Fang L

References (42)

Title : Cardioprotective Response and Senescence in Aged sEH Null Female Mice Exposed to LPS - Yousef_2024_Am.J.Physiol.Heart.Circ.Physiol__
Author(s) : Yousef A , Sosnowski DK , Fang L , Legaspi RJ , Korodimas J , Lee A , Magor KE , Seubert JM
Ref : American Journal of Physiology Heart Circ Physiol , : , 2024
Abstract : Deterioration of physiological systems, like the cardiovascular system, occurs progressively with age impacting an individual's health and increasing susceptibility to injury and disease. Cellular senescence has an underlying role in age-related alterations and can be triggered by natural aging or prematurely by stressors such as the bacterial toxin, lipopolysaccharide (LPS). The metabolism of polyunsaturated fatty acids (PUFAs) by CYP450 enzymes produces numerous bioactive lipid mediators that can be further metabolized by soluble epoxide hydrolase (sEH) into diol metabolites, often with reduced biological effects. In our study, we observed age-related cardiac differences in female mice, where young mice demonstrated resistance to LPS injury, and genetic deletion or pharmacological inhibition of sEH using trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (tAUCB) attenuated LPS-induced cardiac dysfunction in aged female mice. Bulk RNA-sequencing analyses revealed transcriptomics differences in aged female hearts. Confirmatory analysis demonstrated changes to inflammatory and senescence genes markers such as Il-6, Mcp1, Il-1beta, Nlrp3, p21, p16, SA-beta-gal, and Gdf15 were attenuated in the hearts of aged female mice where sEH was deleted or inhibited. Collectively, these findings highlight the role of sEH in modulating the aging process of the heart, whereby targeting sEH is cardioprotective.
ESTHER : Yousef_2024_Am.J.Physiol.Heart.Circ.Physiol__
PubMedSearch : Yousef_2024_Am.J.Physiol.Heart.Circ.Physiol__
PubMedID: 38578240

Title : Case Report: Telitacicept in severe myasthenia gravis: a case study with multiple autoantibodies - Guo_2023_Front.Immunol_14_1270011
Author(s) : Guo Q , Huang Y , Wang F , Fang L
Ref : Front Immunol , 14 :1270011 , 2023
Abstract : Multi-antibody-positive myasthenia gravis (MG) presentations are relatively rare, often found in older patients, and generally predict a poor prognosis. We report a case of a female patient with generalized MG, testing positive for Titin antibodies (Titin-Ab), ryanodine receptor antibodies (RyR-Ab), and acetylcholine receptor antibodies (AChR-Ab), and resistant to acetylcholinesterase inhibitors. Following unsuccessful traditional therapies, she received Telitacicept, leading to significant improvements. This case underscores Telitacicept's potential efficacy for similar patients and offers insights into the clinical characteristics of multi-antibody MG.
ESTHER : Guo_2023_Front.Immunol_14_1270011
PubMedSearch : Guo_2023_Front.Immunol_14_1270011
PubMedID: 38124751

Title : Identification of the Flavone-Inducible Counter-Defense Genes and Their cis-Elements in Helicoverpa armigera - Deng_2023_Toxins.(Basel)_15_
Author(s) : Deng Z , Zhang Y , Fang L , Zhang M , Wang L , Ni X , Li X
Ref : Toxins (Basel) , 15 : , 2023
Abstract : Flavone is widely found in plants and plays an important role in plant defense against pests. Many pests, such as Helicoverpa armigera, use flavone as a cue to upregulate counter-defense genes for detoxification of flavone. Yet the spectrum of the flavone-inducible genes and their linked cis-regulatory elements remains unclear. In this study, 48 differentially expressed genes (DEGs) were found by RNA-seq. These DEGs were mainly concentrated in the retinol metabolism and drug metabolism-cytochrome P450 pathways. Further in silico analysis of the promoter regions of 24 upregulated genes predicted two motifs through MEME and five previously characterized cis-elements including CRE, TRE, EcRE, XRE-AhR and ARE. Functional analysis of the two predicted motifs and two different versions of ARE (named ARE1 and ARE2) in the promoter region of the flavone-inducible carboxylesterase gene CCE001j verified that the two motifs and ARE2 are not responsible for flavone induction of H. armigera counter-defense genes, whereas ARE1 is a new xenobiotic response element to flavone (XRE-Fla) and plays a decisive role in flavone induction of CCE001j. This study is of great significance for further understanding the antagonistic interaction between plants and herbivorous insects.
ESTHER : Deng_2023_Toxins.(Basel)_15_
PubMedSearch : Deng_2023_Toxins.(Basel)_15_
PubMedID: 37368666

Title : Identification and characterization of novel carboxyl ester lipase gene variants in patients with different subtypes of diabetes - Wu_2023_BMJ.Open.Diabetes.Res.Care_11_e003127
Author(s) : Wu H , Shu M , Liu C , Zhao W , Li Q , Song Y , Zhang T , Chen X , Shi Y , Shi P , Fang L , Wang R , Xu C
Ref : BMJ Open Diabetes Res Care , 11 : , 2023
Abstract : INTRODUCTION: Mutations of CEL gene were first reported to cause a new type of maturity-onset diabetes of the young (MODY) denoted as MODY8 and then were also found in patients with type 1 (T1D) and type 2 diabetes (T2D). However, its genotype-phenotype relationship has not been fully determined and how carboxyl ester lipase (CEL) variants result in diabetes remains unclear. The aim of our study was to identify pathogenic variants of CEL in patients with diabetes and confirm their pathogenicity. RESEARCH DESIGN AND METHODS: All five patients enrolled in our study were admitted to Shandong Provincial Hospital and diagnosed with diabetes in the past year. Whole-exome sequencing was performed to identify pathogenic variants in three patients with MODY-like diabetes, one newborn baby with T1D and one patient with atypical T2D, as well as their immediate family members. Then the consequences of the identified variants were predicted by bioinformatic analysis. Furthermore, pathogenic effects of two novel CEL variants were evaluated in HEK293 cells transfected with wild-type and mutant plasmids. Finally, we summarized all CEL gene variants recorded in Human Gene Mutation Database and analyzed the mutation distribution of CEL. RESULTS: Five novel heterozygous variants were identified in CEL gene and they were predicted to be pathogenic by bioinformatic analysis. Moreover, in vitro studies indicated that the expression of CEL(R540C) was remarkably increased, while p.G729_T739del variant did not significantly affect the expression of CEL. Both novel variants obviously abrogated the secretion of CEL. Furthermore, we summarized all reported CEL variants and found that 74.3% of missense mutations were located in exons 1, 3, 4, 10 and 11 and most missense variants clustered near catalytic triad, Arg-83 and Arg-443. CONCLUSION: Our study identified five novel CEL variants in patients with different subtypes of diabetes, expanding the gene mutation spectrum of CEL and confirmed the pathogenicity of several novel variants.
ESTHER : Wu_2023_BMJ.Open.Diabetes.Res.Care_11_e003127
PubMedSearch : Wu_2023_BMJ.Open.Diabetes.Res.Care_11_e003127
PubMedID: 36634979
Gene_locus related to this paper: human-CEL

Title : Identification and Characterization of Two Novel Compounds: Heterozygous Variants of Lipoprotein Lipase in Two Pedigrees With Type I Hyperlipoproteinemia - Wang_2022_Front.Endocrinol.(Lausanne)_13_874608
Author(s) : Wang S , Cheng Y , Shi Y , Zhao W , Gao L , Fang L , Jin X , Han X , Sun Q , Li G , Zhao J , Xu C
Ref : Front Endocrinol (Lausanne) , 13 :874608 , 2022
Abstract : BACKGROUND: Type I hyperlipoproteinemia, characterized by severe hypertriglyceridemia, is caused mainly by loss-of-function mutation of the lipoprotein lipase (LPL) gene. To date, more than 200 mutations in the LPL gene have been reported, while only a limited number of mutations have been evaluated for pathogenesis. OBJECTIVE: This study aims to explore the molecular mechanisms underlying lipoprotein lipase deficiency in two pedigrees with type 1 hyperlipoproteinemia. METHODS: We conducted a systematic clinical and genetic analysis of two pedigrees with type 1 hyperlipoproteinemia. Postheparin plasma of all the members was used for the LPL activity analysis. In vitro studies were performed in HEK-293T cells that were transiently transfected with wild-type or variant LPL plasmids. Furthermore, the production and activity of LPL were analyzed in cell lysates or culture medium. RESULTS: Proband 1 developed acute pancreatitis in youth, and her serum triglycerides (TGs) continued to be at an ultrahigh level, despite the application of various lipid-lowering drugs. Proband 2 was diagnosed with type 1 hyperlipoproteinemia at 9 months of age, and his serum TG levels were mildly elevated with treatment. Two novel compound heterozygous variants of LPL (c.3G>C, p. M1? and c.835_836delCT, p. L279Vfs*3, c.188C>T, p. Ser63Phe and c.662T>C, p. Ile221Thr) were identified in the two probands. The postheparin LPL activity of probands 1 and 2 showed decreases of 72.22 +/- 9.46% (p<0.01) and 54.60 +/- 9.03% (p<0.01), respectively, compared with the control. In vitro studies showed a substantial reduction in the expression or enzyme activity of LPL in the LPL variants. CONCLUSIONS: Two novel compound heterozygous variants of LPL induced defects in the expression and function of LPL and caused type I hyperlipoproteinemia. The functional characterization of these variants was in keeping with the postulated LPL mutant activity.
ESTHER : Wang_2022_Front.Endocrinol.(Lausanne)_13_874608
PubMedSearch : Wang_2022_Front.Endocrinol.(Lausanne)_13_874608
PubMedID: 35923617
Gene_locus related to this paper: human-LPL

