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Publication Abstract from PubMed

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 catalyses 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 Angstroms, revealing a similar active site organization to the cholesterol-metabolizing Mtb CYP125, but having a near-identical organization of distal pocket residues to the branched fatty acid oxidizing Mtb CYP124. The cholesterol oxidizing activity of CYP142 provides an explanation for previous findings that CYP125 deletion strains of M. bovis and M. bovis BCG cannot grow on cholesterol, since 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.

Structural and biochemical characterization of Mycobacterium tuberculosis CYP142: Evidence for multiple cholesterol 27-hydroxylase activities in a human pathogen.,Driscoll MD, McLean KJ, Levy C, Mast N, Pikuleva IA, Lafite P, Rigby SE, Leys D, Munro AW J Biol Chem. 2010 Sep 30. PMID:20889498^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.