Database : MEDLINE
Search on : D08.811.913.050.134.850 [DeCS Category]
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  1 / 169 MEDLINE  
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PMID:28805060
Author:Singh AK; Ekka MK; Kaushik A; Pandya V; Singh RP; Banerjee S; Mittal M; Singh V; Kumaran S
Address:G. N. Ramachandran Protein Center, Institute of Microbial Technology (IMTECH), Council of Scientific and Industrial Research (CSIR) , Sector 39-A, Chandigarh, India 160036.
Title:Substrate-Induced Facilitated Dissociation of the Competitive Inhibitor from the Active Site of O-Acetyl Serine Sulfhydrylase Reveals a Competitive-Allostery Mechanism.
Source:Biochemistry; 56(37):5011-5025, 2017 Sep 19.
ISSN:1520-4995
Country of publication:United States
Language:eng
Abstract:By classical competitive antagonism, a substrate and competitive inhibitor must bind mutually exclusively to the active site. The competitive inhibition of O-acetyl serine sulfhydrylase (OASS) by the C-terminus of serine acetyltransferase (SAT) presents a paradox, because the C-terminus of SAT binds to the active site of OASS with an affinity that is 4-6 log-fold (10 -10 ) greater than that of the substrate. Therefore, we employed multiple approaches to understand how the substrate gains access to the OASS active site under physiological conditions. Single-molecule and ensemble approaches showed that the active site-bound high-affinity competitive inhibitor is actively dissociated by the substrate, which is not consistent with classical views of competitive antagonism. We employed fast-flow kinetic approaches to demonstrate that substrate-mediated dissociation of full length SAT-OASS (cysteine regulatory complex) follows a noncanonical "facilitated dissociation" mechanism. To understand the mechanism by which the substrate induces inhibitor dissociation, we resolved the crystal structures of enzyme·inhibitor·substrate ternary complexes. Crystal structures reveal a competitive allosteric binding mechanism in which the substrate intrudes into the inhibitor-bound active site and disengages the inhibitor before occupying the site vacated by the inhibitor. In summary, here we reveal a new type of competitive allosteric binding mechanism by which one of the competitive antagonists facilitates the dissociation of the other. Together, our results indicate that "competitive allostery" is the general feature of noncanonical "facilitated/accelerated dissociation" mechanisms. Further understanding of the mechanistic framework of "competitive allosteric" mechanism may allow us to design a new family of "competitive allosteric drugs/small molecules" that will have improved selectivity and specificity as compared to their competitive and allosteric counterparts.
Publication type:JOURNAL ARTICLE; VALIDATION STUDIES
Name of substance:0 (Bacterial Proteins); 0 (Enzyme Inhibitors); 0 (Ligands); 0 (Oligopeptides); 0 (Peptide Fragments); 0 (Recombinant Proteins); 452VLY9402 (Serine); 72-89-9 (Acetyl Coenzyme A); 98RA387EKY (dehydroalanine); EC 2.3.1.30 (Serine O-Acetyltransferase); EC 2.5.1.47 (Cysteine Synthase); OF5P57N2ZX (Alanine)