Title : Blood-Brain Barrier Permeable and NO-Releasing Multifunctional Nanoparticles for Alzheimer's Disease Treatment: Targeting NO\/cGMP\/CREB Signaling Pathways - Liu_2021_J.Med.Chem_64_13853
Author(s) : Liu Z , Liu Q , Zhang B , Fang L , Gou S
Ref : Journal of Medicinal Chemistry , 64 :13853 , 2021
Abstract : The development of novel therapeutic strategies for combating Alzheimer's disease (AD) is challenging but imperative. Multifunctional nanoparticles are promising tools for regulating complex pathological dysfunctions for AD treatment. Herein, we constructed multifunctional nanoparticles consisting of regadenoson (Reg), nitric oxide (NO) donor, and YC-1 in a single molecular entity that can spontaneously self-assemble into nanoparticles and load donepezil to yield Reg-nanoparticles (Reg-NPs). The Reg moiety enabled the Reg-NPs to effectively regulate tight junction-associated proteins in the blood-brain barrier, thus facilitating the permeation of donepezil through the barrier and its accumulation in the brain. Moreover, the released NO and YC-1 activated the NO/cGMP/CREB signaling pathway by stimulating soluble guanylyl cyclase and inhibiting phosphodiesterase activity, which finally reduced cytotoxicity induced by aggregated Abeta in the neurons and was beneficial for synaptic plasticity and memory formation.
ESTHER : Liu_2021_J.Med.Chem_64_13853
PubMedSearch : Liu_2021_J.Med.Chem_64_13853
PubMedID: 34517696

Title : Discovery of 7-O-1, 2, 3-triazole hesperetin derivatives as multi-target-directed ligands against Alzheimer's disease - Wang_2021_Chem.Biol.Interact__109489
Author(s) : Wang M , Fang L , Liu T , Chen X , Zheng Y , Zhang Y , Chen S , Li Z
Ref : Chemico-Biological Interactions , :109489 , 2021
Abstract : The development of multi-target-directed ligands (MTDLs) may improve complex central nervous system diseases such as Alzheimer's disease (AD). Here, a series of 7-O-1, 2, 3-triazole hesperetin derivatives was evaluated for their inhibition of cholinesterase, anti-neuroinflammatory, and neuroprotective activity. Among the hesperetin derivatives, compound a8 (7-O-((1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)hesperetin) possessed excellent anti-butyrylcholinesterase activity (IC(50) = 3.08 +/- 0.29 microM) and exhibited good anti-neuroinflammatory activity (IC(50) = 2.91 +/- 0.47 microM) against NO production through remarkably blocking the NF-kappaB signaling pathway and inhibiting the phosphorylation of P65. In addition, a8 showed a remarkable neuroprotective effect and lacked neurotoxicity up to 50 microM concentration. Furthermore, possessing significant self-mediated Abeta(1-42) aggregation inhibitory activity, chelated biometals and reduced ROS production were found in compound a8. In the bi-directional transport assay, a8 exhibited a blood-brain barrier penetrating ability. In this study, the Morris water maze task showed that compound a8 significantly improved the learning and memory impairment of the scopolamine-induced AD mice model. Results highlighted the potential of compound a8 to be a potential MTDL for the development of anti-AD agents.
ESTHER : Wang_2021_Chem.Biol.Interact__109489
PubMedSearch : Wang_2021_Chem.Biol.Interact__109489
PubMedID: 33905740

Title : ROS-responsive and multifunctional anti-Alzheimer prodrugs: Tacrine-ibuprofen hybrids via a phenyl boronate linker - Liu_2020_Eur.J.Med.Chem__112997
Author(s) : Liu Z , Zhang B , Xia S , Fang L , Gou S
Ref : Eur Journal of Medicinal Chemistry , :112997 , 2020
Abstract : Current drugs available in clinic for Alzheimer's disease (AD) treatment can only alleviate disease symptoms without clearly curing or delaying the process of AD. And some AD drugs failed in Phase III clinical trials are only focused on targeting amyloid-beta (Abeta). Therefore, an alternative strategy in AD drug design is meaningful to be involved in the multiple pathogenic factors which can affect each other at multiple levels. Herein, we report a series of ROS-responsive prodrugs based on multi-target-directed ligands (MTDLs) approach, which can specifically release tacrine derivatives and ibuprofen under oxidation of ROS and show acetylcholinesterase (AChE)-inhibiting, neuron-protective and anti-inflammatory effects in extracellular or intracellular assays. Related biological study illustrated that compound 22 was able to permeate blood-brain-barrier (BBB) showing little hepatotoxicity in comparison to tacrine. Besides, 22 hinted a therapeutic clue in AD-treatment by regulating proinflammatory factors (IL-1beta and TNF-alpha) and apoptosis related proteins (Bax, Bcl-2 and cleaved caspase-3). Further spatial memory assays in Abeta-induced AD model showed that 22 enhanced the ability of learning and memory. Our study proves that the strategy of ROS-responsive prodrugs has promise for AD treatments in future and offers a way for AD drug development.
ESTHER : Liu_2020_Eur.J.Med.Chem__112997
PubMedSearch : Liu_2020_Eur.J.Med.Chem__112997
PubMedID: 33189440

Title : Ecological risk assessment of heavy metals in fish from the Dianchi Lake, China using the integrated biomarker response approach - Gao_2020_Environ.Sci.Pollut.Res.Int_27_45712
Author(s) : Gao Y , Fang L , Xiang QQ , Wang D , Ding LY , Ding CZ , Chen LQ
Ref : Environ Sci Pollut Res Int , 27 :45712 , 2020
Abstract : This study used the integrated biomarker response (IBR) index approach to assess the ecological risks of heavy metals in different regions of Dianchi Lake, combined with active monitoring and passive monitoring. The contents of five heavy metals (Cu, As, Cd, Hg, and Pb) and six biomarkers (acetylcholinesterase, sodium-potassium ATPase, metallothionein, superoxide dismutase, glutathione peroxidase, and malondialdehyde) in the muscles of crucians (Carassius auratus) were measured to calculate the IBR value. The results indicate that the contents of heavy metal in the fish under active monitoring and passive monitoring were rather low and did not exceed the National Food Safety Standards of China. The IBR value of day 14 of active monitoring correlated with the heavy metal Cd content in the fish, suggesting a potential risk of Cd pollution in the aquatic environment of Dianchi Lake. The IBR values obtained for different regions of the lake on day 14 can be arranged in the following order: West S3 (9.24) > East S1 (3.97) > South S2 (2.39) > North S4 (0.36). These results suggest a potential risk of heavy metal contamination in the western part of Dianchi Lake.
ESTHER : Gao_2020_Environ.Sci.Pollut.Res.Int_27_45712
PubMedSearch : Gao_2020_Environ.Sci.Pollut.Res.Int_27_45712
PubMedID: 32803585

Title : Unexpected protonation state of Glu197 discovered from simulations of tacrine in butyrylcholinesterase - Wan_2018_Phys.Chem.Chem.Phys_20_14938
Author(s) : Wan X , Yao Y , Fang L , Liu J
Ref : Phys Chem Chem Phys , 20 :14938 , 2018
Abstract : Butyrylcholinesterase (BChE) has been actively involved in drug discoveries from many fields for decades. In the crystal structure of the BChE-tacrine complex, there is an unanticipated formyl-proline molecule resolved very close to tacrine, raising an essential question on how reliable it is to apply the binding pose in a crystal structure to analyze related experimental observations, in which no formyl-proline is actually involved. In this study, by performing a series of 100 ns molecular dynamics simulations, we demonstrate that it is safe to employ the structural information from this crystal structure to analyze related experimental observations. Surprisingly, Glu197 needs to be protonated to have the structures simulated appropriately. It should be noted that Glu197 has been commonly considered as deprotonated in diverse analyses due to its low pKa in aqueous solution, for which some interpretations are inconsistent or unclear. Our further investigation shows that the protonated Glu197 plays a very important role in preserving His438 within the catalytic triad through stabilizing a highly conserved water molecule. Interestingly, the catalytic triad and Glu197 have been long recognized for possibly deviating largely from the crystal structure, which might be catalytically deficient and is generally considered to result from the difference between the crystal and aqueous environment. Herein, our results suggest that the large deviations of the catalytic triad and Glu197 from the crystal structure are caused by the inappropriate protonation state of Glu197. This finding shall provide an important clue that has been long missing for a better understanding of BChE-related puzzles or even reconsideration of some BChE-catalyzed reaction mechanisms.
ESTHER : Wan_2018_Phys.Chem.Chem.Phys_20_14938
PubMedSearch : Wan_2018_Phys.Chem.Chem.Phys_20_14938
PubMedID: 29786716

Title : Design, synthesis and biological evaluation of multifunctional tacrine-curcumin hybrids as new cholinesterase inhibitors with metal ions-chelating and neuroprotective property - Liu_2017_Bioorg.Med.Chem_25_2387
Author(s) : Liu Z , Fang L , Zhang H , Gou S , Chen L
Ref : Bioorganic & Medicinal Chemistry , 25 :2387 , 2017
Abstract : Total sixteen tacrine-curcumin hybrid compounds were designed and synthesized for the purpose of searching for multifunctional anti-Alzheimer agents. In vitro studies showed that these hybrid compounds showed good cholinesterase inhibitory activity. Particularly, the potency of K3-2 is even beyond tacrine. Some of the compounds exhibited different selectivity on acetylcholinesterase or butyrylcholinesterase due to the structural difference. Thus, the structure and activity relationship is summarized and further discussed based on molecular modeling studies. The ORAC and MTT assays indicated that the hybrid compounds possessed pronounced antioxidant activity and could effectively protect PC12 cells from the H2O2/Abeta42-induced toxicity. Moreover, the hybrid compounds also showed positive metal ions-chelating ability in vitro, suggesting a potential to halt ion-induced Abeta aggregation. All the obtained results demonstrated that the tacrine-curcumin hybrid compounds, in particular compound K3-2, can be considered as potential therapeutic agents for Alzheimer's disease.
ESTHER : Liu_2017_Bioorg.Med.Chem_25_2387
PubMedSearch : Liu_2017_Bioorg.Med.Chem_25_2387
PubMedID: 28302511

Title : Association between L55M polymorphism in Paraoxonase 1 and cancer risk: a meta-analysis based on 21 studies - Chen_2016_Onco.Targets.Ther_9_1151
Author(s) : Chen L , Lu W , Fang L , Xiong H , Wu X , Zhang M , Wu S , Yu D
Ref : Onco Targets Ther , 9 :1151 , 2016
Abstract : L55M polymorphism in Paraoxonase 1 (PON1) has been regarded as a risk factor for many cancer types. Nevertheless, the results remain controversial and inconclusive. We therefore performed a meta-analysis of all eligible case-control studies to evaluate the association between L55M polymorphism and cancer risk. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the associations. Finally, a total of 5,627 cases and 6,390 controls, arising from 21 case-control studies, were enrolled in our study. Significant associations between PON1-L55M polymorphism and overall cancer risk were identified in all genetic models. In the stratified analyses by cancer type, PON1-L55M polymorphism was a risk factor for breast cancer in all genetic models, prostate cancer in the heterozygote model (ML vs LL: OR =1.304, 95% CI =1.049-1.620, P heterogeneity=0.067), and ovarian cancer in the recessive model (MM vs ML/LL: OR =1.526, 95% CI =1.110-2.097, P heterogeneity=0.464). Similarly, an increased risk was also identified for the Caucasian population in the heterozygote comparison and homozygote models, and hospital-based controls in all genetic models. To sum up, our study suggests that the PON1-L55M allele increased the risk of cancer. Future well-designed studies with larger sample sizes are warranted to further verify these findings.
ESTHER : Chen_2016_Onco.Targets.Ther_9_1151
PubMedSearch : Chen_2016_Onco.Targets.Ther_9_1151
PubMedID: 27019599

