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| | <StructureSection load='7edz' size='340' side='right'caption='[[7edz]], [[Resolution|resolution]] 1.95Å' scene=''> | | <StructureSection load='7edz' size='340' side='right'caption='[[7edz]], [[Resolution|resolution]] 1.95Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[7edz]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7EDZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7EDZ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7edz]] 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=7EDZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7EDZ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=J1O:4-[[(2R)-3,3-dimethyl-2-oxidanyl-4-phosphonooxy-butanoyl]amino]butanoic+acid'>J1O</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.95Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Phosphopantothenate--cysteine_ligase_(ATP) Phosphopantothenate--cysteine ligase (ATP)], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.3.2.51 6.3.2.51] </span></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=J1O:4-[[(2R)-3,3-dimethyl-2-oxidanyl-4-phosphonooxy-butanoyl]amino]butanoic+acid'>J1O</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=7edz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7edz OCA], [https://pdbe.org/7edz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7edz RCSB], [https://www.ebi.ac.uk/pdbsum/7edz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7edz ProSAT]</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=7edz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7edz OCA], [https://pdbe.org/7edz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7edz RCSB], [https://www.ebi.ac.uk/pdbsum/7edz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7edz ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/PPCS_HUMAN PPCS_HUMAN]] Catalyzes the first step in the biosynthesis of coenzyme A from vitamin B5, where cysteine is conjugated to 4'-phosphopantothenate to form 4-phosphopantothenoylcysteine.<ref>PMID:11923312</ref> <ref>PMID:12906824</ref>
| + | [https://www.uniprot.org/uniprot/PPCS_HUMAN PPCS_HUMAN] Catalyzes the first step in the biosynthesis of coenzyme A from vitamin B5, where cysteine is conjugated to 4'-phosphopantothenate to form 4-phosphopantothenoylcysteine.<ref>PMID:11923312</ref> <ref>PMID:12906824</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: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Anand, R]] | + | [[Category: Anand R]] |
| - | [[Category: Mostert, K J]] | + | [[Category: Mostert KJ]] |
| - | [[Category: Sharma, N]] | + | [[Category: Sharma N]] |
| - | [[Category: Strauss, E]] | + | [[Category: Strauss E]] |
| - | [[Category: Ligase]]
| + | |
| - | [[Category: Phosphopantothenoylcysteine synthetase]]
| + | |
| Structural highlights
7edz is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.95Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
PPCS_HUMAN Catalyzes the first step in the biosynthesis of coenzyme A from vitamin B5, where cysteine is conjugated to 4'-phosphopantothenate to form 4-phosphopantothenoylcysteine.[1] [2]
Publication Abstract from PubMed
The pantothenate analogue hopantenate (HoPan) is widely used as a modulator of coenzyme A (CoA) levels in cell biology and disease models horizontal line especially for pantothenate kinase associated neurodegeneration (PKAN), a genetic disease rooted in impaired CoA metabolism. This use of HoPan was based on reports that it inhibits pantothenate kinase (PanK), the first enzyme of CoA biosynthesis. Using a combination of in vitro enzyme kinetic studies, crystal structure analysis, and experiments in a typical PKAN cell biology model, we demonstrate that instead of inhibiting PanK, HoPan relies on it for metabolic activation. Once phosphorylated, HoPan inhibits the next enzyme in the CoA pathway horizontal line phosphopantothenoylcysteine synthetase (PPCS) horizontal line through formation of a nonproductive substrate complex. Moreover, the obtained structure of the human PPCS in complex with the inhibitor and activating nucleotide analogue provides new insights into the catalytic mechanism of PPCS enzymes horizontal line including the elusive binding mode for cysteine horizontal line and reveals the functional implications of mutations in the human PPCS that have been linked to severe dilated cardiomyopathy. Taken together, this study demonstrates that the molecular mechanism of action of HoPan is more complex than previously thought, suggesting that the results of studies in which it is used as a tool compound must be interpreted with care. Moreover, our findings provide a clear framework for evaluating the various factors that contribute to the potency of CoA-directed inhibitors, one that will prove useful in the future rational development of potential therapies of both human genetic and infectious diseases.
The Coenzyme A Level Modulator Hopantenate (HoPan) Inhibits Phosphopantotenoylcysteine Synthetase Activity.,Mostert KJ, Sharma N, van der Zwaag M, Staats R, Koekemoer L, Anand R, Sibon OCM, Strauss E ACS Chem Biol. 2021 Nov 19;16(11):2401-2414. doi: 10.1021/acschembio.1c00535., Epub 2021 Sep 28. PMID:34582681[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Daugherty M, Polanuyer B, Farrell M, Scholle M, Lykidis A, de Crecy-Lagard V, Osterman A. Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics. J Biol Chem. 2002 Jun 14;277(24):21431-9. Epub 2002 Mar 28. PMID:11923312 doi:http://dx.doi.org/10.1074/jbc.M201708200
- ↑ Manoj N, Strauss E, Begley TP, Ealick SE. Structure of human phosphopantothenoylcysteine synthetase at 2.3 A resolution. Structure. 2003 Aug;11(8):927-36. PMID:12906824
- ↑ Mostert KJ, Sharma N, van der Zwaag M, Staats R, Koekemoer L, Anand R, Sibon OCM, Strauss E. The Coenzyme A Level Modulator Hopantenate (HoPan) Inhibits Phosphopantotenoylcysteine Synthetase Activity. ACS Chem Biol. 2021 Nov 19;16(11):2401-2414. doi: 10.1021/acschembio.1c00535., Epub 2021 Sep 28. PMID:34582681 doi:http://dx.doi.org/10.1021/acschembio.1c00535
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