title: Inhibition of the M. tuberculosis 3β-hydroxysteroid dehydrogenase by azasteroids.
abstract: The cholesterol metabolism pathway in Mycobacterium tuberculosis (M. tb) is a potential source of energy as well as secondary metabolite production that is important for survival of M. tb in the host macrophage. Oxidation and isomerization of 3β-hydroxysterols to 4-en-3-ones is requisite for sterol metabolism and the reaction is catalyzed by 3β-hydroxysteroid dehydrogenase (Rv1106c). Three series of 6-azasteroids and 4-azasteroids were employed to define the substrate preferences of M. tb 3β-hydroxysteroid dehydrogenase. 6-Azasteroids with large, hydrophobic side chains at the C17 position are the most effective inhibitors. Substitutions at C1, C2, C4 and N6 were poorly tolerated. Our structure-activity studies indicate that the 6-aza version of cholesterol is the best and tightest binding competitive inhibitor (K(i)=100 nM) of the steroid substrate and are consistent with cholesterol being the preferred substrate of M. tb 3β-hydroxysteroid dehydrogenase.
authors: Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, United States.
authors: Suzanne T
authors: ST
authors: Thomas
authors: Xinxin
authors: X
authors: Yang
authors: Nicole S
authors: NS
authors: Sampson
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001378:Azasteroids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship
chemical_list: D001378:Azasteroids; D004791:Enzyme Inhibitors; D015096:3-Hydroxysteroid Dehydrogenases