  2 / 169 MEDLINE  
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PMID:28559296
Author:Anderson MT; Mitchell LA; Mobley HLT
Address:University of Michigan Medical School, Department of Microbiology and Immunology, Ann Arbor, Michigan, USA.
Title:Cysteine Biosynthesis Controls Serratia marcescens Phospholipase Activity.
Source:J Bacteriol; 199(16), 2017 Aug 15.
ISSN:1098-5530
Country of publication:United States
Language:eng
Abstract:causes health care-associated opportunistic infections that can be difficult to treat due to a high incidence of antibiotic resistance. One of the many secreted proteins of is the PhlA phospholipase enzyme. Genes involved in the production and secretion of PhlA were identified by screening a transposon insertion library for phospholipase-deficient mutants on phosphatidylcholine-containing medium. Mutations were identified in four genes ( , , , and ) that are involved in the flagellum-dependent PhlA secretion pathway. An additional phospholipase-deficient isolate harbored a transposon insertion in the gene encoding a predicted serine -acetyltransferase required for cysteine biosynthesis. The requirement for extracellular phospholipase activity was confirmed using a fluorogenic phospholipase substrate. Phospholipase activity was restored to the mutant by the addition of exogenous l-cysteine or -acetylserine to the culture medium and by genetic complementation. Additionally, transcript levels were decreased 6-fold in bacteria lacking and were restored with added cysteine, indicating a role for cysteine-dependent transcriptional regulation of phospholipase activity. mutants also exhibited a defect in swarming motility that was correlated with reduced levels of and flagellar regulator gene transcription. Together, these findings suggest a model in which cysteine is required for the regulation of both extracellular phospholipase activity and surface motility in is known to secrete multiple extracellular enzymes, but PhlA is unusual in that this protein is thought to be exported by the flagellar transport apparatus. In this study, we demonstrate that both extracellular phospholipase activity and flagellar function are dependent on the cysteine biosynthesis pathway. Furthermore, a disruption of cysteine biosynthesis results in decreased and flagellar gene transcription, which can be restored by supplying bacteria with exogenous cysteine. These results identify a previously unrecognized role for CysE and cysteine in the secretion of phospholipase and in bacterial motility.
Publication type:JOURNAL ARTICLE
Name of substance:0 (Culture Media); 0 (DNA Transposable Elements); 452VLY9402 (Serine); EC 2.3.1.30 (Serine O-Acetyltransferase); EC 3.1.- (Phospholipases); G05L7T7ZEQ (O-acetylserine); K848JZ4886 (Cysteine)


  3 / 169 MEDLINE  
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PMID:28414426
Author:Kaushik A; Ekka MK; Kumaran S
Address:G. N. Ramachandran Protein Center, Council of Scientific and Industrial Research (CSIR), Institute of Microbial Technology (IMTECH) , Sector 39-A, Chandigarh 160036, India.
Title:Two Distinct Assembly States of the Cysteine Regulatory Complex of Salmonella typhimurium Are Regulated by Enzyme-Substrate Cognate Pairs.
Source:Biochemistry; 56(18):2385-2399, 2017 May 09.
ISSN:1520-4995
Country of publication:United States
Language:eng
Abstract:Serine acetyltransferase (SAT) and O-acetylserine sulfhydrylase (OASS), which catalyze the last two steps of cysteine biosynthesis, interact and form the cysteine regulatory complex (CRC). The current model of Salmonella typhimurium predicts that CRC is composed of one [SAT] unit and two molecules of [OASS] . However, it is not clear why [SAT] cannot engage all of its six high-affinity binding sites. We examined the assembly state(s) of CRC by size exclusion chromatography, analytical ultracentrifugation (AUC), isothermal titration calorimetry (ITC), and surface plasmon resonance (SPR) approaches. We show that CRC exists in two major assembly states, low-molecular weight (CRC ; 1[SAT] + 2[OASS] ) and high-molecular weight (CRC ; 1[SAT] + 4[OASS] ) states. Along with AUC results, ITC and SPR studies show that [OASS] binds to [SAT] in a stepwise manner but the formation of fully saturated CRC (1[SAT] + 6[OASS] ) is not favorable. The fraction of CRC increases as the [OASS] /[SAT] ratio increases to >4-fold, but CRC can be selectively dissociated into either CRC or free enzymes, in the presence of OAS and sulfide, in a concentration-dependent manner. Together, we show that CRC is a regulatable multienzyme assembly, sensitive to OASS-substrate(s) levels but subject to negative cooperativity and steric hindrance. Our results constitute the first report of the dual-assembly-state nature of CRC and suggest that physiological conditions, which limit sulfate uptake, would favor CRC over CRC .
Publication type:JOURNAL ARTICLE
Name of substance:0 (Recombinant Proteins); EC 2.3.1.30 (Serine O-Acetyltransferase); EC 2.5.1.47 (Cysteine Synthase); K848JZ4886 (Cysteine)