Title : Ferulic acid-carbazole hybrid compounds: Combination of cholinesterase inhibition, antioxidant and neuroprotection as multifunctional anti-Alzheimer agents - Fang_2016_Bioorg.Med.Chem_24_886
Author(s) : Fang L , Chen M , Liu Z , Fang X , Gou S , Chen L
Ref : Bioorganic & Medicinal Chemistry , 24 :886 , 2016
Abstract : In order to search for novel multifunctional anti-Alzheimer agents, a series of ferulic acid-carbazole hybrid compounds were designed and synthesized. Ellman's assay revealed that the hybrid compounds showed moderate to potent inhibitory activity against the cholinesterases. Particularly, the AChE inhibition potency of compound 5k (IC50 1.9muM) was even 5-fold higher than that of galantamine. In addition, the target compounds showed pronounced antioxidant ability and neuroprotective property, especially against the ROS-induced toxicity. Notably, the neuroprotective effect of 5k was obviously superior to that of the mixture of ferulic acid and carbazole, indicating the therapeutic effect of the hybrid compound is better than the combination administration of the corresponding mixture.
ESTHER : Fang_2016_Bioorg.Med.Chem_24_886
PubMedSearch : Fang_2016_Bioorg.Med.Chem_24_886
PubMedID: 26795115

Title : Timosaponin B-II ameliorates scopolamine-induced cognition deficits by attenuating acetylcholinesterase activity and brain oxidative damage in mice - Zhao_2016_Metab.Brain.Dis_31_1455
Author(s) : Zhao X , Liu C , Qi Y , Fang L , Luo J , Bi K , Jia Y
Ref : Metabolic Brain Disease , 31 :1455 , 2016
Abstract : Timosaponin B-II (TB-II) is a main active saponin isolated from the rhizome of Anemarrhena asphodeloides Bge., which is widely used in traditional Chinese medicine. In this study, the effect of TB-II on learning and memory was investigated in a scopolamine-induced mouse model of Alzheimer's disease. The results of behavioral tests indicated that TB-II significantly increased the spontaneous alternation in the Y-maze test, and reversed the shortening of step-through latency induced by scopolamine in the passive avoidance test, showing protective effects on short-term and working memory. In the Morris water maze test, TB-II reduced the escape latency time in the training trial, and increased the swimming time in the target quadrant in the probe trial. Biochemical data demonstrated that TB-II significantly inhibited acetylcholinesterase (AChE) activity in the cerebral cortex and hippocampus of mice. Moreover, TB-II markably attenuated the reduction in glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities, and decreased malondialdehyde (MDA) levels, which are key biomarkers of brain oxidative stress. These results indicated that TB-II offers protection against scopolamine-induced deficits in learning and memory, possibly by inhibiting AChE and preventing oxidative stress damage. The findings suggested that TB-II has a potential therapeutic effect on cognitive and behavioral impairment.
ESTHER : Zhao_2016_Metab.Brain.Dis_31_1455
PubMedSearch : Zhao_2016_Metab.Brain.Dis_31_1455
PubMedID: 27444169

Title : Rational design, preparation, and characterization of a therapeutic enzyme mutant with improved stability and function for cocaine detoxification - Fang_2014_ACS.Chem.Biol_9_1764
Author(s) : Fang L , Chow KM , Hou S , Xue L , Chen X , Rodgers DW , Zheng F , Zhan CG
Ref : ACS Chemical Biology , 9 :1764 , 2014
Abstract : Cocaine esterase (CocE) is known as the most efficient natural enzyme for cocaine hydrolysis. The major obstacle to the clinical application of wild-type CocE is the thermoinstability with a half-life of only approximately 12 min at 37 degrees C. The previously designed T172R/G173Q mutant (denoted as enzyme E172-173) with an improved in vitro half-life of approximately 6 h at 37 degrees C is currently in clinical trial Phase II for cocaine overdose treatment. Through molecular modeling and dynamics simulation, we designed and characterized a promising new mutant of E172-173 with extra L196C/I301C mutations (denoted as enzyme E196-301) to produce cross-subunit disulfide bonds that stabilize the dimer structure. The cross-subunit disulfide bonds were confirmed by X-ray diffraction. The designed L196C/I301C mutations have not only considerably extended the in vitro half-life at 37 degrees C to >100 days, but also significantly improved the catalytic efficiency against cocaine by approximately 150%. In addition, the thermostable E196-301 can be PEGylated to significantly prolong the residence time in mice. The PEGylated E196-301 can fully protect mice from a lethal dose of cocaine (180 mg/kg, LD100) for at least 3 days, with an average protection time of approximately 94h. This is the longest in vivo protection of mice from the lethal dose of cocaine demonstrated within all studies using an exogenous enzyme reported so far. Hence, E196-301 may be developed to become a more valuable therapeutic enzyme for cocaine abuse treatment, and it demonstrates that a general design strategy and protocol to simultaneously improve both the stability and function are feasible for rational protein drug design.
ESTHER : Fang_2014_ACS.Chem.Biol_9_1764
PubMedSearch : Fang_2014_ACS.Chem.Biol_9_1764
PubMedID: 24919140
Gene_locus related to this paper: rhosm-cocE

Title : Amino-acid mutations to extend the biological half-life of a therapeutically valuable mutant of human butyrylcholinesterase - Fang_2014_Chem.Biol.Interact_214C_18
Author(s) : Fang L , Hou S , Xue L , Zheng F , Zhan CG
Ref : Chemico-Biological Interactions , 214C :18 , 2014
Abstract : Cocaine is a widely abused and addictive drug without an FDA-approved medication. Our recently designed and discovered cocaine hydrolase, particularly E12-7 engineered from human butyrylcholinesterase (BChE), has the promise of becoming a valuable cocaine abuse treatment. An ideal anti-cocaine therapeutic enzyme should have not only a high catalytic efficiency against cocaine, but also a sufficiently long biological half-life. However, recombinant human BChE and the known BChE mutants have a much shorter biological half-life compared to the native human BChE. The present study aimed to extend the biological half-life of the cocaine hydrolase without changing its high catalytic activity against cocaine. Our strategy was to design possible amino-acid mutations that can introduce cross-subunit disulfide bond(s) and, thus, change the distribution of the oligomeric forms and extend the biological half-life. Three new BChE mutants (E364-532, E377-516, and E535) were predicted to have a more stable dimer structure with the desirable cross-subunit disulfide bond(s) and, therefore, a different distribution of the oligomeric forms and a prolonged biological half-life. The rational design was followed by experimental tests in vitro and in vivo, confirming that the rationally designed new BChE mutants, i.e. E364-532, E377-516, and E535, indeed had a remarkably different distribution of the oligomeric forms and prolonged biological half-life in rats from approximately 7 to approximately 13h without significantly changing the catalytic activity against (-)-cocaine. This is the first demonstration that rationally designed amino-acid mutations can significantly prolong the biological half-life of a high-activity enzyme without significantly changing the catalytic activity.
ESTHER : Fang_2014_Chem.Biol.Interact_214C_18
PubMedSearch : Fang_2014_Chem.Biol.Interact_214C_18
PubMedID: 24582612
Gene_locus related to this paper: human-BCHE

Title : Neuroprotective effects of sulforaphane on cholinergic neurons in mice with Alzheimer's disease-like lesions - Zhang_2014_Int.J.Mol.Sci_15_14396
Author(s) : Zhang R , Zhang J , Fang L , Li X , Zhao Y , Shi W , An L
Ref : Int J Mol Sci , 15 :14396 , 2014
Abstract : Alzheimer's disease (AD) is a common neurodegenerative disease in elderly individuals, and effective therapies are unavailable. This study was designed to investigate the neuroprotective effects of sulforaphane (an activator of NF-E2-related factor 2) on mice with AD-like lesions induced by combined administration of aluminum and d-galactose. Step-down-type passive avoidance tests showed sulforaphane ameliorated cognitive impairment in AD-like mice. Immunohistochemistry results indicated sulforaphane attenuated cholinergic neuron loss in the medial septal and hippocampal CA1 regions in AD-like mice. However, spectrophotometry revealed no significant difference in acetylcholine level or the activity of choline acetyltransferase or acetylcholinesterase in the cerebral cortex among groups of control and AD-like mice with and without sulforaphane treatment. Sulforaphane significantly increased the numbers of 5-bromo-2'-deoxyuridine-positive neurons in the subventricular and subgranular zones in AD-like mice which were significantly augmented compared with controls. Atomic absorption spectrometry revealed significantly lower aluminum levels in the brains of sulforaphane-treated AD-like mice than in those that did not receive sulforaphane treatment. In conclusion, sulforaphane ameliorates neurobehavioral deficits by reducing cholinergic neuron loss in the brains of AD-like mice, and the mechanism may be associated with neurogenesis and aluminum load reduction. These findings suggest that phytochemical sulforaphane has potential application in AD therapeutics.
ESTHER : Zhang_2014_Int.J.Mol.Sci_15_14396
PubMedSearch : Zhang_2014_Int.J.Mol.Sci_15_14396
PubMedID: 25196440

