{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:45:39Z","timestamp":1791218739968,"version":"4.1.0"},"reference-count":49,"publisher":"American Chemical Society (ACS)","issue":"11","license":[{"start":{"date-parts":[[2015,9,9]],"date-time":"2015-09-09T00:00:00Z","timestamp":1441756800000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL53306"],"award-info":[{"award-number":["HL53306"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01-GM100021"],"award-info":[{"award-number":["R01-GM100021"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI065251"],"award-info":[{"award-number":["AI065251"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI085349"],"award-info":[{"award-number":["AI085349"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI092455"],"award-info":[{"award-number":["AI092455"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["F30-ES022930"],"award-info":[{"award-number":["F30-ES022930"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000076","name":"Directorate for Biological Sciences","doi-asserted-by":"publisher","award":["BIO1039771"],"award-info":[{"award-number":["BIO1039771"]}],"id":[{"id":"10.13039\/100000076","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000097","name":"National Center for Research Resources","doi-asserted-by":"publisher","award":["RR021008"],"award-info":[{"award-number":["RR021008"]}],"id":[{"id":"10.13039\/100000097","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000138","name":"U.S. Department of Education","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100000138","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,11,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The Mycobacterium tuberculosis (Mtb) igr operon plays an essential role in Mtb cholesterol metabolism, which is critical for pathogenesis during the latent stage of Mtb infection. Here we report the first structure of a heterotetrameric MaoC-like enoyl-CoA hydratase, ChsH1-ChsH2, which is encoded by two adjacent genes from the igr operon. We demonstrate that ChsH1-ChsH2 catalyzes the hydration of a steroid enoyl-CoA, 3-oxo-4,17-pregnadiene-20-carboxyl-CoA, in the modified \u03b2-oxidation pathway for cholesterol side chain degradation. The ligand-bound and apoenzyme structures of ChsH1-ChsH2N reveal an unusual, modified hot-dog fold with a severely truncated central \u03b1-helix that creates an expanded binding site to accommodate the bulkier steroid ring system. The structures show quaternary structure shifts that accommodate the four rings of the steroid substrate and offer an explanation for why the unusual heterotetrameric assembly is utilized for hydration of this steroid. The unique \u03b1\u03b2 heterodimer architecture utilized by ChsH1-ChsH2 to bind its distinctive substrate highlights an opportunity for the development of new antimycobacterial drugs that target a pathway specific to Mtb.<\/jats:p>","DOI":"10.1021\/cb500232h","type":"journal-article","created":{"date-parts":[[2014,9,22]],"date-time":"2014-09-22T14:33:29Z","timestamp":1411396409000},"page":"2632-2645","source":"Crossref","is-referenced-by-count":70,"title":["A Distinct MaoC-like Enoyl-CoA Hydratase Architecture\nMediates Cholesterol Catabolism in\n                    <i>Mycobacterium tuberculosis<\/i>"],"prefix":"10.1021","volume":"9","author":[{"given":"Meng","family":"Yang","sequence":"first","affiliation":[{"name":"Stony Brook University , , , ,","place":["Stony Brook, New York, United States, 11794-3400"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kip E.","family":"Guja","sequence":"additional","affiliation":[{"name":"Stony Brook University , , , ,","place":["Stony Brook, New York, United States, 11794-8651"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne T.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Stony Brook University , , , ,","place":["Stony Brook, New York, United States, 11794-3400"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Garcia-Diaz","sequence":"additional","affiliation":[{"name":"Stony Brook University , , , ,","place":["Stony Brook, New York, United States, 11794-8651"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole S.","family":"Sampson","sequence":"additional","affiliation":[{"name":"Stony Brook University , , , ,","place":["Stony Brook, New York, United States, 11794-3400"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,9,9]]},"reference":[{"key":"2026090302044056200_cit1","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/nrmicro2797","article-title":"Global tuberculosis\ncontrol: Lessons\nlearnt and future prospects","volume":"10","author":"Lienhardt","year":"2012","journal-title":"Nat. Rev. Microbiol."},{"key":"2026090302044056200_cit2","unstructured":"The World\nHealth Organization. (2012) Global Tuberculosis Report."},{"key":"2026090302044056200_cit3","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1038\/ni.1781","article-title":"Foamy macrophages\nand the progression of the human tuberculosis granuloma","volume":"10","author":"Russell","year":"2009","journal-title":"Nat. Immunol."