Download MendeleyStructural and Biochemical Characterization of Mycobacterium Tuberculosis Cyp142: Evidence for Multiple Cholesterol 27-Hydroxylase Activities in a Human Pathogen.
Driscoll, M.D., Mclean, K.J., Levy, C.W., Mast, N., Pikuleva, I.A., Lafite, P., Rigby, S.E.J., Leys, D., Munro, A.W.(2010) J Biol Chem 285: 38270
- PubMed: 20889498
- DOI: https://doi.org/10.1074/jbc.M110.164293
- Primary Citation of Related Structures:
2XKR - PubMed Abstract:
The Mycobacterium tuberculosis cytochrome P450 enzyme CYP142 is encoded in a large gene cluster involved in metabolism of host cholesterol. CYP142 was expressed and purified as a soluble, low spin P450 hemoprotein. CYP142 binds tightly to cholesterol and its oxidized derivative cholest-4-en-3-one, with extensive shift of the heme iron to the high spin state. High affinity for azole antibiotics was demonstrated, highlighting their therapeutic potential. CYP142 catalyzes either 27-hydroxylation of cholesterol/cholest-4-en-3-one or generates 5-cholestenoic acid/cholest-4-en-3-one-27-oic acid from these substrates by successive sterol oxidations, with the catalytic outcome dependent on the redox partner system used. The CYP142 crystal structure was solved to 1.6 ?, revealing a similar active site organization to the cholesterol-metabolizing M. tuberculosis CYP125, but having a near-identical organization of distal pocket residues to the branched fatty acid oxidizing M. tuberculosis CYP124. The cholesterol oxidizing activity of CYP142 provides an explanation for previous findings that ¦¤CYP125 strains of Mycobacterium bovis and M. bovis BCG cannot grow on cholesterol, because these strains have a defective CYP142 gene. CYP142 is revealed as a cholesterol 27-oxidase with likely roles in host response modulation and cholesterol metabolism.
Organizational Affiliation:
Manchester Interdisciplinary Biocentre, Faculty of Life Sciences, University of Manchester, 131 Princess Street, Manchester M1 7DN, United Kingdom.