Title : Catalytic activities of a cocaine hydrolase engineered from human butyrylcholinesterase against (+)- and (-)-cocaine - Xue_2013_Chem.Biol.Interact_203_57
Author(s) : Xue L , Hou S , Yang W , Fang L , Zheng F , Zhan CG
Ref : Chemico-Biological Interactions , 203 :57 , 2013
Abstract : It can be argued that an ideal anti-cocaine medication would be one that accelerates cocaine metabolism producing biologically inactive metabolites via a route similar to the primary cocaine-metabolizing pathway, i.e., hydrolysis catalyzed by butyrylcholinesterase (BChE) in plasma. However, wild-type BChE has a low catalytic efficiency against naturally occurring (-)-cocaine. Interestingly, wild-type BChE has a much higher catalytic activity against unnatural (+)-cocaine. According to available positron emission tomography (PET) imaging analysis using [(11)C](-)-cocaine and [(11)C](+)-cocaine tracers in human subjects, only [(11)C](-)-cocaine was observed in the brain, whereas no significant [(11)C](+)-cocaine signal was observed in the brain. The available PET data imply that an effective therapeutic enzyme for treatment of cocaine abuse could be an exogenous cocaine-metabolizing enzyme with a catalytic activity against (-)-cocaine comparable to that of wild-type BChE against (+)-cocaine. Our recently designed A199S/F227A/S287G/A328 W/Y332G mutant of human BChE has a considerably improved catalytic efficiency against (-)-cocaine and has been proven active in vivo. In the present study, we have characterized the catalytic activities of wild-type BChE and the A199S/F227A/S287G/A328 W/Y332G mutant against both (+)- and (-)-cocaine at the same time under the same experimental conditions. Based on the obtained kinetic data, the A199S/F227A/S287G/A328 W/Y332G mutant has a similarly high catalytic efficiency (kcat/KM) against (+)- and (-)-cocaine, and indeed has a catalytic efficiency (kcat/KM=1.84x10(9)M(-1)min(-1)) against (-)-cocaine comparable to that (kcat/KM=1.37x10(9)M(-1)min(-1)) of wild-type BChE against (+)-cocaine. Thus, the mutant may be used to effectively prevent (-)-cocaine from entering brain and producing physiological effects in the enzyme-based treatment of cocaine abuse.
ESTHER : Xue_2013_Chem.Biol.Interact_203_57
PubMedSearch : Xue_2013_Chem.Biol.Interact_203_57
PubMedID: 22917637

Title : Preparation and in vivo characterization of a cocaine hydrolase engineered from human butyrylcholinesterase for metabolizing cocaine - Xue_2013_Biochem.J_453_447
Author(s) : Xue L , Hou S , Tong M , Fang L , Chen X , Jin Z , Tai HH , Zheng F , Zhan CG
Ref : Biochemical Journal , 453 :447 , 2013
Abstract : Cocaine is a widely abused drug without an FDA (Food and Drug Administration)-approved medication. It has been recognized that an ideal anti-cocaine medication would accelerate cocaine metabolism producing biologically inactive metabolites via a route similar to the primary cocaine-metabolizing pathway, i.e. human BChE (butyrylcholinesterase)-catalysed hydrolysis. However, the native human BChE has a low catalytic activity against cocaine. We recently designed and discovered a BChE mutant (A199S/F227A/S287G/A328W/Y332G) with a high catalytic activity (kcat=5700 min-1, Km=3.1 muM) specifically for cocaine, and the mutant was proven effective in protecting mice from acute cocaine toxicity of a lethal dose of cocaine (180 mg/kg of body weight, LD100). Further characterization in animal models requires establishment of a high-efficiency stable cell line for the BChE mutant production at a relatively larger scale. It has been extremely challenging to develop a high-efficiency stable cell line expressing BChE or its mutant. In the present study, we successfully developed a stable cell line efficiently expressing the BChE mutant by using a lentivirus-based repeated-transduction method. The scaled-up protein production enabled us to determine for the first time the in vivo catalytic activity and the biological half-life of this high-activity mutant of human BChE in accelerating cocaine clearance. In particular, it has been demonstrated that the BChE mutant (administered to mice 1 min prior to cocaine) can quickly metabolize cocaine and completely eliminate cocaine-induced hyperactivity in rodents, implying that the BChE mutant may be developed as a promising therapeutic agent for cocaine abuse treatment.
ESTHER : Xue_2013_Biochem.J_453_447
PubMedSearch : Xue_2013_Biochem.J_453_447
PubMedID: 23849058

Title : Substrate selectivity of high-activity mutants of human butyrylcholinesterase - Hou_2013_Org.Biomol.Chem_11_7477
Author(s) : Hou S , Xue L , Yang W , Fang L , Zheng F , Zhan CG
Ref : Org Biomol Chem , 11 :7477 , 2013
Abstract : Cocaine is one of the most addictive drugs, and there is still no FDA (Food and Drug Administration)-approved medication specific for cocaine abuse. A promising therapeutic strategy is to accelerate cocaine metabolism, producing biologically inactive metabolites via a route similar to the primary cocaine-metabolizing pathway, i.e. cocaine hydrolysis catalyzed by butyrylcholinesterase (BChE) in plasma. However, the native BChE has a low catalytic efficiency against the abused cocaine, i.e. (-)-cocaine. Our recently designed and discovered A199S/F227A/S287G/A328W/Y332G mutant and other mutants of human BChE have a considerably improved catalytic efficiency against (-)-cocaine. In the present study, we carried out both computational modeling and experimental kinetic analysis on the catalytic activities of these promising new BChE mutants against other known substrates, including neurotransmitter acetylcholine (ACh), acetylthiocholine (ATC), butyrylthiocholine (BTC), and (+)-cocaine, in comparison with the corresponding catalytic activity against (-)-cocaine. Both the computational modeling and kinetic analysis have consistently revealed that all the examined amino acid mutations only considerably improve the catalytic efficiency of human BChE against (-)-cocaine, without significantly improving the catalytic efficiency of the enzyme against any of the other substrates examined. In particular, all the examined BChE mutants have a slightly lower catalytic efficiency against neurotransmitter ACh compared to the wild-type BChE. This observation gives us confidence in developing an anti-cocaine enzyme therapy by using one of these BChE mutants, particularly the A199S/F227A/S287G/A328W/Y332G mutant.
ESTHER : Hou_2013_Org.Biomol.Chem_11_7477
PubMedSearch : Hou_2013_Org.Biomol.Chem_11_7477
PubMedID: 24077614

Title : Current progresses of novel natural products and their derivatives\/ analogs as anti-Alzheimer candidates: an update - Fang_2013_Mini.Rev.Med.Chem_13_870
Author(s) : Fang L , Gou S , Fang X , Cheng L , Fleck C
Ref : Mini Rev Med Chem , 13 :870 , 2013
Abstract : Alzheimer's disease (AD) is one of the most threatening diseases affecting the aged with high incidence. Though AD has been defined for more than 100 years, it is still incurable. The drugs clinically used for the treatment of this disease, such as acetylcholinesterase inhibitors (AChEIs) and N-methyl-D-aspartate (NMDA) receptor antagonist, can only provide a limited therapeutic effect. The need of effective drugs has stimulated the search for new compounds with potential clinical utility. Natural products are rich and unexplored sources for discovering novel leading compounds. Currently, a great number of natural products have been found possessing anti-AD property counteracting different etiological factors of AD. This review will give an update demonstration on the novel anti-AD natural products and their derivatives/analogues, which have been divided into five subgroups according to their different action mechanisms: AChEIs, antioxidants, neuroprotective agents, monoamine oxidase (MAO) inhibitors, and tau hyperphosphorylation inhibitors. We put special emphasis on the findings in the past 5 years. Besides, the drug design strategy as well as the structure-activity relationship of the relevant compounds is also discussed when it is possible.
ESTHER : Fang_2013_Mini.Rev.Med.Chem_13_870
PubMedSearch : Fang_2013_Mini.Rev.Med.Chem_13_870
PubMedID: 23305400

Title : A model of glycosylated human butyrylcholinesterase - Fang_2013_Mol.Biosyst_10_348
Author(s) : Fang L , Zheng F , Zhan CG
Ref : Mol Biosyst , 10 :348 , 2013
Abstract : Human butyrylcholinesterase (BChE) and its mutants have shown great potential in treating cocaine overdose and addiction. In order to effectively suppress cocaine reward in the brain for a long period of time after an exogenous cocaine hydrolase administration, the therapeutic enzyme should have not only a high catalytic efficiency against cocaine, but also a sufficiently long circulation time. It has been known that PEGylation (covalent attachment of polyethylene glycol) modification of a therapeutic protein can prolong the biological half-life of the protein without affecting its biological function. However, the asparagine-linked glycans on the surface of glycosylated BChE may interfere with the PEGylation modification. In this study, we built a three-dimensional (3D) model of glycosylated human BChE to investigate the influence of glycans on the PEGylation modification. Glycans did not change the overall stability of the BChE structure, but could increase the flexibility of some local structures. For further evaluating the accessibility of the PEGylation reaction sites, particularly lysine residues, on the protein surface, we calculated the Solvent Accessible Surface Areas (SASAs) of these residues. The results indicate that some lysine residues show a significant decrease in SASA due to the direct or indirect influence of their surrounding glycans. The results also indicate that PEGylation reaction agents with smaller functional groups could have a better chance to react with lysine residues. This investigation provides a structural basis for rational engineering of human BChE and its mutants as therapeutic candidates.
ESTHER : Fang_2013_Mol.Biosyst_10_348
PubMedSearch : Fang_2013_Mol.Biosyst_10_348
PubMedID: 24327294

Title : Reaction pathway and free energy profiles for butyrylcholinesterase-catalyzed hydrolysis of acetylthiocholine - Chen_2012_Biochemistry_51_1297
Author(s) : Chen X , Fang L , Liu J , Zhan CG
Ref : Biochemistry , 51 :1297 , 2012
Abstract : The catalytic mechanism for butyrylcholineserase (BChE)-catalyzed hydrolysis of acetylthiocholine (ATCh) has been studied by performing pseudobond first-principles quantum mechanical/molecular mechanical-free energy (QM/MM-FE) calculations on both acylation and deacylation of BChE. Additional quantum mechanical (QM) calculations have been carried out, along with the QM/MM-FE calculations, to understand the known substrate activation effect on the enzymatic hydrolysis of ATCh. It has been shown that the acylation of BChE with ATCh consists of two reaction steps including the nucleophilic attack on the carbonyl carbon of ATCh and the dissociation of thiocholine ester. The deacylation stage includes nucleophilic attack of a water molecule on the carboxyl carbon of substrate and dissociation between the carboxyl carbon of substrate and hydroxyl oxygen of Ser198 side chain. QM/MM-FE calculation results reveal that the acylation of BChE is rate-determining. It has also been demonstrated that an additional substrate molecule binding to the peripheral anionic site (PAS) of BChE is responsible for the substrate activation effect. In the presence of this additional substrate molecule at PAS, the calculated free energy barrier for the acylation stage (rate-determining step) is decreased by ~1.7 kcal/mol. All of our computational predictions are consistent with available experimental kinetic data. The overall free energy barriers calculated for BChE-catalyzed hydrolysis of ATCh at regular hydrolysis phase and substrate activation phase are ~13.6 and ~11.9 kcal/mol, respectively, which are in reasonable agreement with the corresponding experimentally derived activation free energies of 14.0 kcal/mol (for regular hydrolysis phase) and 13.5 kcal/mol (for substrate activation phase).
ESTHER : Chen_2012_Biochemistry_51_1297
PubMedSearch : Chen_2012_Biochemistry_51_1297
PubMedID: 22304234

