{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T16:44:12Z","timestamp":1789922652373,"version":"4.0.1"},"reference-count":37,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2018,8,8]],"date-time":"2018-08-08T00:00:00Z","timestamp":1533686400000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"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\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI134054"],"award-info":[{"award-number":["AI134054"]}],"id":[{"id":"10.13039\/100000060","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\/100000153","name":"Division of Biological Infrastructure","doi-asserted-by":"publisher","award":["BIO1039771"],"award-info":[{"award-number":["BIO1039771"]}],"id":[{"id":"10.13039\/100000153","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["FZ82"],"award-info":[{"award-number":["FZ82"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SFB630"],"award-info":[{"award-number":["SFB630"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,9,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a highly successful human pathogen and has infected approximately one-third of the world\u2019s population. Multiple drug resistant (MDR) and extensively drug resistant (XDR) TB strains and coinfection with HIV have increased the challenges of successfully treating this disease pandemic. The metabolism of host cholesterol by Mtb is an important factor for both its virulence and pathogenesis. In Mtb, the cholesterol side chain is degraded through multiple cycles of \u03b2-oxidation and FadA5 (Rv3546) catalyzes side chain thiolysis in the first two cycles. Moreover, FadA5 is important during the chronic stage of infection in a mouse model of Mtb infection. Here, we report the redox control of FadA5 catalytic activity that results from reversible disulfide bond formation between Cys59-Cys91 and Cys93-Cys377. Cys93 is the thiolytic nucleophile, and Cys377 is the general acid catalyst for cleavage of the \u03b2-keto-acyl-CoA substrate. The disulfide bond formed between the two catalytic residues Cys93 and Cys377 blocks catalysis. The formation of the disulfide bonds is accompanied by a large domain swap at the FadA5 dimer interface that serves to bring Cys93 and Cys377 in close proximity for disulfide bond formation. The catalytic activity of FadA5 has a midpoint potential of \u2212220 mV, which is close to the Mtb mycothiol potential in the activated macrophage. The redox profile of FadA5 suggests that FadA5 is fully active when Mtb resides in the unactivated macrophage to maximize flux into cholesterol catabolism. Upon activation of the macrophage, the oxidative shift in the mycothiol potential will decrease the thiolytic activity by 50%. Thus, the FadA5 midpoint potential is poised to rapidly restrict cholesterol side chain degradation in response to oxidative stress from the host macrophage environment.<\/jats:p>","DOI":"10.1021\/acsinfecdis.7b00072","type":"journal-article","created":{"date-parts":[[2017,8,8]],"date-time":"2017-08-08T10:51:03Z","timestamp":1502189463000},"page":"666-675","source":"Crossref","is-referenced-by-count":24,"title":["Catabolism of the Cholesterol Side Chain in\n                    <i>Mycobacterium tuberculosis<\/i>\n                    Is Controlled by a Redox-Sensitive\nThiol Switch"],"prefix":"10.1021","volume":"3","author":[{"given":"Rui","family":"Lu","sequence":"first","affiliation":[{"name":"Stony Brook University , , , ,","place":["Stony Brook, New York, United States, 11794-3400"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christin M.","family":"Schaefer","sequence":"additional","affiliation":[{"name":"University of Wu\u0308rzburg , , Josef-Schneider-Str. 2 , , ,","place":["Wu\u0308rzburg, Germany, D-97080"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha M.","family":"Nesbitt","sequence":"additional","affiliation":[{"name":"Stony Brook University , , , ,","place":["Stony Brook, New York, United States, 11794-3400"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jochen","family":"Kuper","sequence":"additional","affiliation":[{"name":"University of Wu\u0308rzburg , , Josef-Schneider-Str. 2 , , ,","place":["Wu\u0308rzburg, Germany, D-97080"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Kisker","sequence":"additional","affiliation":[{"name":"University of Wu\u0308rzburg , , Josef-Schneider-Str. 2 , , ,","place":["Wu\u0308rzburg, Germany, D-97080"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2835-7760","authenticated-orcid":true,"given":"Nicole S.","family":"Sampson","sequence":"additional","affiliation":[{"name":"Stony Brook University , , , ,","place":["Stony Brook, New York, United States, 11794-3400"]},{"name":"Wallenberg Research Centre at Stellenbosch University , , , ,","place":["Stellenbosch, South Africa, 7600"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2017,8,8]]},"reference":[{"key":"2026090303550508200_cit1","unstructured":"WHO.\n          \n          2016)  Global tuberculosis report, http:\/\/www.who.int\/tb\/publications\/global_report\/en\/."},{"key":"2026090303550508200_cit2","unstructured":"WHO.\n          \n          2016)  Multidrug-resistant\ntuberculosis (MDR-TB), http:\/\/www.who.int\/tb\/challenges\/mdr\/mdr_tb_factsheet.pdf."},{"issue":"6","key":"2026090303550508200_cit3","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1038\/nchembio884","article-title":"Diarylquinolines target subunit c\nof mycobacterial ATP synthase","volume":"3","author":"Koul","year":"2007","journal-title":"Nat. Chem. Biol."},{"issue":"1","key":"2026090303550508200_cit4","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1128\/IAI.00893-09","article-title":"A thiolase of Mycobacterium tuberculosis is required for virulence and production of androstenedione and\nandrostadienedione from cholesterol","volume":"78","author":"Nesbitt","year":"2010","journal-title":"Infect.\nImmun."},{"issue":"6","key":"2026090303550508200_cit5","doi-asserted-by":"publisher","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."},{"issue":"5","key":"2026090303550508200_cit6","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1086\/520089","article-title":"Identification of Mycobacterial genes that alter growth\nand pathology in macrophages and in mice","volume":"196","author":"Chang","year":"2007","journal-title":"J.\nInfect. Dis."},{"issue":"16","key":"2026090303550508200_cit7","doi-asserted-by":"publisher","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."},{"issue":"11","key":"2026090303550508200_cit8","doi-asserted-by":"publisher","first-page":"4376","DOI":"10.1073\/pnas.0711159105","article-title":"Mycobacterial persistence\nrequires the utilization of host cholesterol","volume":"105","author":"Pandey","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"5","key":"2026090303550508200_cit9","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1084\/jem.20030846","article-title":"Transcriptional\nAdaptation of Mycobacterium tuberculosis within Macrophages:\nInsights into the Phagosomal Environment","volume":"198","author":"Schnappinger","year":"2003","journal-title":"J.\nExp. Med."},{"issue":"2","key":"2026090303550508200_cit10","doi-asserted-by":"publisher","first-page":"e1004679","DOI":"10.1371\/journal.ppat.1004679","article-title":"Novel inhibitors\nof cholesterol degradation in Mycobacterium tuberculosis reveal how the bacterium\u2019s metabolism is constrained by the\nintracellular environment","volume":"11","author":"VanderVen","year":"2015","journal-title":"PLoS Pathog."},{"issue":"1","key":"2026090303550508200_cit11","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.str.2014.10.010","article-title":"FadA5 a thiolase from Mycobacterium tuberculosis: a steroid-binding pocket reveals\nthe potential for drug development against tuberculosis","volume":"23","author":"Schaefer","year":"2015","journal-title":"Structure"},{"issue":"1","key":"2026090303550508200_cit12","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.tibs.2005.11.011","article-title":"The thiolase superfamily:\ncondensing enzymes with diverse reaction specificities","volume":"31","author":"Haapalainen","year":"2006","journal-title":"Trends Biochem. Sci."