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Inhibition of the M. tuberculosis 3?-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 3?-hydroxysterols to 4-en-3-ones is requisite for sterol metabolism and the reaction is catalyzed by 3?-hydroxysteroid dehydrogenase (Rv1106c). Three series of 6-azasteroids and 4-azasteroids were employed to define the substrate preferences of M. tb 3?-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 3?-hydroxysteroid dehydrogenase.

SUBMITTER: Thomas ST 

PROVIDER: S-EPMC3077731 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Inhibition of the M. tuberculosis 3β-hydroxysteroid dehydrogenase by azasteroids.

Thomas Suzanne T ST   Yang Xinxin X   Sampson Nicole S NS  

Bioorganic & medicinal chemistry letters 20110306 8


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-hyd  ...[more]

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