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| | <StructureSection load='6nba' size='340' side='right'caption='[[6nba]], [[Resolution|resolution]] 2.50Å' scene=''> | | <StructureSection load='6nba' size='340' side='right'caption='[[6nba]], [[Resolution|resolution]] 2.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6nba]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NBA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NBA FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6nba]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NBA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6NBA FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=P1T:2-[({3-HYDROXY-2-METHYL-5-[(PHOSPHONOOXY)METHYL]PYRIDIN-4-YL}METHYL)AMINO]ACRYLIC+ACID'>P1T</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.495Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CTH ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=P1T:2-[({3-HYDROXY-2-METHYL-5-[(PHOSPHONOOXY)METHYL]PYRIDIN-4-YL}METHYL)AMINO]ACRYLIC+ACID'>P1T</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cystathionine_gamma-lyase Cystathionine gamma-lyase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.4.1.1 4.4.1.1] </span></td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6nba FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nba OCA], [https://pdbe.org/6nba PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6nba RCSB], [https://www.ebi.ac.uk/pdbsum/6nba PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6nba ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6nba FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nba OCA], [http://pdbe.org/6nba PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nba RCSB], [http://www.ebi.ac.uk/pdbsum/6nba PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nba ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/CGL_HUMAN CGL_HUMAN]] Defects in CTH are the cause of cystathioninuria (CSTNU) [MIM:[http://omim.org/entry/219500 219500]]. It is an autosomal recessive phenotype characterized by abnormal accumulation of plasma cystathionine, leading to increased urinary excretion.<ref>PMID:18476726</ref> <ref>PMID:12574942</ref> | + | [https://www.uniprot.org/uniprot/CGL_HUMAN CGL_HUMAN] Defects in CTH are the cause of cystathioninuria (CSTNU) [MIM:[https://omim.org/entry/219500 219500]. It is an autosomal recessive phenotype characterized by abnormal accumulation of plasma cystathionine, leading to increased urinary excretion.<ref>PMID:18476726</ref> <ref>PMID:12574942</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CGL_HUMAN CGL_HUMAN]] Catalyzes the last step in the trans-sulfuration pathway from methionine to cysteine. Has broad substrate specificity. Converts cystathionine to cysteine, ammonia and 2-oxobutanoate. Converts two cysteine molecules to lanthionine and hydrogen sulfide. Can also accept homocysteine as substrate. Specificity depends on the levels of the endogenous substrates. Generates the endogenous signaling molecule hydrogen sulfide (H2S), and so contributes to the regulation of blood pressure. Acts as a cysteine-protein sulfhydrase by mediating sulfhydration of target proteins: sulfhydration consists of converting -SH groups into -SSH on specific cysteine residues of target proteins such as GAPDH, PTPN1 and NF-kappa-B subunit RELA, thereby regulating their function.<ref>PMID:19261609</ref> <ref>PMID:22169477</ref> <ref>PMID:19019829</ref> | + | [https://www.uniprot.org/uniprot/CGL_HUMAN CGL_HUMAN] Catalyzes the last step in the trans-sulfuration pathway from methionine to cysteine. Has broad substrate specificity. Converts cystathionine to cysteine, ammonia and 2-oxobutanoate. Converts two cysteine molecules to lanthionine and hydrogen sulfide. Can also accept homocysteine as substrate. Specificity depends on the levels of the endogenous substrates. Generates the endogenous signaling molecule hydrogen sulfide (H2S), and so contributes to the regulation of blood pressure. Acts as a cysteine-protein sulfhydrase by mediating sulfhydration of target proteins: sulfhydration consists of converting -SH groups into -SSH on specific cysteine residues of target proteins such as GAPDH, PTPN1 and NF-kappa-B subunit RELA, thereby regulating their function.<ref>PMID:19261609</ref> <ref>PMID:22169477</ref> <ref>PMID:19019829</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Cystathionine gamma-lyase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Banerjee, R]] | + | [[Category: Banerjee R]] |
| - | [[Category: Cho, U S]] | + | [[Category: Cho U-S]] |
| - | [[Category: Kim, H]] | + | [[Category: Kim H]] |
| - | [[Category: Yadav, P K]] | + | [[Category: Yadav PK]] |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Lyase]]
| + | |
| Structural highlights
Disease