},{"issue":"2","key":"2026090303550508200_cit13","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1016\/j.jmb.2006.03.032","article-title":"The crystal structure of a plant 3-ketoacyl-CoA thiolase\nreveals the potential for redox control of peroxisomal fatty acid\nbeta-oxidation","volume":"359","author":"Sundaramoorthy","year":"2006","journal-title":"J. Mol. Biol."},{"issue":"31","key":"2026090303550508200_cit14","doi-asserted-by":"publisher","first-page":"24078","DOI":"10.1074\/jbc.M110.106013","article-title":"Peroxisomal\nplant 3-ketoacyl-CoA thiolase structure and activity are regulated\nby a sensitive redox switch","volume":"285","author":"Pye","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2026090303550508200_cit15","doi-asserted-by":"publisher","first-page":"8410","DOI":"10.1038\/ncomms9410","article-title":"Redox-switch\nregulatory mechanism of thiolase from Clostridium acetobutylicum","volume":"6","author":"Kim","year":"2015","journal-title":"Nat. Commun."},{"issue":"6","key":"2026090303550508200_cit16","doi-asserted-by":"publisher","first-page":"2888","DOI":"10.1074\/jbc.M115.684597","article-title":"Mycobacterium tuberculosis WhiB3 Responds to Vacuolar pH-induced Changes in Mycothiol Redox\nPotential to Modulate Phagosomal Maturation and Virulence","volume":"291","author":"Mehta","year":"2016","journal-title":"J. Biol. Chem."},{"key":"2026090303550508200_cit17","doi-asserted-by":"publisher","first-page":"61","DOI":"10.2741\/3676","article-title":"Biomolecular\nstudies by circular dichroism","volume":"16","author":"Dodero","year":"2011","journal-title":"Front. Biosci.,\nLandmark Ed."},{"issue":"2","key":"2026090303550508200_cit18","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.bbapap.2005.06.005","article-title":"How to\nstudy proteins by circular dichroism","volume":"1751","author":"Kelly","year":"2005","journal-title":"Biochim.\nBiophys. Acta, Proteins Proteomics"},{"issue":"4","key":"2026090303550508200_cit19","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1107\/S0567739478001114","article-title":"On the treatment of\nnegative intensity observations","volume":"34","author":"French","year":"1978","journal-title":"Acta Crystallogr.,\nSect. A: Cryst. Phys., Diffr., Theor. Gen. Crystallogr."},{"issue":"4","key":"2026090303550508200_cit20","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1107\/S0907444910045749","article-title":"Overview\nof the CCP4 suite and current developments","volume":"67","author":"Winn","year":"2011","journal-title":"Acta Crystallogr., Sect. D: Biol. Crystallogr."},{"issue":"1","key":"2026090303550508200_cit21","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1107\/S0907444909042073","article-title":"MolProbity: all-atom structure validation for macromolecular\ncrystallography","volume":"66","author":"Chen","year":"2010","journal-title":"Acta Crystallogr., Sect. D:\nBiol. Crystallogr."},{"issue":"3","key":"2026090303550508200_cit22","doi-asserted-by":"publisher","first-page":"774","DOI":"10.1016\/j.jmb.2007.05.022","article-title":"Inference of macromolecular assemblies\nfrom crystalline state","volume":"372","author":"Krissinel","year":"2007","journal-title":"J. Mol. Biol."},{"issue":"9","key":"2026090303550508200_cit23","doi-asserted-by":"publisher","first-page":"e124","DOI":"10.1371\/journal.pcbi.0020124","article-title":"The many faces of protein-protein\ninteractions: A compendium of interface geometry","volume":"2","author":"Kim","year":"2006","journal-title":"PLoS Comput. Biol."},{"issue":"2","key":"2026090303550508200_cit24","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1128\/iai.63.2.736-740.1995","article-title":"Effects of nitric oxide synthase inhibitors on murine\ninfection with Mycobacterium tuberculosis","volume":"63","author":"Chan","year":"1995","journal-title":"Infect. Immun."},{"issue":"5","key":"2026090303550508200_cit25","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1016\/j.chom.2007.09.006","article-title":"Mycobacterium tuberculosis invasion of macrophages: linking bacterial gene expression to environmental\ncues","volume":"2","author":"Rohde","year":"2007","journal-title":"Cell Host Microbe"},{"issue":"1","key":"2026090303550508200_cit26","doi-asserted-by":"publisher","first-page":"e1003902","DOI":"10.1371\/journal.ppat.1003902","article-title":"Reengineering redox sensitive GFP\nto measure mycothiol redox potential of Mycobacterium tuberculosis during infection","volume":"10","author":"Bhaskar","year":"2014","journal-title":"PLoS Pathog."