α-Methyl Acyl CoA Racemase Provides Mycobacterium tuberculosis Catabolic Access to Cholesterol Esters.
Metabolism of cholesterol by Mycobacterium tuberculosis (Mtb) contributes to its pathogenesis. We show that ChsE4-ChsE5 (Rv3504/Rv3505) specifically catalyzes dehydrogenation of the (25S)-3-oxo-cholest-4-en-26-oyl-CoA diastereomer in cholesterol side chain β-oxidation. Thus, a dichotomy between the supply of both 25R and 25S metabolic precursors by upstream cytochrome P450s and the substrate stereospecificity of ChsE4-ChsE5 exists. We reconcile the dilemma of 25R metabolite production by demonstrating that mycobacterial MCR (Rv1143) can efficiently epimerize C25 diastereomers of 3-oxo-cholest-4-en-26-oyl-CoA. Our data suggest that cholesterol and cholesterol ester precursors can converge into a single catabolic pathway, thus widening the metabolic niche in which Mtb survives.
Department of Chemistry, Stony Brook University , Stony Brook, New York 11794-3400, United States.
Rui
R
Lu
Lehrstuhl für Biochemie und Molekularbiologie, Biozentrum-Am Hubland , 7074 Würzburg, Germany.
Werner
W
Schmitz
Department of Chemistry, Stony Brook University , Stony Brook, New York 11794-3400, United States.
Nicole S
NS
Sampson
D000214:Acyl Coenzyme A / Q000737:chemistry* / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D002788:Cholesterol Esters / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D053858:Metabolic Networks and Pathways; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D010084:Oxidation-Reduction; D019998:Racemases and Epimerases / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism
D000214:Acyl Coenzyme A; D001426:Bacterial Proteins; D002788:Cholesterol Esters; D002784:Cholesterol; D019998:Racemases and Epimerases; C108352:alpha-methylacyl-CoA racemase