatic activity. The inhibition by MAFP is consistent with the catalytic mechanism proposed for the enzyme - a serine hydrolase with a catalytic triad composed of Ser-119, Asp-174 and His-208.
ESTHER : Wang_1999_Biochim.Biophys.Acta_1437_157
PubMedSearch : Wang_1999_Biochim.Biophys.Acta_1437_157
PubMedID: 10064899
Gene_locus related to this paper: human-LYPLA1

Title : Cloning, expression, and catalytic mechanism of murine lysophospholipase I - Wang_1997_J.Biol.Chem_272_12723
Author(s) : Wang A , Deems RA , Dennis EA
Ref : Journal of Biological Chemistry , 272 :12723 , 1997
Abstract : A lysophospholipase (LysoPLA I) has been purified and characterized from the mouse macrophage-like P388D1 cell line (Zhang, Y. Y, and Dennis, E. A. (1988) J. Biol. Chem. 263, 9965-9972). This enzyme has now been sequenced, cloned, and expressed in Escherichia coli cells. The enzyme contains 230 amino acid residues with a calculated molecular mass of 24.7 kDa. It has a high helical content in its predicated secondary structure, which is also indicated in its CD spectrum. The cloned LysoPLA I was purified to homogeneity from the transformed E. coli cells by a gel filtration column and an ion exchange column. The specific activity of the purified protein is 1. 47 micromol/min.mg toward 1-palmitoyl-sn-glycero-3-phosphorylcholine at pH 8.0 and 40 degrees C, corresponding to the reported value of 1.3-1.7 micromol/min.mg for the protein purified from the P388D1 cells. In addition, the cloned protein cross-reacted with an antibody raised against LysoPLA I also purified from the P388D1 cells. The deduced LysoPLA I sequence contains a well conserved GXSXG motif found in the active site of many serine enzymes, and the activity of the LysoPLA I was irreversibly inhibited by the classical serine protease inhibitor diisopropyl fluorophosphate. Furthermore, site-directed mutagenesis was employed to change Ser-119 in the GXSXG motif to an Ala. The resulting mutant protein lost all of its lysophospholipase activity, even though it had the same overall protein conformation as that of the wild-type LysoPLA I. Therefore, LysoPLA I has been demonstrated to be a serine enzyme with Ser-119 at the active site.
ESTHER : Wang_1997_J.Biol.Chem_272_12723
PubMedSearch : Wang_1997_J.Biol.Chem_272_12723
PubMedID: 9139730
Gene_locus related to this paper: mouse-lypla1

Title : Regiospecificity and catalytic triad of lysophospholipase I - Wang_1997_J.Biol.Chem_272_22030
Author(s) : Wang A , Loo R , Chen Z , Dennis EA
Ref : Journal of Biological Chemistry , 272 :22030 , 1997
Abstract : A 25-kDa murine lysophospholipase (LysoPLA I) has been cloned and expressed, and Ser-119 has been shown to be essential for the enzyme activity (Wang, A., Deems, R. A., and Dennis, E. A. (1997) J. Biol. Chem. 272, 12723-12729). In the present study, we show that LysoPLA I represents a new member of the serine hydrolase family with Ser-119, Asp-174, and His-208 composing the catalytic triad. The Asp-174 and His-208 are conserved among several esterases and are demonstrated herein to be essential for LysoPLA I activity as the mutation of either residue to Ala abolished LysoPLA I activity, whereas the global conformation of the mutants remained unchanged. Furthermore, the predicted secondary structure of LysoPLA I resembles that of the alpha/beta-hydrolase fold, with Ser-119, Asp-174, and His-208 occupying the conserved topological location of the catalytic triad in the alpha/beta-hydrolases. Structural modeling of LysoPLA I also indicates that the above three residues orient in such a manner that they would comprise a charge-relay network necessary for catalysis. In addition, the regiospecificity of LysoPLA I was studied using 31P NMR, and the result shows that LysoPLA I has similar LysoPLA1 and LysoPLA2 activity. This finding suggests that LysoPLA I may play an important role in removing lysophospholipids produced by both phospholipase A1 and A2 in vivo.
ESTHER : Wang_1997_J.Biol.Chem_272_22030
PubMedSearch : Wang_1997_J.Biol.Chem_272_22030
PubMedID: 9268342
Gene_locus related to this paper: mouse-lypla1