  4 / 169 MEDLINE  
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PMID:28337759
Author:Benoni R; De Bei O; Paredi G; Hayes CS; Franko N; Mozzarelli A; Bettati S; Campanini B
Address:Dipartimento di Medicina e Chirurgia, Università di Parma, Italy.
Title:Modulation of Escherichia coli serine acetyltransferase catalytic activity in the cysteine synthase complex.
Source:FEBS Lett; 591(9):1212-1224, 2017 May.
ISSN:1873-3468
Country of publication:England
Language:eng
Abstract:In bacteria and plants, serine acetyltransferase (CysE) and O-acetylserine sulfhydrylase-A sulfhydrylase (CysK) collaborate to synthesize l-Cys from l-Ser. CysE and CysK bind one another with high affinity to form the cysteine synthase complex (CSC). We demonstrate that bacterial CysE is activated when bound to CysK. CysE activation results from the release of substrate inhibition, with the K for l-Ser increasing from 4 mm for free CysE to 16 mm for the CSC. Feedback inhibition of CysE by l-Cys is also relieved in the bacterial CSC. These findings suggest that the CysE active site is allosterically altered by CysK to alleviate substrate and feedback inhibition in the context of the CSC.
Publication type:JOURNAL ARTICLE
Name of substance:0 (Escherichia coli Proteins); EC 2.3.1.30 (CysE protein, E coli); EC 2.3.1.30 (Serine O-Acetyltransferase); EC 2.5.1.47 (Cysteine Synthase); K848JZ4886 (Cysteine)


  5 / 169 MEDLINE  
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PMID:28138713
Author:Qiu J; Zang S; Ma Y; Owusu L; Zhou L; Jiang T; Xin Y
Address:Centralab, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China.
Title:Homology modeling and identification of amino acids involved in the catalytic process of Mycobacterium tuberculosis serine acetyltransferase.
Source:Mol Med Rep; 15(3):1343-1347, 2017 Mar.
ISSN:1791-3004
Country of publication:Greece
Language:eng
Abstract:Serine acetyltransferase (CysE) belongs to the hexapeptide acetyltransferase family and is involved in the biosynthesis of L­cysteine in microorganisms. Mycobacterium tuberculosis CysE is regarded as a potential target for anti­tuberculosis (TB) drugs; however, the structure and active sites of M. tuberculosis CysE remain unknown. The present study aimed to predict the secondary structure and to construct a 3D model for M. tuberculosis CysE using bioinformatics analysis. To determine the essential amino acids that are associated with CysE enzymatic activity, amino acid sequences from several microorganisms were compared, and a consensus sequence was identified. Subsequently, site­directed mutagenesis was used to generate mutant M. tuberculosis CysE proteins. Enzyme assays demonstrated that D67A, H82A and H117A mutants abolished ~75% activity of M. tuberculosis CysE. Prediction of the protein structure and identification of the active amino acids for M. tuberculosis CysE is essential for designing inhibitors, which may aid the discovery of effective anti­TB drugs.
Publication type:JOURNAL ARTICLE
Name of substance:0 (Amino Acids); EC 2.3.1.30 (Serine O-Acetyltransferase)


  6 / 169 MEDLINE  
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PMID:28126739
Author:Dharavath S; Raj I; Gourinath S
Address:School of Life Sciences, Jawaharlal Nehru University, New Delhi - 110067, India.
Title:Structure-based mutational studies of -acetylserine sulfhydrylase reveal the reason for the loss of cysteine synthase complex formation in .
Source:Biochem J; 474(7):1221-1239, 2017 Mar 23.
ISSN:1470-8728
Country of publication:England
Language:eng
Abstract:Cysteine biosynthesis takes place via a two-step pathway in bacteria, fungi, plants and protozoan parasites, but not in humans, and hence, the machinery of cysteine biosynthesis is an opportune target for therapeutics. The decameric cysteine synthase complex (CSC) is formed when the C-terminal tail of serine acetyltransferase (SAT) binds in the active site of -acetylserine sulfydrylase (OASS), playing a role in the regulation of this pathway. Here, we show that OASS from (BaOASS) does not interact with its cognate SAT C-terminal tail. Crystal structures of native BaOASS showed that residues Gln96 and Tyr125 occupy the active-site pocket and interfere with the entry of the SAT C-terminal tail. The BaOASS (Q96A-Y125A) mutant showed relatively strong binding ( = 32.4 µM) to BaSAT C-terminal peptides in comparison with native BaOASS. The mutant structure looks similar except that the active-site pocket has enough space to bind the SAT C-terminal end. Surface plasmon resonance results showed a relatively strong (7.3 µM ) interaction between BaSAT and the BaOASS (Q96A-Y125A), but no interaction with native BaOASS. Taken together, our observations suggest that the CSC does not form in .
Publication type:JOURNAL ARTICLE
Name of substance:0 (Bacterial Proteins); 0 (Recombinant Proteins); EC 2.3.1.30 (Serine O-Acetyltransferase); EC 2.5.1.47 (Cysteine Synthase); K848JZ4886 (Cysteine)