Title : Discovery of a novel acetylcholinesterase inhibitor by structure-based virtual screening techniques - Chen_2012_Bioorg.Med.Chem.Lett_22_3181
Author(s) : Chen Y , Fang L , Peng S , Liao H , Lehmann J , Zhang Y
Ref : Bioorganic & Medicinal Chemistry Lett , 22 :3181 , 2012
Abstract : Acetylcholinesterase (AChE) is considered to be one of the most important targets for the treatment of Alzheimer's disease (AD). Previously our group has reported a series of tacrine-based hybrids as potent AChE inhibitors (AChEI). To discover more novel scaffolds, molecular docking and dynamics stimulation were applied to acquire the binding models of AChE with the most prominent compounds from our work. A structure-based pharmacophore model plus shape constraints was generated from the binding models and it was then employed to virtually screen commercial databases, giving a focused hit list of candidates. Subsequently, we scored the hit compounds by their molecular binding energies, which were calculated by MM/PBSA method. Fifteen compounds were selected and purchased for testing their anti-AChE effects, while seven of them showed inhibitory effects with IC(50) values ranging from 1.5 to 9.8 muM. The drug-like properties of these compounds, including LogD, AlogP, molecular volume and Lipinski rule of five, were also calculated. Compounds 12 and 16 (IC(50)=2.5 and 1.5 muM, respectively) exhibited potent activity and acceptable drug-like properties, thus might serve as leads for further modification. The data suggest that the presented model might be a valid approach for identification and development of new AChEIs.
ESTHER : Chen_2012_Bioorg.Med.Chem.Lett_22_3181
PubMedSearch : Chen_2012_Bioorg.Med.Chem.Lett_22_3181
PubMedID: 22472693

Title : Tacrine-ferulic acid-nitric oxide (NO) donor trihybrids as potent, multifunctional acetyl- and butyrylcholinesterase inhibitors - Chen_2012_J.Med.Chem_55_4309
Author(s) : Chen Y , Sun J , Fang L , Liu M , Peng S , Liao H , Lehmann J , Zhang Y
Ref : Journal of Medicinal Chemistry , 55 :4309 , 2012
Abstract : In search of multifunctional cholinesterase inhibitors as potential anti-Alzheimer drug candidates, tacrine-ferulic acid-NO donor trihybrids were synthesized and tested for their cholinesterase inhibitory activities, release of nitric oxide, vasodilator properties, cognition improving potency, and hepatotoxicity. All of the novel target compounds show higher in vitro cholinesterase inhibitory activity than tacrine. Three selected compounds (3a, 3f, and 3k) produce moderate vasorelaxation in vitro, which correlates with the release of nitric oxide. Compared to its non-nitrate dihybrid analogue (3u), the trihybrid 3f exhibits better performance in improving the scopolamine-induced cognition impairment (mice) and, furthermore, less hepatotoxicity than tacrine.
ESTHER : Chen_2012_J.Med.Chem_55_4309
PubMedSearch : Chen_2012_J.Med.Chem_55_4309
PubMedID: 22512543

Title : Active site gating and substrate specificity of butyrylcholinesterase and acetylcholinesterase: insights from molecular dynamics simulations - Fang_2011_J.Phys.Chem.B_115_8797
Author(s) : Fang L , Pan Y , Muzyka JL , Zhan CG
Ref : J Phys Chem B , 115 :8797 , 2011
Abstract : Butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) are highly homologous proteins with distinct substrate preferences. In this study we compared the active sites of monomers and tetramers of human BChE and human AChE after performing molecular dynamics (MD) simulations in water-solvated systems. By comparing the conformational dynamics of gating residues of AChE and BChE, we found that the gating mechanisms of the main door of AChE and BChE are responsible for their different substrate specificities. Our simulation of the tetramers of AChE and BChE indicates that both enzymes could have two dysfunctional active sites due to their restricted accessibility to substrates. The further study on catalytic mechanisms of multiple forms of AChE and BChE would benefit from our comparison of the active sites of the monomers and tetramers of both enzymes.
ESTHER : Fang_2011_J.Phys.Chem.B_115_8797
PubMedSearch : Fang_2011_J.Phys.Chem.B_115_8797
PubMedID: 21682268

Title : Complete genome sequence of Mycoplasma hyopneumoniae strain 168 - Liu_2011_J.Bacteriol_193_1016
Author(s) : Liu W , Feng Z , Fang L , Zhou Z , Li Q , Li S , Luo R , Wang L , Chen H , Shao G , Xiao S
Ref : Journal of Bacteriology , 193 :1016 , 2011
Abstract : Mycoplasma hyopneumoniae strain 168, a pathogenic strain prevalent in China, was isolated in 1974. Although this strain has been widespread for a long time, the genome sequence had not been determined. Here, we announce the complete genome sequence of M. hyopneumoniae strain 168.
ESTHER : Liu_2011_J.Bacteriol_193_1016
PubMedSearch : Liu_2011_J.Bacteriol_193_1016
PubMedID: 21148737

Title : Design, preparation, and characterization of high-activity mutants of human butyrylcholinesterase specific for detoxification of cocaine - Xue_2011_Mol.Pharmacol_79_290
Author(s) : Xue L , Ko MC , Tong M , Yang W , Hou S , Fang L , Liu J , Zheng F , Woods JH , Tai HH , Zhan CG
Ref : Molecular Pharmacology , 79 :290 , 2011
Abstract : Cocaine is a widely abused drug without a U.S. Food and Drug Administration-approved medication. There is a recognized, promising anticocaine medication to accelerate cocaine metabolism, producing biologically inactive metabolites via a route similar to the primary cocaine-metabolizing pathway [i.e., cocaine hydrolysis catalyzed by butyrylcholinesterase (BChE) in plasma]. An ideal, therapeutically valuable mutant of human BChE should have not only a significantly improved catalytic activity against (-)-cocaine but also certain selectivity for (-)-cocaine over neurotransmitter acetylcholine (ACh), such that one would not expect systemic administration of the BChE mutant to interrupt cholinergic transmission. The present study accounting for the mutation-caused changes of the catalytic activities of BChE against both (-)-cocaine and ACh by means of molecular modeling and site-directed mutagenesis has led to identification of three BChE mutants that have not only a considerably improved catalytic efficiency against (-)-cocaine but also the desirable selectivity for (-)-cocaine over ACh. Two representative BChE mutants have been confirmed to be potent in actual protection of mice from acute toxicity (convulsion and lethality) of a lethal dose of cocaine (180 mg/kg). Pretreatment with the BChE mutant (i.e., 1 min before cocaine administration) dose-dependently protected mice against cocaine-induced convulsions and lethality. In particular, all mice pretreated with the mutant (e.g., 0.02 mg or more of A199S/F227A/S287G/A328W/E441D BChE) survived. The in vivo data reveal the primary factor (i.e., the relative catalytic efficiency), determining the efficacy in practical protection of mice from the acute cocaine toxicity and future direction for further improving the efficacy of the enzyme in the cocaine overdose treatment.
ESTHER : Xue_2011_Mol.Pharmacol_79_290
PubMedSearch : Xue_2011_Mol.Pharmacol_79_290
PubMedID: 20971807

Title : The genome of the mesopolyploid crop species Brassica rapa - Wang_2011_Nat.Genet_43_1035
Author(s) : Wang X , Wang H , Wang J , Sun R , Wu J , Liu S , Bai Y , Mun JH , Bancroft I , Cheng F , Huang S , Li X , Hua W , Freeling M , Pires JC , Paterson AH , Chalhoub B , Wang B , Hayward A , Sharpe AG , Park BS , Weisshaar B , Liu B , Li B , Tong C , Song C , Duran C , Peng C , Geng C , Koh C , Lin C , Edwards D , Mu D , Shen D , Soumpourou E , Li F , Fraser F , Conant G , Lassalle G , King GJ , Bonnema G , Tang H , Belcram H , Zhou H , Hirakawa H , Abe H , Guo H , Jin H , Parkin IA , Batley J , Kim JS , Just J , Li J , Xu J , Deng J , Kim JA , Yu J , Meng J , Min J , Poulain J , Hatakeyama K , Wu K , Wang L , Fang L , Trick M , Links MG , Zhao M , Jin M , Ramchiary N , Drou N , Berkman PJ , Cai Q , Huang Q , Li R , Tabata S , Cheng S , Zhang S , Sato S , Sun S , Kwon SJ , Choi SR , Lee TH , Fan W , Zhao X , Tan X , Xu X , Wang Y , Qiu Y , Yin Y , Li Y , Du Y , Liao Y , Lim Y , Narusaka Y , Wang Z , Li Z , Xiong Z , Zhang Z
Ref : Nat Genet , 43 :1035 , 2011
Abstract : We report the annotation and analysis of the draft genome sequence of Brassica rapa accession Chiifu-401-42, a Chinese cabbage. We modeled 41,174 protein coding genes in the B. rapa genome, which has undergone genome triplication. We used Arabidopsis thaliana as an outgroup for investigating the consequences of genome triplication, such as structural and functional evolution. The extent of gene loss (fractionation) among triplicated genome segments varies, with one of the three copies consistently retaining a disproportionately large fraction of the genes expected to have been present in its ancestor. Variation in the number of members of gene families present in the genome may contribute to the remarkable morphological plasticity of Brassica species. The B. rapa genome sequence provides an important resource for studying the evolution of polyploid genomes and underpins the genetic improvement of Brassica oil and vegetable crops.
ESTHER : Wang_2011_Nat.Genet_43_1035
PubMedSearch : Wang_2011_Nat.Genet_43_1035
PubMedID: 21873998
Gene_locus related to this paper: braol-Q8GTM3 , braol-Q8GTM4 , brarp-m4ei94 , brarp-m4c988 , brana-a0a078j4a9 , brana-a0a078e1m0 , brana-a0a078cd75 , brarp-m4dwa6 , brana-a0a078j4f0 , brana-a0a078cus4 , brana-a0a078f8c2 , brana-a0a078jql1 , brana-a0a078dgj3 , brana-a0a078hw50 , brana-a0a078cuu0 , brana-a0a078dfa9 , brana-a0a078ic91 , brarp-m4ctw3 , brana-a0a078ca65 , brana-a0a078ctc8 , brana-a0a078h021 , brana-a0a078jx23 , brarp-m4da84 , brarp-m4dwr7 , brana-a0a078dh94 , brana-a0a078h612 , brana-a0a078j2t3 , braol-a0a0d3dpb2 , braol-a0a0d3dx76 , brana-a0a078jxa8 , brana-a0a078i2k3 , brarp-m4cwq4 , brarp-m4dcj8 , brarp-m4eh17 , brarp-m4eey4 , brarp-m4dnj8 , brarp-m4ey83 , brarp-m4ey84

