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| | ==Crystal structure of Mycobacterium tuberculosis IpdAB== | | ==Crystal structure of Mycobacterium tuberculosis IpdAB== |
| - | <StructureSection load='6con' size='340' side='right' caption='[[6con]], [[Resolution|resolution]] 2.10Å' scene=''> | + | <StructureSection load='6con' size='340' side='right'caption='[[6con]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6con]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CON OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CON FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6con]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CON OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CON FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">gctA, CRX58_09925, ERS007663_04080, ERS007665_02371, ERS023446_02783, ERS027646_00148, ERS027654_03521, ERS027656_00696, ERS124361_01188, SAMEA2682864_02618, SAMEA2683035_00650 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884]), catJ, CRX58_09930, ERS007657_01926, ERS007661_02237, ERS007665_02370, ERS007670_03185, ERS007672_03945, ERS007679_04090, ERS007681_03977, ERS007688_03438, ERS007703_04697, ERS007722_01813, ERS007741_03174, ERS023446_02782, ERS024213_01521, ERS024276_02483, ERS027644_04603, ERS027646_00147, ERS027656_00695, ERS027659_03102, ERS027661_03605, ERS027666_03707, ERS124361_01187, SAMEA2682864_02619, SAMEA2683035_00651 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</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]] 2.1Å</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=6con FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6con OCA], [http://pdbe.org/6con PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6con RCSB], [http://www.ebi.ac.uk/pdbsum/6con PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6con 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=6con FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6con OCA], [https://pdbe.org/6con PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6con RCSB], [https://www.ebi.ac.uk/pdbsum/6con PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6con ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/IPDA_MYCTU IPDA_MYCTU] Involved in the final steps of cholesterol and steroid degradation (PubMed:28377529). Opens the last steroid ring of cholesterol by catalyzing the hydrolysis of (3E)-2-(2-carboxylatoethyl)-3-methyl-6-oxocyclohex-1-ene-1-carboxyl-CoA (COCHEA-CoA) to 6-methyl-3,7-dioxodecanedioyl-CoA (MeDODA-CoA) (PubMed:29581275).<ref>PMID:28377529</ref> <ref>PMID:29581275</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: Crowe, A M]] | + | [[Category: Large Structures]] |
| - | [[Category: Eltis, L D]] | + | [[Category: Mycobacterium tuberculosis]] |
| - | [[Category: Strynadka, N C.J]] | + | [[Category: Crowe AM]] |
| - | [[Category: Watanabe, N]] | + | [[Category: Eltis LD]] |
| - | [[Category: Workman, S D]] | + | [[Category: Strynadka NCJ]] |
| - | [[Category: Worrall, L J]] | + | [[Category: Watanabe N]] |
| - | [[Category: Cholesterol]] | + | [[Category: Workman SD]] |
| - | [[Category: Hydrolase]] | + | [[Category: Worrall LJ]] |
| - | [[Category: Ring cleaving]]
| + | |
| - | [[Category: Virulence factor]]
| + | |
| Structural highlights
Function
IPDA_MYCTU Involved in the final steps of cholesterol and steroid degradation (PubMed:28377529). Opens the last steroid ring of cholesterol by catalyzing the hydrolysis of (3E)-2-(2-carboxylatoethyl)-3-methyl-6-oxocyclohex-1-ene-1-carboxyl-CoA (COCHEA-CoA) to 6-methyl-3,7-dioxodecanedioyl-CoA (MeDODA-CoA) (PubMed:29581275).[1] [2]
Publication Abstract from PubMed
Mycobacterium tuberculosis (Mtb) grows on host-derived cholesterol during infection. IpdAB, found in all steroid-degrading bacteria and a determinant of pathogenicity, has been implicated in the hydrolysis of the last steroid ring. Phylogenetic analyses revealed that IpdAB orthologs form a clade of CoA transferases (CoTs). In a coupled assay with a thiolase, IpdAB transformed the cholesterol catabolite (R)-2-(2-carboxyethyl)-3-methyl-6-oxocyclohex-1-ene-1-carboxyl-CoA (COCHEA-CoA) and CoASH to 4-methyl-5-oxo-octanedioyl-CoA (MOODA-CoA) and acetyl-CoA with high specificity (kcat/Km = 5.8 +/- 0.8 x 10(4) M(-1)s(-1)). The structure of MOODA-CoA was consistent with IpdAB hydrolyzing COCHEA-CoA to a beta-keto-thioester, a thiolase substrate. Contrary to characterized CoTs, IpdAB exhibited no activity toward small CoA thioesters. Further, IpdAB lacks the catalytic glutamate residue that is conserved in the beta-subunit of characterized CoTs and a glutamyl-CoA intermediate was not trapped during turnover. By contrast, Glu105(A), conserved in the alpha-subunit of IpdAB, was essential for catalysis. A crystal structure of the IpdAB.COCHEA-CoA complex, solved to 1.4 A, revealed that Glu105(A) is positioned to act as a catalytic base. Upon titration with COCHEA-CoA, the E105A(A) variant accumulated a yellow-colored species (lambdamax = 310 nm; Kd = 0.4 +/- 0.2 muM) typical of beta-keto enolates. In the presence of D2O, IpdAB catalyzed the deuteration of COCHEA-CoA adjacent to the hydroxylation site at rates consistent with kcat Based on these data and additional IpdAB variants, we propose a retro-Claisen condensation-like mechanism for the IpdAB-mediated hydrolysis of COCHEA-CoA. This study expands the range of known reactions catalyzed by the CoT superfamily and provides mechanistic insight into an important determinant of Mtb pathogenesis.
IpdAB, a virulence factor in Mycobacterium tuberculosis, is a cholesterol ring-cleaving hydrolase.,Crowe AM, Workman SD, Watanabe N, Worrall LJ, Strynadka NCJ, Eltis LD Proc Natl Acad Sci U S A. 2018 Mar 26. pii: 1717015115. doi:, 10.1073/pnas.1717015115. PMID:29581275[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Crowe AM, Casabon I, Brown KL, Liu J, Lian J, Rogalski JC, Hurst TE, Snieckus V, Foster LJ, Eltis LD. Catabolism of the Last Two Steroid Rings in Mycobacterium tuberculosis and Other Bacteria. mBio. 2017 Apr 4;8(2):e00321-17. PMID:28377529 doi:10.1128/mBio.00321-17
- ↑ Crowe AM, Workman SD, Watanabe N, Worrall LJ, Strynadka NCJ, Eltis LD. IpdAB, a virulence factor in Mycobacterium tuberculosis, is a cholesterol ring-cleaving hydrolase. Proc Natl Acad Sci U S A. 2018 Mar 26. pii: 1717015115. doi:, 10.1073/pnas.1717015115. PMID:29581275 doi:http://dx.doi.org/10.1073/pnas.1717015115
- ↑ Crowe AM, Workman SD, Watanabe N, Worrall LJ, Strynadka NCJ, Eltis LD. IpdAB, a virulence factor in Mycobacterium tuberculosis, is a cholesterol ring-cleaving hydrolase. Proc Natl Acad Sci U S A. 2018 Mar 26. pii: 1717015115. doi:, 10.1073/pnas.1717015115. PMID:29581275 doi:http://dx.doi.org/10.1073/pnas.1717015115
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