  7 / 169 MEDLINE  
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PMID:27638321
Author:Singh K; Singh KP; Equbal A; Suman SS; Zaidi A; Garg G; Pandey K; Das P; Ali V
Address:Laboratory of Molecular Biochemistry and Cell Biology, Department of Biochemistry, Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, 800007, India; Department of Biotechnology, National Institute of Pharmaceutical Education and Research, EPIP Complex, Hajipur, 844102, India.
Title:Interaction between cysteine synthase and serine O-acetyltransferase proteins and their stage specific expression in Leishmania donovani.
Source:Biochimie; 131:29-44, 2016 Dec.
ISSN:1638-6183
Country of publication:France
Language:eng
Abstract:Leishmania possess a unique trypanothione redox metabolism with undebated roles in protection from oxidative damage and drug resistance. The biosynthesis of trypanothione depends on l-cysteine bioavailability which is regulated by cysteine biosynthesis pathway. The de novo cysteine biosynthesis pathway is comprised of serine O-acetyltransferase (SAT) and cysteine synthase (CS) enzymes which sequentially mediate two consecutive steps of cysteine biosynthesis, and is absent in mammalian host. However, despite the apparent dependency of redox metabolism on cysteine biosynthesis pathway, the role of SAT and CS in redox homeostasis has been unexplored in Leishmania parasites. Herein, we have characterized CS and SAT to investigate their interaction and relative abundance of these proteins in promastigote vs. amastigote growth stages of L. donovani. CS and SAT genes of L. donovani (LdCS and LdSAT) were cloned, expressed, and fusion proteins purified to homogeneity with affinity column chromatography. Purified LdCS contains PLP as cofactor and showed optimum enzymatic activity at pH 7.5. Enzyme kinetics showed that LdCS catalyses the synthesis of cysteine using O-acetylserine and sulfide with a K of 15.86 mM and 0.17 mM, respectively. Digitonin fractionation and indirect immunofluorescence microscopy showed that LdCS and LdSAT are localized in the cytoplasm of promastigotes. Size exclusion chromatography, co-purification, pull down and immuno-precipitation assays demonstrated a stable complex formation between LdCS and LdSAT proteins. Furthermore, LdCS and LdSAT proteins expression/activity was upregulated in amastigote growth stage of the parasite. Thus, the stage specific differential expression of LdCS and LdSAT suggests that it may have a role in the redox homeostasis of Leishmania.
Publication type:JOURNAL ARTICLE
Name of substance:0 (Protozoan Proteins); EC 2.3.1.30 (Serine O-Acetyltransferase); EC 2.5.1.47 (Cysteine Synthase); K848JZ4886 (Cysteine)


  8 / 169 MEDLINE  
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PMID:27376536
Author:Zheng C; Chen M; Wang D; Zhang L; Wang J; Zhang X
Address:School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou, 014010, People's Republic of China.
Title:Interplay Between Expression of Sulfur Assimilation Pathway Genes and Zn(2+) and Pb(2+) Stress in Acidithiobacillus ferrooxidans.
Source:Curr Microbiol; 73(4):527-33, 2016 Oct.
ISSN:1432-0991
Country of publication:United States
Language:eng
Abstract:We have previously demonstrated that in Acidithiobacillus ferrooxidans, resistance to the highly toxic divalent cation Cd(2+) is mediated in part by the sulfur assimilation pathway (SAP) and enhanced intracellular concentrations of cysteine and glutathione(GSH) (Zheng et al., Extremophiles 19:429-436, 2015). In this paper, we investigate the interplay between Zn(2+) and Pb(2+) resistances, SAP gene expression, and thiol-containing metabolite levels. Cells grown in the presence of 300 mM Zn(2+) had enhanced activities of the following enzymes: adenosylphosphosulphate reductase (APR, 40-fold), serine acetyltransferase (SAT, 180-fold), and O-acetylserine (thiol) lyase (OAS-TL, 230-fold). We investigated the concentrations of mRNA transcripts of the genes encoding these enzymes in cells grown in the presence of 600 mM Zn(2+): transcripts for 4 SAP genes-ATPS(ATP sulphurylase), APR, SiR(sulfite reductase), SAT, and OAS-TL-each showed a more than three-fold increase in concentration. At the metabolite level, concentrations of intracellular cysteine and glutathione (GSH) were nearly doubled. When cells were grown in the presence of 10 mM Pb(2+), SAP gene transcript concentrations, cysteine, and GSH concentrations were all decreased, as were SAP enzyme activities. These results suggested that Zn(2+) induced SAP pathway gene transcription, while Pb(2+) inhibited SAP gene expression and enzyme activities compared to the pathway in most organisms. Because of the detoxification function of thiol pool, the results also suggested that the high resistance of A. ferrooxidans to Zn(2+) may also be due to regulation of GSH and the cysteine synthesis pathway.
Publication type:JOURNAL ARTICLE
Name of substance:0 (Bacterial Proteins); 2P299V784P (Lead); 70FD1KFU70 (Sulfur); EC 1.- (Oxidoreductases); EC 2.3.1.30 (Serine O-Acetyltransferase); EC 2.5.1.47 (Cysteine Synthase); GAN16C9B8O (Glutathione); J41CSQ7QDS (Zinc); K848JZ4886 (Cysteine)