Title : Complete genome sequence of Mycoplasma hyorhinis strain HUB-1 - Liu_2010_J.Bacteriol_192_5844
Author(s) : Liu W , Fang L , Li S , Li Q , Zhou Z , Feng Z , Luo R , Shao G , Wang L , Chen H , Xiao S
Ref : Journal of Bacteriology , 192 :5844 , 2010
Abstract : Mycoplasma hyorhinis is generally considered a swine pathogen yet is most commonly found infecting laboratory cell lines. An increasing body of evidence suggests that chronic infections with M. hyorhinis may cause oncogenic transformation. Here, we announce the complete genome sequence of M. hyorhinis strain HUB-1.
ESTHER : Liu_2010_J.Bacteriol_192_5844
PubMedSearch : Liu_2010_J.Bacteriol_192_5844
PubMedID: 20802032

Title : Hybrid molecules from xanomeline and tacrine: enhanced tacrine actions on cholinesterases and muscarinic M1 receptors - Fang_2010_J.Med.Chem_53_2094
Author(s) : Fang L , Jumpertz S , Zhang Y , Appenroth D , Fleck C , Mohr K , Trankle C , Decker M
Ref : Journal of Medicinal Chemistry , 53 :2094 , 2010
Abstract : A set of amide- and amine-linked hybrid molecules comprising moieties of the orthosteric M(1) muscarinic receptor agonist xanomeline and the cholinesterase inhibitor and allosteric receptor modulator tacrine were prepared with varying spacer length of 10-17 atoms. The hybrids inhibited acetylcholinesterase with similar or higher potency compared to tacrine. M(1) receptor binding affinity was similar or higher relative to xanomeline and far higher relative to tacrine. Affinities hardly changed when the receptors' orthosteric site was occupied by an inverse agonist ligand. When occupied by the orthosteric activator acetylcholine, affinity for the hybrids declined to unmeasureably low levels. Hybrids did not activate M(1) receptors. In vivo studies assaying cognition impairment in rats induced by scopolamine revealed pronounced enhancement of scopolamine action. Taken together, instead of dualsteric (simultaneous allosteric/orthosteric) binding, the hybrids seem to prefer purely allosteric binding at the inactive M(1) receptor.
ESTHER : Fang_2010_J.Med.Chem_53_2094
PubMedSearch : Fang_2010_J.Med.Chem_53_2094
PubMedID: 20158205

Title : Free energy perturbation simulation on transition states and high-activity mutants of human butyrylcholinesterase for (-)-cocaine hydrolysis - Yang_2010_J.Phys.Chem.B_114_10889
Author(s) : Yang W , Pan Y , Fang L , Gao D , Zheng F , Zhan CG
Ref : J Phys Chem B , 114 :10889 , 2010
Abstract : A unified computational approach based on free energy perturbation (FEP) simulations of transition states has been employed to calculate the mutation-caused shifts of the free energy change from the free enzyme to the rate-determining transition state for (-)-cocaine hydrolysis catalyzed by the currently most promising series of mutants of human butyrylcholinesterase (BChE) that contain the A199S/A328W/Y332G mutations. The FEP simulations were followed by Michaelis-Menten kinetics analysis determining the individual k(cat) and K(M) values missing for the A199S/F227A/A328W/Y332G mutant in this series. The calculated mutation-caused shifts of the free energy change from the free enzyme to the rate-determining transition state are in good agreement with the experimental kinetic data, demonstrating that the unified computational approach based on the FEP simulations of the transition states may be valuable for future computational design of new BChE mutants with a further improved catalytic efficiency against (-)-cocaine.
ESTHER : Yang_2010_J.Phys.Chem.B_114_10889
PubMedSearch : Yang_2010_J.Phys.Chem.B_114_10889
PubMedID: 20677742

Title : Characterization of a high-activity mutant of human butyrylcholinesterase against (-)-cocaine - Yang_2010_Chem.Biol.Interact_187_148
Author(s) : Yang W , Xue L , Fang L , Chen X , Zhan CG
Ref : Chemico-Biological Interactions , 187 :148 , 2010
Abstract : Cocaine addiction and overdose are a well-known public health problem. There is no approved medication available for cocaine abuse treatment. Our recently designed and discovered high-activity mutant (A199S/S287G/A328W/Y332G) of human butyrylcholinesterase (BChE) has been recognized to be worth exploring for clinical application in humans as a potential anti-cocaine medication. The catalytic rate constant (k(cat)) and Michaelis-Menten constant (K(M)) for (-)-cocaine hydrolysis catalyzed by A199S/S287G/A328W/Y332G BChE (without fusion with any other peptide) have been determined to be 3,060 min(-1) and 3.1 microM, respectively, in the present study. The determined kinetic parameters reveal that the un-fused A199S/S287G/A328W/Y332G mutant has a approximately 1,080-fold improved catalytic efficiency (k(cat)/K(M)) against (-)-cocaine compared to the wild-type BChE. The approximately 1,080-fold improvement in the catalytic efficiency of the un-fused A199S/S287G/A328W/Y332G mutant is very close to the previously reported the approximately 1,000-fold improvement in the catalytic efficiency of the A199S/S287G/A328W/Y332G mutant fused with human serum albumin. These results suggest that the albumin fusion did not significantly change the catalytic efficiency of the BChE mutant while extending the plasma half-life. In addition, we have also examined the catalytic activities of the A199S/S287G/A328W/Y332G mutant against two other substrates, acetylthiocholine (ATC) and butyrylthiocholine (BTC). It has been shown that the A199S/S287G/A328W/Y332G mutations actually decreased the catalytic efficiencies of BChE against ATC and BTC, while considerably improving the catalytic efficiency of BChE against (-)-cocaine.
ESTHER : Yang_2010_Chem.Biol.Interact_187_148
PubMedSearch : Yang_2010_Chem.Biol.Interact_187_148
PubMedID: 20060817

Title : The sequence and de novo assembly of the giant panda genome - Li_2010_Nature_463_311
Author(s) : Li R , Fan W , Tian G , Zhu H , He L , Cai J , Huang Q , Cai Q , Li B , Bai Y , Zhang Z , Zhang Y , Wang W , Li J , Wei F , Li H , Jian M , Nielsen R , Li D , Gu W , Yang Z , Xuan Z , Ryder OA , Leung FC , Zhou Y , Cao J , Sun X , Fu Y , Fang X , Guo X , Wang B , Hou R , Shen F , Mu B , Ni P , Lin R , Qian W , Wang G , Yu C , Nie W , Wang J , Wu Z , Liang H , Min J , Wu Q , Cheng S , Ruan J , Wang M , Shi Z , Wen M , Liu B , Ren X , Zheng H , Dong D , Cook K , Shan G , Zhang H , Kosiol C , Xie X , Lu Z , Li Y , Steiner CC , Lam TT , Lin S , Zhang Q , Li G , Tian J , Gong T , Liu H , Zhang D , Fang L , Ye C , Zhang J , Hu W , Xu A , Ren Y , Zhang G , Bruford MW , Li Q , Ma L , Guo Y , An N , Hu Y , Zheng Y , Shi Y , Li Z , Liu Q , Chen Y , Zhao J , Qu N , Zhao S , Tian F , Wang X , Wang H , Xu L , Liu X , Vinar T , Wang Y , Lam TW , Yiu SM , Liu S , Huang Y , Yang G , Jiang Z , Qin N , Li L , Bolund L , Kristiansen K , Wong GK , Olson M , Zhang X , Li S , Yang H
Ref : Nature , 463 :311 , 2010
Abstract : Using next-generation sequencing technology alone, we have successfully generated and assembled a draft sequence of the giant panda genome. The assembled contigs (2.25 gigabases (Gb)) cover approximately 94% of the whole genome, and the remaining gaps (0.05 Gb) seem to contain carnivore-specific repeats and tandem repeats. Comparisons with the dog and human showed that the panda genome has a lower divergence rate. The assessment of panda genes potentially underlying some of its unique traits indicated that its bamboo diet might be more dependent on its gut microbiome than its own genetic composition. We also identified more than 2.7 million heterozygous single nucleotide polymorphisms in the diploid genome. Our data and analyses provide a foundation for promoting mammalian genetic research, and demonstrate the feasibility for using next-generation sequencing technologies for accurate, cost-effective and rapid de novo assembly of large eukaryotic genomes.
ESTHER : Li_2010_Nature_463_311
PubMedSearch : Li_2010_Nature_463_311
PubMedID: 20010809
Gene_locus related to this paper: ailme-ABH15 , ailme-ACHE , ailme-BCHE , ailme-d2gtv3 , ailme-d2gty9 , ailme-d2gu87 , ailme-d2gu97 , ailme-d2gve7 , ailme-d2gwu1 , ailme-d2gx08 , ailme-d2gyt0 , ailme-d2gz36 , ailme-d2gz37 , ailme-d2gz38 , ailme-d2gz39 , ailme-d2gz40 , ailme-d2h5r9 , ailme-d2h7b7 , ailme-d2h9c9 , ailme-d2h794 , ailme-d2hau7 , ailme-d2hau8 , ailme-d2hcd9 , ailme-d2hdi6 , ailme-d2heu6 , ailme-d2hga4 , ailme-d2hqw5 , ailme-d2hs98 , ailme-d2hsx4 , ailme-d2hti6 , ailme-d2htv3 , ailme-d2htz6 , ailme-d2huc7 , ailme-d2hwj8 , ailme-d2hwy7 , ailme-d2hxm1 , ailme-d2hyc8 , ailme-d2hyv2 , ailme-d2hz11 , ailme-d2hza3 , ailme-d2hzr4 , ailme-d2i1l4 , ailme-d2i2g8 , ailme-g1l7m3 , ailme-g1lu36 , ailme-g1m769 , ailme-g1mc29 , ailme-g1mdj8 , ailme-g1mdr5 , ailme-g1mfp4 , ailme-g1mfx5 , ailme-g1lj41 , ailme-g1lm28 , ailme-g1l3u1 , ailme-g1l7l1 , ailme-g1m5i3 , ailme-g1l2f6 , ailme-g1lji5 , ailme-g1lqk3 , ailme-g1l8s9 , ailme-d2h717 , ailme-d2h718 , ailme-d2h719 , ailme-d2h720 , ailme-g1m5v0 , ailme-g1m5y7 , ailme-g1lkt7 , ailme-g1l2a1 , ailme-g1lsc8 , ailme-g1lrp4 , ailme-d2gv02 , ailme-g1mik5 , ailme-g1ljr1 , ailme-g1lxw7 , ailme-d2h8b5 , ailme-d2h2r2 , ailme-d2h9w7 , ailme-g1meh3 , ailme-g1m719