},{"issue":"1","key":"2026090303550508200_cit27","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1042\/bj1390109","article-title":"The kinetic mechanism and properties\nof the cytoplasmic acetoacetyl-coenzyme A thiolase from rat liver","volume":"139","author":"Middleton","year":"1974","journal-title":"Biochem. J."},{"issue":"2","key":"2026090303550508200_cit28","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1016\/j.ab.2006.07.027","article-title":"Thermofluor-based\nhigh-throughput stability optimization of proteins for structural\nstudies","volume":"357","author":"Ericsson","year":"2006","journal-title":"Anal. Biochem."},{"issue":"4","key":"2026090303550508200_cit29","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1107\/S0907444910048675","article-title":"iMOSFLM: a new graphical\ninterface for diffraction-image\nprocessing with MOSFLM","volume":"67","author":"Battye","year":"2011","journal-title":"Acta Crystallogr., Sect.\nD: Biol. Crystallogr."},{"issue":"4","key":"2026090303550508200_cit30","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1107\/S090744491003982X","article-title":"An introduction to data reduction:\nspace-group determination, scaling and intensity statistics","volume":"67","author":"Evans","year":"2011","journal-title":"Acta Crystallogr., Sect. D: Biol. Crystallogr."},{"issue":"4","key":"2026090303550508200_cit31","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1107\/S0021889807021206","article-title":"Phaser\ncrystallographic software","volume":"40","author":"McCoy","year":"2007","journal-title":"J. Appl. Crystallogr."},{"issue":"12","key":"2026090303550508200_cit32","doi-asserted-by":"publisher","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."},{"issue":"4","key":"2026090303550508200_cit33","doi-asserted-by":"publisher","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":"2026090303550508200_cit34","unstructured":"DeLano, W. L.\n           (2006)  The PyMOL Molecular Graphics System, http:\/\/www.pymol.org\/."},{"issue":"Database\nissue","key":"2026090303550508200_cit35","doi-asserted-by":"publisher","first-page":"D411","DOI":"10.1093\/nar\/gkq1105","article-title":"A series of\nPDB related databases for everyday needs","volume":"39","author":"Joosten","year":"2011","journal-title":"Nucleic\nAcids Res."},{"issue":"12","key":"2026090303550508200_cit36","doi-asserted-by":"publisher","first-page":"2577","DOI":"10.1002\/bip.360221211","article-title":"Dictionary of protein\nsecondary structure: pattern recognition of hydrogen-bonded and geometrical\nfeatures","volume":"22","author":"Kabsch","year":"1983","journal-title":"Biopolymers"},{"issue":"2","key":"2026090303550508200_cit37","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1107\/S0907444909047337","article-title":"XDS","volume":"66","author":"Kabsch","year":"2010","journal-title":"Acta Crystallogr.,\nSect. D: Biol. Crystallogr."}],"container-title":["ACS Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsinfecdis.7b00072","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/3\/9\/666\/67182820\/acsinfecdis.7b00072.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/3\/9\/666\/67182820\/acsinfecdis.7b00072.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T07:55:14Z","timestamp":1788422114000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article\/3\/9\/666\/687199\/Catabolism-of-the-Cholesterol-Side-Chain-in"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8,8]]},"references-count":37,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2017,8,8]]},"published-print":{"date-parts":[[2017,9,8]]}},"URL":"https:\/\/doi.org\/10.1021\/acsinfecdis.7b00072","relation":{},"ISSN":["2373-8227"],"issn-type":[{"value":"2373-8227","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,8,8]]}}}