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| | ==Structural and biochemical basis for the inhibition of cell death by APIP, a methionine salvage enzyme== | | ==Structural and biochemical basis for the inhibition of cell death by APIP, a methionine salvage enzyme== |
| - | <StructureSection load='4m6r' size='340' side='right' caption='[[4m6r]], [[Resolution|resolution]] 2.00Å' scene=''> | + | <StructureSection load='4m6r' size='340' side='right'caption='[[4m6r]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4m6r]] 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=4M6R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4M6R FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4m6r]] 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=4M6R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4M6R FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 2Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">APIP, CGI-29 ([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=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Methylthioribulose_1-phosphate_dehydratase Methylthioribulose 1-phosphate dehydratase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.2.1.109 4.2.1.109] </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=4m6r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m6r OCA], [https://pdbe.org/4m6r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4m6r RCSB], [https://www.ebi.ac.uk/pdbsum/4m6r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4m6r 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=4m6r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m6r OCA], [http://pdbe.org/4m6r PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4m6r RCSB], [http://www.ebi.ac.uk/pdbsum/4m6r PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4m6r ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MTNB_HUMAN MTNB_HUMAN]] Catalyzes the dehydration of methylthioribulose-1-phosphate (MTRu-1-P) into 2,3-diketo-5-methylthiopentyl-1-phosphate (DK-MTP-1-P). Functions in the methionine salvage pathway, which plays a key role in cancer, apoptosis, microbial proliferation and inflammation. May inhibit the CASP1-related inflammatory response (pyroptosis), the CASP9-dependent apoptotic pathway and the cytochrome c-dependent and APAF1-mediated cell death.<ref>PMID:15262985</ref> <ref>PMID:23285211</ref> <ref>PMID:22837397</ref> | + | [https://www.uniprot.org/uniprot/MTNB_HUMAN MTNB_HUMAN] Catalyzes the dehydration of methylthioribulose-1-phosphate (MTRu-1-P) into 2,3-diketo-5-methylthiopentyl-1-phosphate (DK-MTP-1-P). Functions in the methionine salvage pathway, which plays a key role in cancer, apoptosis, microbial proliferation and inflammation. May inhibit the CASP1-related inflammatory response (pyroptosis), the CASP9-dependent apoptotic pathway and the cytochrome c-dependent and APAF1-mediated cell death.<ref>PMID:15262985</ref> <ref>PMID:23285211</ref> <ref>PMID:22837397</ref> |
| - | <div style="background-color:#fffaf0;">
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| - | == Publication Abstract from PubMed ==
| + | |
| - | APIP, Apaf-1 interacting protein, has been known to inhibit two main types of programmed cell death, apoptosis and pyroptosis, and was recently found to be associated with cancers and inflammatory diseases. Distinct from its inhibitory role in cell death, APIP was also shown to act as a 5-methylthioribulose-1-phosphate dehydratase, or MtnB, in the methionine salvage pathway. Here we report the structural and enzymatic characterization of human APIP as an MtnB enzyme with a Km of 9.32 muM and a Vmax of 1.39 mumol min(-1) mg(-1). The crystal structure was determined at 2.0-A resolution, revealing an overall fold similar to members of the zinc-dependent class II aldolase family. APIP/MtnB exists as a tetramer in solution and exhibits an assembly with C4 symmetry in the crystal lattice. The pocket-shaped active site is located at the end of a long cleft between two adjacent subunits. We propose an enzymatic reaction mechanism involving Glu139* as a catalytic acid/base, as supported by enzymatic assay, substrate-docking study, and sequence conservation analysis. We explored the relationship between two distinct functions of APIP/MtnB, cell death inhibition, and methionine salvage, by measuring the ability of enzymatic mutants to inhibit cell death, and determined that APIP/MtnB functions as a cell death inhibitor independently of its MtnB enzyme activity for apoptosis induced by either hypoxia or etoposide, but dependently for caspase-1-induced pyroptosis. Our results establish the structural and biochemical groundwork for future mechanistic studies of the role of APIP/MtnB in modulating cell death and inflammation and in the development of related diseases.