Title : The genome of the cucumber, Cucumis sativus L - Huang_2009_Nat.Genet_41_1275
Author(s) : Huang S , Li R , Zhang Z , Li L , Gu X , Fan W , Lucas WJ , Wang X , Xie B , Ni P , Ren Y , Zhu H , Li J , Lin K , Jin W , Fei Z , Li G , Staub J , Kilian A , van der Vossen EA , Wu Y , Guo J , He J , Jia Z , Tian G , Lu Y , Ruan J , Qian W , Wang M , Huang Q , Li B , Xuan Z , Cao J , Asan , Wu Z , Zhang J , Cai Q , Bai Y , Zhao B , Han Y , Li Y , Li X , Wang S , Shi Q , Liu S , Cho WK , Kim JY , Xu Y , Heller-Uszynska K , Miao H , Cheng Z , Zhang S , Wu J , Yang Y , Kang H , Li M , Liang H , Ren X , Shi Z , Wen M , Jian M , Yang H , Zhang G , Yang Z , Chen R , Ma L , Liu H , Zhou Y , Zhao J , Fang X , Fang L , Liu D , Zheng H , Zhang Y , Qin N , Li Z , Yang G , Yang S , Bolund L , Kristiansen K , Li S , Zhang X , Wang J , Sun R , Zhang B , Jiang S , Du Y
Ref : Nat Genet , 41 :1275 , 2009
Abstract : Cucumber is an economically important crop as well as a model system for sex determination studies and plant vascular biology. Here we report the draft genome sequence of Cucumis sativus var. sativus L., assembled using a novel combination of traditional Sanger and next-generation Illumina GA sequencing technologies to obtain 72.2-fold genome coverage. The absence of recent whole-genome duplication, along with the presence of few tandem duplications, explains the small number of genes in the cucumber. Our study establishes that five of the cucumber's seven chromosomes arose from fusions of ten ancestral chromosomes after divergence from Cucumis melo. The sequenced cucumber genome affords insight into traits such as its sex expression, disease resistance, biosynthesis of cucurbitacin and 'fresh green' odor. We also identify 686 gene clusters related to phloem function. The cucumber genome provides a valuable resource for developing elite cultivars and for studying the evolution and function of the plant vascular system.
ESTHER : Huang_2009_Nat.Genet_41_1275
PubMedSearch : Huang_2009_Nat.Genet_41_1275
PubMedID: 19881527
Gene_locus related to this paper: cucsa-a0a0a0ktw5 , cucsa-a0a0a0lnt6 , cucsa-a0a0a0kpn7 , cucsa-a0a0a0lvt9 , cucsa-a0a0a0kdx8 , cucsa-a0a0a0m228 , cucsa-a0a0a0kz31 , cucsa-a0a0a0k5t5 , cucsa-a0a0a0kfs7 , cucsa-a0a0a0kjj7 , cucsa-a0a0a0kzs7 , cucsa-a0a0a0l0a6 , cucsa-a0a0a0l4w4 , cucsa-a0a0a0lpz0 , cucsa-a0a0a0ls66

Title : Design, synthesis and evaluation of galanthamine derivatives as acetylcholinesterase inhibitors - Jia_2009_Eur.J.Med.Chem_44_772
Author(s) : Jia P , Sheng R , Zhang J , Fang L , He Q , Yang B , Hu Y
Ref : Eur Journal of Medicinal Chemistry , 44 :772 , 2009
Abstract : A new series of galanthamine derivatives have been designed, synthesized and evaluated as acetylcholinesterase inhibitors. All of the new compounds prepared showed high AChE inhibitory activities, with compound 3e that has an N-hexyl-benzyl piperidine substituent on the nitrogen atom reaching the best inhibitory activity for AChE (IC(50)=5.62 nM). The docking study performed with AutoDock demonstrated that 3e was nicely accommodated by AChE.
ESTHER : Jia_2009_Eur.J.Med.Chem_44_772
PubMedSearch : Jia_2009_Eur.J.Med.Chem_44_772
PubMedID: 18550228

Title : NO-donating tacrine hybrid compounds improve scopolamine-induced cognition impairment and show less hepatotoxicity - Fang_2008_J.Med.Chem_51_7666
Author(s) : Fang L , Appenroth D , Decker M , Kiehntopf M , Lupp A , Peng S , Fleck C , Zhang Y , Lehmann J
Ref : Journal of Medicinal Chemistry , 51 :7666 , 2008
Abstract : A series of tacrine-NO donor hybrid compounds are synthesized and evaluated for cholinesterase inhibitory activity, cognition improving activity, and hepatotoxicity. The pharmacological results indicate that hybrid compounds 1, 2, and 3a potently inhibit cholinesterase in vitro and significantly improve the scopolamine-induced cognition impairment, whereas an analogue (3h) of 2 without the NO donor moiety does not. Compared to tacrine, 1 and 2 show much less hepatotoxicity. Molecular modeling studies suggest that 2 may interact with the catalytic and the peripheral anionic site of acetylcholinesterase.
ESTHER : Fang_2008_J.Med.Chem_51_7666
PubMedSearch : Fang_2008_J.Med.Chem_51_7666
PubMedID: 19053746

Title : Synthesis and biological evaluation of NO-donor-tacrine hybrids as hepatoprotective anti-Alzheimer drug candidates - Fang_2008_J.Med.Chem_51_713
Author(s) : Fang L , Appenroth D , Decker M , Kiehntopf M , Roegler C , Deufel T , Fleck C , Peng S , Zhang Y , Lehmann J
Ref : Journal of Medicinal Chemistry , 51 :713 , 2008
Abstract : In search of safer anti-Alzheimer drugs, 14 NO-donor-tacrine hybrids (1- 14) were synthesized and evaluated for their ability to inhibit cholinesterases and for vasorelaxation effects. Compounds 1- 13 showed good cholinesterases inhibitory activities in vitro, while 14, particularly, was highly selective, preferring butyrylcholinesterase rather than acetylcholinesterase. Four selected compounds (1, 9, 11, and 14) moderately relaxed the porcine pulmonary arteries in organ bath. In the hepatotoxicity study, significant hepatotoxicity was caused by tacrine but not by 9.
ESTHER : Fang_2008_J.Med.Chem_51_713
PubMedSearch : Fang_2008_J.Med.Chem_51_713
PubMedID: 18232655

Title : Design and synthesis of tacrine-ferulic acid hybrids as multi-potent anti-Alzheimer drug candidates - Fang_2008_Bioorg.Med.Chem.Lett_18_2905
Author(s) : Fang L , Kraus B , Lehmann J , Heilmann J , Zhang Y , Decker M
Ref : Bioorganic & Medicinal Chemistry Lett , 18 :2905 , 2008
Abstract : Five tacrine-ferulic acid hybrids (6a-e) were designed and synthesized as multi-potent anti-Alzheimer drug candidates. All target compounds have better acetylcholinesterase inhibitory activity and comparable butyrylcholinesterase inhibitory activity in relation to tacrine. Interestingly, 6d showed a reversible and non-competitive inhibitory action for acetylcholinesterase indicating interaction with the peripheral anionic site, whereas a reversible but competitive inhibitory action for butyrylcholinesterase. The antioxidant study revealed that four target compounds have, compared to Trolox, high ability to absorb reactive oxygen species.
ESTHER : Fang_2008_Bioorg.Med.Chem.Lett_18_2905
PubMedSearch : Fang_2008_Bioorg.Med.Chem.Lett_18_2905
PubMedID: 18406135

Title : Tyrosine phosphorylated Par3 regulates epithelial tight junction assembly promoted by EGFR signaling - Wang_2006_EMBO.J_25_5058
Author(s) : Wang Y , Du D , Fang L , Yang G , Zhang C , Zeng R , Ullrich A , Lottspeich F , Chen Z
Ref : EMBO Journal , 25 :5058 , 2006
Abstract : The conserved polarity complex, comprising the partitioning-defective (Par) proteins Par3 and Par6, and the atypical protein kinase C, functions in various cell-polarization events and asymmetric cell divisions. However, little is known about whether and how external stimuli-induced signals may regulate Par3 function in epithelial cell polarity. Here, we found that Par3 was tyrosine phosphorylated through phosphoproteomic profiling of pervanadate-induced phosphotyrosine proteins. We also demonstrated that the tyrosine phosphorylation event induced by multiple growth factors including epidermal growth factor (EGF) was dependent on activation of Src family kinase (SFK) members c-Src and c-Yes. The tyrosine residue 1127 (Y1127) of Par3 was identified as the major EGF-induced phosphorylation site. Moreover, we found that Y1127 phosphorylation reduced the association of Par3 with LIM kinase 2 (LIMK2), thus enabling LIMK2 to regulate cofilin phosphorylation dynamics. Substitution of Y1127 for phenylalanine impaired the EGF-induced Par3 and LIMK2 dissociation and delayed epithelial tight junction (TJ) assembly considerably. Collectively, these data suggest a novel, phosphotyrosine-dependent fine-tuning mechanism of Par3 in epithelial TJ assembly controlled by the EGF receptor-SFK signaling pathway.
ESTHER : Wang_2006_EMBO.J_25_5058
PubMedSearch : Wang_2006_EMBO.J_25_5058
PubMedID: 17053785