  9 / 169 MEDLINE  
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PMID:27250663
Author:Kumano T; Suzuki T; Shimizu S; Kobayashi M
Address:Institute of Applied Biochemistry, and Graduate School of Life and Environmental Sciences, University of Tsukuba.
Title:Nitrile-synthesizing enzyme: Screening, purification and characterization.
Source:J Gen Appl Microbiol; 62(4):167-73, 2016 Sep 12.
ISSN:1349-8037
Country of publication:Japan
Language:eng
Abstract:Cyanide is known as a toxic compound for almost all living organisms. We have searched for cyanide-resistant bacteria from the soil and stock culture collection of our laboratory, and have found the existence of a lot of microorganisms grown on culture media containing 10 mM potassium cyanide. Almost all of these cyanide-resistant bacteria were found to show ß-cyano-L-alanine (ß-CNAla) synthetic activity. ß-CNAla synthase is known to catalyze nitrile synthesis: the formation of ß-CNAla from potassium cyanide and O-acetyl-L-serine or L-cysteine. We found that some microorganisms were able to detoxify cyanide using O-methyl-DL-serine, O-phospho-L-serine and ß-chloro-DL-alanine. In addition, we purified ß-CNAla synthase from Pseudomonas ovalis No. 111 in nine steps, and characterized the purified enzyme. This enzyme has a molecular mass of 60,000 and appears to consist of two identical subunits. The purified enzyme exhibits a maximum activity at pH 8.5-9.0 at an optimal temperature of 40-50°C. The enzyme is specific for O-acetyl-L-serine and ß-chloro-DL-alanine. The Km value for O-acetyl-L-serine is 10.0 mM and Vmax value is 3.57 µmol/min/mg.
Publication type:JOURNAL ARTICLE
Name of substance:0 (Culture Media); 0 (Cyanides); 0 (Nitriles); 452VLY9402 (Serine); 923-01-3 (3-cyanoalanine); EC 2.3.1.30 (Serine O-Acetyltransferase); EC 4.- (Lyases); EC 4.4.1.9 (beta-cyanoalanine synthase); K848JZ4886 (Cysteine); OF5P57N2ZX (Alanine)


  10 / 169 MEDLINE  
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PMID:26971871
Author:Boshoff HI
Address:Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: hboshoff@niaid.nih.gov.
Title:Uncovering the Serine Hydrolytic Landscape of Mycobacterium tuberculosis.
Source:Cell Chem Biol; 23(2):209-211, 2016 Feb 18.
ISSN:2451-9456
Country of publication:United States
Language:eng
Abstract:In this issue of Cell Chemical Biology, Ortega et al. (2016) present a study utilizing a click-chemistry-enabled fluorophosphonate for activity-based identification of serine hydrolases, pinpointing a range of proteins including previously annotated hypotheticals. The application of this technology on both actively replicating and non-replicating Mycobacterium tuberculosis gives us a glimpse of its serine hydrolytic landscape during different stages of metabolic activity.
Publication type:COMMENT; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., INTRAMURAL
Name of substance:0 (Antitubercular Agents); 0 (Bacterial Proteins); 0 (Serine Proteinase Inhibitors); 452VLY9402 (Serine); EC 2.3.1.30 (Serine O-Acetyltransferase); EC 3.- (Hydrolases); EC 3.4.- (Serine Proteases); EC 3.4.21.- (Serine Endopeptidases)



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