Inhibition of α- and β-Hydroxysteroid Dehydrogenases and Steroid Δ-Isomerase by Substrate Analogues1

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Abstract
The inhibition of the 3 (or 17)[beta]-hydroxysteroid dehydrogenase of Pseudomonas testosteroni by the substrate analogues, 2[alpha]-cyano-17[alpha]-hydroxy-4,4,17[alpha]-trimethyl-androst-5-en-3-one and 17[beta]-hydroxy-2-hydroxymethylene-17[alpha]-methyl-5[alpha]-androstan-3-one was reexamined to ascertain their specificity for this enzyme system. The 3(or 17)[beta]- and 3[alpha]-hydroxy-steroid dehydro-genases and steroid [DELTA] -isomerase were isolated from extracts of P. testosteroni and separated from each other. Both steroids acted as noncompetitive inhibitors of both dehydrogenases and as competitive inhibitors of the isomerase. They exert reversible inhibition and do not interact with either the substrates or the coenzymes. All 3 enzyme systems have high affinities for the 2 inhibitory steroids. One molecule of each inhibitor is bound/active site of the dehydrogenases and isomerase. The inhibitors reduce the affinities of the dehydrogenases for their substrates without significantly changing their affinities for NAD. When androst-4-ene-3,17-dione and NADH are used as substrates for the [beta]-hydroxysteroid dehydrogenase reaction, reduction occurs principally at C-17, but also at C-3.