},{"key":"2026090302044056200_cit4","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1038\/35021074","article-title":"Persistence of Mycobacterium tuberculosis in macrophages and mice requires\nthe glyoxylate shunt enzyme isocitrate lyase","volume":"406","author":"McKinney","year":"2000","journal-title":"Nature"},{"key":"2026090302044056200_cit5","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/31159","article-title":"Deciphering the\nbiology of Mycobacterium tuberculosis from the complete\ngenome sequence","volume":"393","author":"Cole","year":"1998","journal-title":"Nature"},{"key":"2026090302044056200_cit6","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1086\/520089","article-title":"Identification\nof\nmycobacterial genes that alter growth and pathology in macrophages\nand in mice","volume":"196","author":"Chang","year":"2007","journal-title":"J. Infect. Dis."},{"key":"2026090302044056200_cit7","doi-asserted-by":"crossref","first-page":"8327","DOI":"10.1073\/pnas.0503272102","article-title":"Genome-wide requirements\nfor Mycobacterium tuberculosis adaptation and survival\nin macrophages","volume":"102","author":"Rengarajan","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090302044056200_cit8","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/S0968-0896(02)00333-4","article-title":"Enoyl-CoA hydratase.\nReaction, mechanism, and inhibition","volume":"11","author":"Agnihotri","year":"2003","journal-title":"Bioorg.\nMed. Chem."},{"key":"2026090302044056200_cit9","doi-asserted-by":"crossref","first-page":"269","DOI":"10.3109\/10409238.2014.895700","article-title":"Pathogen\nroid rage: Cholesterol utilization\nby Mycobacterium tuberculosis","volume":"49","author":"Wipperman","year":"2014","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"2026090302044056200_cit10","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.1073\/pnas.0605728104","article-title":"A gene cluster encoding\ncholesterol catabolism in a soil actinomycete provides insight into Mycobacterium tuberculosis survival in macrophages","volume":"104","author":"Van der Geize","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090302044056200_cit11","doi-asserted-by":"crossref","first-page":"5232","DOI":"10.1128\/JB.00452-09","article-title":"igr Genes and Mycobacterium tuberculosis cholesterol metabolism","volume":"191","author":"Chang","year":"2009","journal-title":"J. Bacteriol."},{"key":"2026090302044056200_cit12","doi-asserted-by":"crossref","first-page":"43668","DOI":"10.1074\/jbc.M111.313643","article-title":"Pathway\nprofiling in Mycobacterium tuberculosis: Elucidation\nof cholesterol-derived catabolite and enzymes that catalyze its metabolism","volume":"286","author":"Thomas","year":"2011","journal-title":"J. Biol. Chem."},{"key":"2026090302044056200_cit13","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1111\/j.1365-2958.2010.07243.x","article-title":"Mycobacterium tuberculosis CYP125A1, a steroid C27 monooxygenase\nthat detoxifies intracellularly generated cholest-4-en-3-one","volume":"77","author":"Ouellet","year":"2010","journal-title":"Mol. Microbiol."},{"key":"2026090302044056200_cit14","doi-asserted-by":"crossref","first-page":"36352","DOI":"10.1074\/jbc.M110.161117","article-title":"Functional redundancy\nof steroid C26-monooxygenase activity in Mycobacterium tuberculosis revealed by biochemical and genetic analyses","volume":"285","author":"Johnston","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2026090302044056200_cit15","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.1021\/bi4002979","article-title":"Mycobacterium tuberculosis utilizes\na unique heterotetrameric structure for dehydrogenation of the cholesterol\nside chain","volume":"52","author":"Thomas","year":"2013","journal-title":"Biochemistry"},{"key":"2026090302044056200_cit16","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1074\/jbc.M205484200","article-title":"Crystal structure of the (R)-specific enoyl-CoA\nhydratase from Aeromonas caviae involved in polyhydroxyalkanoate\nbiosynthesis","volume":"278","author":"Hisano","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2026090302044056200_cit17","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1093\/oxfordjournals.jbchem.a021615","article-title":"Physiological\nrole of D-3-hydroxyacyl-CoA dehydratase\/D-3-hydroxyacyl-CoA dehydrogenase\nbifunctional protein","volume":"121","author":"Jiang","year":"1997","journal-title":"J. Biochem."},{"key":"2026090302044056200_cit18","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1146\/annurev.biochem.72.121801.161712","article-title":"The enzymes,\nregulation, and genetics of bile acid synthesis","volume":"72","author":"Russell","year":"2003","journal-title":"Annu. Rev. Biochem."