Title : The Genomes of Oryza sativa: a history of duplications - Yu_2005_PLoS.Biol_3_e38
Author(s) : Yu J , Wang J , Lin W , Li S , Li H , Zhou J , Ni P , Dong W , Hu S , Zeng C , Zhang J , Zhang Y , Li R , Xu Z , Li X , Zheng H , Cong L , Lin L , Yin J , Geng J , Li G , Shi J , Liu J , Lv H , Li J , Deng Y , Ran L , Shi X , Wang X , Wu Q , Li C , Ren X , Li D , Liu D , Zhang X , Ji Z , Zhao W , Sun Y , Zhang Z , Bao J , Han Y , Dong L , Ji J , Chen P , Wu S , Xiao Y , Bu D , Tan J , Yang L , Ye C , Xu J , Zhou Y , Yu Y , Zhang B , Zhuang S , Wei H , Liu B , Lei M , Yu H , Li Y , Xu H , Wei S , He X , Fang L , Huang X , Su Z , Tong W , Tong Z , Ye J , Wang L , Lei T , Chen C , Chen H , Huang H , Zhang F , Li N , Zhao C , Huang Y , Li L , Xi Y , Qi Q , Li W , Hu W , Tian X , Jiao Y , Liang X , Jin J , Gao L , Zheng W , Hao B , Liu S , Wang W , Yuan L , Cao M , McDermott J , Samudrala R , Wong GK , Yang H
Ref : PLoS Biol , 3 :e38 , 2005
Abstract : We report improved whole-genome shotgun sequences for the genomes of indica and japonica rice, both with multimegabase contiguity, or almost 1,000-fold improvement over the drafts of 2002. Tested against a nonredundant collection of 19,079 full-length cDNAs, 97.7% of the genes are aligned, without fragmentation, to the mapped super-scaffolds of one or the other genome. We introduce a gene identification procedure for plants that does not rely on similarity to known genes to remove erroneous predictions resulting from transposable elements. Using the available EST data to adjust for residual errors in the predictions, the estimated gene count is at least 38,000-40,000. Only 2%-3% of the genes are unique to any one subspecies, comparable to the amount of sequence that might still be missing. Despite this lack of variation in gene content, there is enormous variation in the intergenic regions. At least a quarter of the two sequences could not be aligned, and where they could be aligned, single nucleotide polymorphism (SNP) rates varied from as little as 3.0 SNP/kb in the coding regions to 27.6 SNP/kb in the transposable elements. A more inclusive new approach for analyzing duplication history is introduced here. It reveals an ancient whole-genome duplication, a recent segmental duplication on Chromosomes 11 and 12, and massive ongoing individual gene duplications. We find 18 distinct pairs of duplicated segments that cover 65.7% of the genome; 17 of these pairs date back to a common time before the divergence of the grasses. More important, ongoing individual gene duplications provide a never-ending source of raw material for gene genesis and are major contributors to the differences between members of the grass family.
ESTHER : Yu_2005_PLoS.Biol_3_e38
PubMedSearch : Yu_2005_PLoS.Biol_3_e38
PubMedID: 15685292
Gene_locus related to this paper: orysa-Q7XTC5 , orysa-Q852M6 , orysa-Q8GSE8 , orysa-Q9S7P1 , orysa-Q9FYP7 , orysa-Q5ZBH3 , orysa-Q5ZA26 , orysa-Q5JLP6 , orysa-Q8H5P9 , orysa-Q8H5P5 , orysa-Q7F1Y5 , orysa-Q949C9 , orysa-cbp1 , orysa-cbp3 , orysa-cbpx , orysa-Q33B71 , orysa-Q8GSJ3 , orysa-LPL1 , orysa-Q6YSZ8 , orysa-Q8S5X5 , orysa-Q8LIG3 , orysa-Q6K7F5 , orysa-Q7F1B1 , orysa-Q8H4S9 , orysa-Q69UB1 , orysa-Q9FW17 , orysa-Q337C3 , orysa-Q7F959 , orysa-Q84QZ6 , orysa-Q84QY7 , orysa-Q851E3 , orysa-Q6YTH5 , orysa-Q0JK71 , orysa-Q8S1D9 , orysa-Q5N8V4 , orysa-Q0JCY4 , orysa-Q8GTK2 , orysa-B9EWJ8 , orysa-Q8H3K6 , orysa-Q6ZDG8 , orysa-Q6ZDG6 , orysa-Q6ZDG5 , orysa-Q6ZDG4 , orysa-Q5NAI4 , orysa-Q658B2 , orysa-Q5JMQ8 , orysa-Q5QMD9 , orysa-Q5N7L1 , orysa-Q8RYV9 , orysa-Q8H3R3 , orysa-Q5SNH3 , orysa-Q8W0F0 , orysa-pir7a , orysa-pir7b , orysa-q2qlm4 , orysa-q2qm78 , orysa-q2qm82 , orysa-q2qn31 , orysa-q2qnj4 , orysa-q2qnt9 , orysa-q2qur1 , orysa-q2qx94 , orysa-q2qyi1 , orysa-q2qyj1 , orysa-q2r051 , orysa-q2r077 , orysa-q2ram0 , orysa-q2rat1 , orysa-q2rbb3 , orysa-Q4VWY7 , orysa-q5na00 , orysa-q5nbu1 , orysa-Q5QLC0 , orysa-q5smv5 , orysa-Q5VP27 , orysa-q5vrt2 , orysa-q5w6c5 , orysa-q5z5a3 , orysa-q5z9i2 , orysa-q5z417 , orysa-q5z901 , orysa-Q5ZAM8 , orysa-Q5ZBI5 , orysa-Q5ZCR3 , orysa-q6atz0 , orysa-q6ave2 , orysa-q6f358 , orysa-q6h6s1 , orysa-q6h7i6 , orysa-q6i5q3 , orysa-q6i5u7 , orysa-q6j657 , orysa-q6k3d9 , orysa-q6k4q2 , orysa-q6k880 , orysa-q6l5b6 , orysa-Q6L5F5 , orysa-q6l556 , orysj-q6yse8 , orysa-q6yy42 , orysa-q6yzk1 , orysa-q6z8b1 , orysa-q6z995 , orysa-q6zc62 , orysa-q6zia4 , orysa-q6zjq6 , orysa-q7x7y5 , orysa-Q7XC50 , orysa-q7xej4 , orysa-q7xem8 , orysa-q7xkj9 , orysa-q7xr62 , orysa-q7xr63 , orysa-q7xr64 , orysa-q7xsg1 , orysa-q7xsq2 , orysa-q7xts6 , orysa-q7xv53 , orysa-Q7XVB5 , orysa-Q8L562 , orysa-Q8LQS5 , orysa-Q8RZ40 , orysa-Q8RZ79 , orysa-Q8S0U8 , orysa-Q8S0V0 , orysa-Q8S125 , orysa-Q8SAY7 , orysa-Q8SAY9 , orysa-Q8W3C6 , orysa-Q8W3F2 , orysa-Q8W3F4 , orysa-Q8W3F6 , orysa-Q9LHX5 , orysa-q33aq0 , orysa-q53lh1 , orysa-q53m20 , orysa-q53nd8 , orysa-q60e79 , orysa-q60ew8 , orysa-q67iz2 , orysa-q67iz3 , orysa-q67iz7 , orysa-q67iz8 , orysa-q67j02 , orysa-q67j05 , orysa-q67j07 , orysa-q67j09 , orysa-q67j10 , orysa-q67tr6 , orysa-q67tv0 , orysa-q67uz1 , orysa-q67v34 , orysa-q67wz5 , orysa-q69j38 , orysa-q69k08 , orysa-q69md7 , orysa-q69me0 , orysa-q69pf3 , orysa-q69ti3 , orysa-q69xr2 , orysa-q69y12 , orysa-q69y21 , orysa-q75hy2 , orysa-q75i01 , orysa-Q94JD7 , orysa-Q0J0A4 , orysa-q651a8 , orysa-q651z3 , orysa-q652g4 , orysa-q688m0 , orysa-q688m8 , orysa-q688m9 , orysa-Q6H8G1 , orysi-a2wn01 , orysi-a2xc83 , orysi-a2yh83 , orysi-a2z179 , orysi-a2zef2 , orysi-b8a7e6 , orysi-b8a7e7 , orysi-b8bfe5 , orysi-b8bhp9 , orysj-a3b9l8 , orysj-b9eub8 , orysj-b9eya5 , orysj-b9fi05 , orysj-b9fkb0 , orysj-b9fn42 , orysj-b9gbb7 , orysj-cgep , orysj-PLA7 , orysj-q0d4u5 , orysj-q0djj0 , orysj-q0jaf0 , orysj-q5jl22 , orysj-q5jlw7 , orysj-q5z419 , orysj-q6h7q9 , orysj-q6yvk6 , orysj-q6z6i1 , orysj-q7f8x1 , orysj-q7xcx3 , orysj-q9fwm6 , orysj-q10j20 , orysj-q10ss2 , orysj-q69uw6 , orysj-q94d71 , orysj-q338c0 , orysi-b8bly4 , orysj-b9gbs4 , orysi-a2zb88 , orysj-b9gbs1 , orysi-b8b698 , orysj-pla4 , orysj-pla1

Title : A prodrug approach toward the development of water soluble fluoroquinolones and structure--activity relationships of quinoline-3-carboxylic acids - Baker_2004_J.Med.Chem_47_4693
Author(s) : Baker WR , Cai S , Dimitroff M , Fang L , Huh KK , Ryckman DR , Shang X , Shawar RM , Therrien JH
Ref : Journal of Medicinal Chemistry , 47 :4693 , 2004
Abstract : A fluoroquinolone prodrug, PA2808, was prepared and shown to convert to the highly active parent drug PA2789. In vitro and in vivo activation of PA2808 by alkaline phosphatase was demonstrated using disk diffusion and rat lung infection models. The water solubility of PA2808 showed a marked increase compared to PA2789 over a pH range suitable for aerosol drug delivery. A total of 48 analogues based on PA2789 were prepared and screened against a panel of Gram-positive and Gram-negative pathogens. Incorporating a cyclopropane-fused pyrrolidine (amine) at C-7 resulted in some of the most active analogues.
ESTHER : Baker_2004_J.Med.Chem_47_4693
PubMedSearch : Baker_2004_J.Med.Chem_47_4693
PubMedID: 15341485