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| - | Structural and biochemical basis for the inhibition of cell death by APIP, a methionine salvage enzyme.,Kang W, Hong SH, Lee HM, Kim NY, Lim YC, Le le TM, Lim B, Kim HC, Kim TY, Ashida H, Yokota A, Hah SS, Chun KH, Jung YK, Yang JK Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):E54-61. doi: 10.1073/pnas.1308768111., Epub 2013 Dec 23. PMID:24367089<ref>PMID:24367089</ref>
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| - | <div class="pdbe-citations 4m6r" style="background-color:#fffaf0;"></div>
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| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Methylthioribulose 1-phosphate dehydratase]] | + | [[Category: Large Structures]] |
| - | [[Category: Ashida, H]] | + | [[Category: Ashida H]] |
| - | [[Category: Chun, K H]] | + | [[Category: Chun KH]] |
| - | [[Category: Hah, S S]] | + | [[Category: Hah SS]] |
| - | [[Category: Hong, S H]] | + | [[Category: Hong SH]] |
| - | [[Category: Jung, Y K]] | + | [[Category: Jung YK]] |
| - | [[Category: Kang, W]] | + | [[Category: Kang W]] |
| - | [[Category: Kim, H C]] | + | [[Category: Kim HC]] |
| - | [[Category: Kim, N Y]] | + | [[Category: Kim NY]] |
| - | [[Category: Kim, T Y]] | + | [[Category: Kim TY]] |
| - | [[Category: Le, L T.M]] | + | [[Category: Le LTM]] |
| - | [[Category: Lee, H M]] | + | [[Category: Lee HM]] |
| - | [[Category: Lim, B]] | + | [[Category: Lim B]] |
| - | [[Category: Lim, Y C]] | + | [[Category: Lim YC]] |
| - | [[Category: Yang, J K]] | + | [[Category: Yang JK]] |
| - | [[Category: Yokota, A]] | + | [[Category: Yokota A]] |
| - | [[Category: Apip]]
| + | |
| - | [[Category: Class ii aldolase family]]
| + | |
| - | [[Category: Dehydratase]]
| + | |
| - | [[Category: Lyase]]
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| - | [[Category: Mtnb]]
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| Structural highlights
Function
MTNB_HUMAN Catalyzes the dehydration of methylthioribulose-1-phosphate (MTRu-1-P) into 2,3-diketo-5-methylthiopentyl-1-phosphate (DK-MTP-1-P). Functions in the methionine salvage pathway, which plays a key role in cancer, apoptosis, microbial proliferation and inflammation. May inhibit the CASP1-related inflammatory response (pyroptosis), the CASP9-dependent apoptotic pathway and the cytochrome c-dependent and APAF1-mediated cell death.[1] [2] [3]
References
- ↑ Cho DH, Hong YM, Lee HJ, Woo HN, Pyo JO, Mak TW, Jung YK. Induced inhibition of ischemic/hypoxic injury by APIP, a novel Apaf-1-interacting protein. J Biol Chem. 2004 Sep 17;279(38):39942-50. Epub 2004 Jul 15. PMID:15262985 doi:http://dx.doi.org/10.1074/jbc.M405747200
- ↑ Mary C, Duek P, Salleron L, Tienz P, Bumann D, Bairoch A, Lane L. Functional identification of APIP as human mtnB, a key enzyme in the methionine salvage pathway. PLoS One. 2012;7(12):e52877. doi: 10.1371/journal.pone.0052877. Epub 2012 Dec 28. PMID:23285211 doi:http://dx.doi.org/10.1371/journal.pone.0052877
- ↑ Ko DC, Gamazon ER, Shukla KP, Pfuetzner RA, Whittington D, Holden TD, Brittnacher MJ, Fong C, Radey M, Ogohara C, Stark AL, Akey JM, Dolan ME, Wurfel MM, Miller SI. Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death. Proc Natl Acad Sci U S A. 2012 Aug 28;109(35):E2343-52. doi:, 10.1073/pnas.1206701109. Epub 2012 Jul 25. PMID:22837397 doi:http://dx.doi.org/10.1073/pnas.1206701109
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