},{"key":"2026090302044056200_cit19","doi-asserted-by":"crossref","first-page":"24666","DOI":"10.1074\/jbc.M400293200","article-title":"A two-domain structure\nof one subunit explains unique features of eukaryotic hydratase 2","volume":"279","author":"Koski","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2026090302044056200_cit20","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2105-5-109","article-title":"The Hotdog fold: Wrapping up a superfamily of thioesterases\nand dehydratases","volume":"5","author":"Dillon","year":"2004","journal-title":"BMC Bioinf."},{"key":"2026090302044056200_cit21","doi-asserted-by":"crossref","first-page":"W545","DOI":"10.1093\/nar\/gkq366","article-title":"Dali server:\nConservation mapping in 3D","volume":"38","author":"Holm","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"2026090302044056200_cit22","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1016\/j.jmb.2004.11.009","article-title":"Crystal structure of\n2-enoyl-CoA hydratase 2 from human peroxisomal multifunctional enzyme\ntype 2","volume":"345","author":"Koski","year":"2005","journal-title":"J. Mol. Biol."},{"key":"2026090302044056200_cit23","doi-asserted-by":"crossref","first-page":"4822","DOI":"10.1021\/ma00118a007","article-title":"Microbial synthesis and characterization\nof poly(3-hydroxybutyrate-co-3-hydroxyhexanoate)","volume":"28","author":"Doi","year":"1995","journal-title":"Macromolecules"},{"key":"2026090302044056200_cit24","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1038\/nature12576","article-title":"Discovery of new\nenzymes and metabolic pathways by using structure and genome context","volume":"502","author":"Zhao","year":"2013","journal-title":"Nature"},{"key":"2026090302044056200_cit25","doi-asserted-by":"crossref","first-page":"4331","DOI":"10.1128\/JB.00502-13","article-title":"Shrinking the FadE\nproteome of Mycobacterium tuberculosis: Insights\ninto cholesterol metabolism through identification of an \u03b12\u03b22 heterotetrameric acyl-Coenzyme A dehydrogenase\nfamily","volume":"195","author":"Wipperman","year":"2013","journal-title":"J. Bacteriol."},{"key":"2026090302044056200_cit26","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1107\/S1744309110002514","article-title":"The structure of SSO2064, the first\nrepresentative of Pfam family PF01796, reveals a novel two-domain\nzinc-ribbon OB-fold architecture with a potential acyl-CoA-binding\nrole","volume":"66","author":"Krishna","year":"2010","journal-title":"Acta Crystallogr., Sect. F: Struct. Biol.\nCommun."},{"key":"2026090302044056200_cit27","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1107\/S1744309110035736","article-title":"TOPSAN: Use of a collaborative environment\nfor annotating, analyzing and disseminating data on JCSG and PSI structures","volume":"66","author":"Krishna","year":"2010","journal-title":"Acta Crystallogr., Sect. F: Struct. Biol. Commun."},{"key":"2026090302044056200_cit28","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1126\/science.285.5428.751","article-title":"Detecting\nprotein function and protein-protein interactions from genome sequences","volume":"285","author":"Marcotte","year":"1999","journal-title":"Science"},{"key":"2026090302044056200_cit29","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1038\/47056","article-title":"Protein interaction\nmaps for complete genomes based on gene fusion events","volume":"402","author":"Enright","year":"1999","journal-title":"Nature"},{"key":"2026090302044056200_cit30","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1110\/ps.051442305","article-title":"Rv0216, a\nconserved hypothetical protein from Mycobacterium tuberculosis that is essential for bacterial survival during infection, has a\ndouble hotdog fold","volume":"14","author":"Castell","year":"2005","journal-title":"Protein Sci."},{"key":"2026090302044056200_cit31","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.bbapap.2006.11.016","article-title":"Rv3389C from Mycobacterium tuberculosis, a member of the (R)-specific\nhydratase\/dehydratase\nfamily","volume":"1774","author":"Sacco","year":"2007","journal-title":"Biochim. Biophys. Acta, Proteins Proteomics"},{"key":"2026090302044056200_cit32","doi-asserted-by":"crossref","first-page":"2300","DOI":"10.1110\/ps.062309306","article-title":"Structure\nand function of Rv0130, a conserved hypothetical protein from Mycobacterium tuberculosis","volume":"15","author":"Johansson","year":"2006","journal-title":"Protein\nSci."},{"key":"2026090302044056200_cit33","first-page":"29","article-title":"Multiple site-directed mutagenesis in vitro","volume-title":"In Vitro Mutagenesis Protocols","author":"Kim","year":"2001"},{"key":"2026090302044056200_cit34","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1002\/rcm.4384","article-title":"ESIprot: A\nuniversal tool for charge state determination and molecular weight\ncalculation of proteins from electrospray ionization mass spectrometry\ndata","volume":"24","author":"Winkler","year":"2010","journal-title":"Rapid Commun. Mass Spectrom."