CGL_HUMAN Defects in CTH are the cause of cystathioninuria (CSTNU) [MIM:219500. It is an autosomal recessive phenotype characterized by abnormal accumulation of plasma cystathionine, leading to increased urinary excretion.[1] [2]
Function
CGL_HUMAN Catalyzes the last step in the trans-sulfuration pathway from methionine to cysteine. Has broad substrate specificity. Converts cystathionine to cysteine, ammonia and 2-oxobutanoate. Converts two cysteine molecules to lanthionine and hydrogen sulfide. Can also accept homocysteine as substrate. Specificity depends on the levels of the endogenous substrates. Generates the endogenous signaling molecule hydrogen sulfide (H2S), and so contributes to the regulation of blood pressure. Acts as a cysteine-protein sulfhydrase by mediating sulfhydration of target proteins: sulfhydration consists of converting -SH groups into -SSH on specific cysteine residues of target proteins such as GAPDH, PTPN1 and NF-kappa-B subunit RELA, thereby regulating their function.[3] [4] [5]
Publication Abstract from PubMed
Hydrogen sulfide (H2S) is a gaseous signaling molecule, which modulates a wide range of mammalian physiological processes. Cystathionine gamma-lyase (CSE) catalyzes H2S synthesis and is a potential target for modulating H2S levels under pathophysiological conditions. CSE is inhibited by propargylglycine (PPG), a widely used mechanism-based inhibitor. In this study, we report that inhibition of H2S synthesis from cysteine but not the canonical cystathionine cleavage reaction catalyzed by CSE in vitro, is sensitive to pre-incubation of the enzyme with PPG. In contrast, the efficacy of S-3-carboxpropyl-L-cysteine (CPC) a new inhibitor described herein, was not dependent on the order of substrate/inhibitor addition. We observed that CPC inhibited the gamma-elimination reaction of cystathionine and H2S synthesis from cysteine by human CSE with Ki values of 50 +/- 3 microM and 180 +/- 15 microM, respectively. We noted that CPC spared the other enzymes involved either directly (cystathionine beta-synthase, mercaptopyruvate sulfurtransferase) or indirectly (cysteine aminotransferase) in H2S biogenesis. CPC also targeted CSE in cultured cells inhibiting transsulfuration flux by 80-90% as monitored by the transfer of radiolabel from [35S]-methionine to glutathione. The 2.5A resolution crystal structure of human CSE in complex with the CPC-derived aminoacrylate intermediate, provided a structural framework for the molecular basis of its inhibitory effect. In summary, our study reveals a previously unknown confounding effect of PPG, widely used to inhibit CSE-dependent H2S synthesis, and reports on an alternative inhibitor, CPC, which could be used as a scaffold to develop more potent H2S biogenesis inhibitors.
S-3-Carboxypropyl-L-cysteine specifically inhibits cystathionine gamma-lyase-dependent hydrogen sulfide synthesis.,Yadav PK, Vitvitsky V, Kim H, White A, Cho US, Banerjee R J Biol Chem. 2019 Jun 3. pii: RA119.009047. doi: 10.1074/jbc.RA119.009047. PMID:31160338[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Zhu W, Lin A, Banerjee R. Kinetic properties of polymorphic variants and pathogenic mutants in human cystathionine gamma-lyase. Biochemistry. 2008 Jun 10;47(23):6226-32. doi: 10.1021/bi800351a. Epub 2008 May, 14. PMID:18476726 doi:10.1021/bi800351a
- ↑ Wang J, Hegele RA. Genomic basis of cystathioninuria (MIM 219500) revealed by multiple mutations in cystathionine gamma-lyase (CTH). Hum Genet. 2003 Apr;112(4):404-8. Epub 2003 Feb 6. PMID:12574942 doi:10.1007/s00439-003-0906-8
- ↑ Chiku T, Padovani D, Zhu W, Singh S, Vitvitsky V, Banerjee R. H2S biogenesis by human cystathionine gamma-lyase leads to the novel sulfur metabolites lanthionine and homolanthionine and is responsive to the grade of hyperhomocysteinemia. J Biol Chem. 2009 Apr 24;284(17):11601-12. doi: 10.1074/jbc.M808026200. Epub 2009, Mar 4. PMID:19261609 doi:10.1074/jbc.M808026200
- ↑ Krishnan N, Fu C, Pappin DJ, Tonks NK. H2S-Induced sulfhydration of the phosphatase PTP1B and its role in the endoplasmic reticulum stress response. Sci Signal. 2011 Dec 13;4(203):ra86. doi: 10.1126/scisignal.2002329. PMID:22169477 doi:10.1126/scisignal.2002329
- ↑ Sun Q, Collins R, Huang S, Holmberg-Schiavone L, Anand GS, Tan CH, van-den-Berg S, Deng LW, Moore PK, Karlberg T, Sivaraman J. Structural basis for the inhibition mechanism of human cystathionine gamma-lyase, an enzyme responsible for the production of H(2)S. J Biol Chem. 2009 Jan 30;284(5):3076-85. Epub 2008 Nov 19. PMID:19019829 doi:http://dx.doi.org/10.1074/jbc.M805459200
- ↑ Yadav PK, Vitvitsky V, Kim H, White A, Cho US, Banerjee R. S-3-Carboxypropyl-L-cysteine specifically inhibits cystathionine gamma-lyase-dependent hydrogen sulfide synthesis. J Biol Chem. 2019 Jun 3. pii: RA119.009047. doi: 10.1074/jbc.RA119.009047. PMID:31160338 doi:http://dx.doi.org/10.1074/jbc.RA119.009047
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