},{"key":"2026090302044056200_cit35","doi-asserted-by":"crossref","first-page":"10755","DOI":"10.1021\/bi00108a021","article-title":"Spiropentaneacetic\nacid as a specific\ninhibitor of medium-chain acyl-CoA dehydrogenase","volume":"30","author":"Tserng","year":"1991","journal-title":"Biochemistry"},{"key":"2026090302044056200_cit36","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1021\/ja01537a041","article-title":"Ozonolysis.\nII. The effect of pyridine\non the ozonolysis of 4, 22-stigmastadien-3-one","volume":"80","author":"Slomp","year":"1958","journal-title":"J. Am. Chem. Soc."},{"key":"2026090302044056200_cit37","doi-asserted-by":"crossref","first-page":"6712","DOI":"10.1128\/JB.01169-12","article-title":"Gene cluster encoding cholate catabolism\nin Rhodococcus spp","volume":"194","author":"Mohn","year":"2012","journal-title":"J. Bacteriol."},{"key":"2026090302044056200_cit38","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1111\/mmi.12095","article-title":"FadD3 is an acyl-CoA\nsynthetase that initiates catabolism of cholesterol rings C and D\nin actinobacteria","volume":"87","author":"Casabon","year":"2013","journal-title":"Mol. Microbiol."},{"key":"2026090302044056200_cit39","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1107\/S0907444909047337","article-title":"XDS","volume":"66","author":"Kabsch","year":"2010","journal-title":"Acta Crystallogr.,\nSect. D: Biol. Crystallogr."},{"key":"2026090302044056200_cit40","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1107\/S0907444913000061","article-title":"How good are my data and what is the resolution?","volume":"69","author":"Evans","year":"2013","journal-title":"Acta Crystallogr., Sect. D: Biol. Crystallogr."},{"key":"2026090302044056200_cit41","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1107\/S0907444911007773","article-title":"Data processing and\nanalysis with the autoPROC toolbox","volume":"67","author":"Vonrhein","year":"2011","journal-title":"Acta Crystallogr.,\nSect. D: Biol. Crystallogr."},{"key":"2026090302044056200_cit42","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1107\/S0108767307043930","article-title":"A short history\nof SHELX","volume":"64","author":"Sheldrick","year":"2008","journal-title":"Acta Crystallogr., Sect. A: Found.\nCrystallogr."},{"key":"2026090302044056200_cit43","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1107\/S090744490200118X","article-title":"Jolly SAD","volume":"58","author":"Dauter","year":"2002","journal-title":"Acta Crystallogr., Sect. D: Biol. Crystallogr."},{"key":"2026090302044056200_cit44","first-page":"215","article-title":"Automated\nstructure solution with autoSHARP","volume-title":"Methods\nin Molecular Biology","author":"Vonrhein","year":"2007"},{"key":"2026090302044056200_cit45","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1038\/nprot.2008.91","article-title":"Automated macromolecular\nmodel building for X-ray crystallography using ARP\/wARP version 7","volume":"3","author":"Langer","year":"2008","journal-title":"Nat. Protoc."},{"key":"2026090302044056200_cit46","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1107\/S0907444904019158","article-title":"Coot: Model-building tools for molecular graphics","volume":"60","author":"Emsley","year":"2004","journal-title":"Acta Crystallogr., Sect. D: Biol. Crystallogr."},{"key":"2026090302044056200_cit47","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1107\/S0907444911001314","article-title":"REFMAC5\nfor the refinement of macromolecular crystal structures","volume":"67","author":"Murshudov","year":"2011","journal-title":"Acta Crystallogr., Sect. D: Biol. Crystallogr."},{"key":"2026090302044056200_cit48","doi-asserted-by":"crossref","first-page":"1948","DOI":"10.1107\/S0907444902016657","article-title":"PHENIX:\nBuilding new software for\nautomated crystallographic structure determination","volume":"58","author":"Adams","year":"2002","journal-title":"Acta Crystallogr., Sect. D: Biol. Crystallogr."},{"key":"2026090302044056200_cit49","doi-asserted-by":"crossref","first-page":"W375","DOI":"10.1093\/nar\/gkm216","article-title":"MolProbity: All-atom contacts and\nstructure validation for proteins and nucleic acids","volume":"35","author":"Davis","year":"2007","journal-title":"Nucleic Acids Res."}],"container-title":["ACS Chemical Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/cb500232h","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acbcct\/article-pdf\/9\/11\/2632\/15709318\/cb500232h.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acbcct\/article-pdf\/9\/11\/2632\/15709318\/cb500232h.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T06:04:56Z","timestamp":1788415496000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acbcct\/article\/9\/11\/2632\/1477998\/A-Distinct-MaoC-like-Enoyl-CoA-Hydratase"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,9,9]]},"references-count":49,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2014,9,9]]},"published-print":{"date-parts":[[2014,11,21]]}},"URL":"https:\/\/doi.org\/10.1021\/cb500232h","relation":{},"ISSN":["1554-8929","1554-8937"],"issn-type":[{"value":"1554-8929","type":"print"},{"value":"1554-8937","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,9,9]]}}}