Structure and function of steroid dehydrogenases involved in hypertension, fertility, and cancer.
Short-chain dehydrogenase reductase (SDR) enzymes influence mammalian reproduction, hypertension, neoplasia, and digestion. The three-dimensional structures of two members of the SDR family reveal the position of the conserved catalytic triad, a possible mechanism of keto-hydroxyl interconversion, the molecular mechanism of inhibition, and the basis for selectivity. Glycyrrhizic acid, the active ingredient in licorice, and its metabolite carbenoxolone are potent inhibitors of bacterial 3 alpha, 20 beta-hydroxysteroid dehydrogenase (3 alpha, 20 beta-HSD). The three-dimensional structure of the 3 alpha,20 beta-HSD carbenoxolone complex unequivocally verifies the postulated active site of the enzyme, shows that inhibition is a result of direct competition with the substrate for binding, and provides a plausible model for the mechanism of inhibition of 11 beta-hydroxysteroid dehydrogenase and 15-hydroxyprostaglandin dehydrogenase by carbenoxolone. The structure of human 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD) suggests the details of binding of estrone and 17 beta-estradiol in the active site of the enzyme and the possible roles of various amino acids in the catalytic cleft. The SDR family includes over 50 proteins from human, mammalian, insect, and bacterial sources. Only five residues are conserved in all members of the family, including the YXXXK sequence. X-ray crystal structures of five members of the family have been completed. When the alpha-carbon backbone of the cofactor binding domains of the five structures are superimposed, the conserved residues are at the core of the structure and in the cofactor binding domain, but not in the substrate binding pocket.
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Hauptman-Woodward Medical Research Institute, Buffalo, New York 4203, USA.
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D000450:Aldosterone / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D017124:Conserved Sequence; D003349:Cortisone Reductase / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D005298:Fertility / Q000502:physiology*; D006035:Glycyrrhiza / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D006913:Hydroxysteroid Dehydrogenases / Q000737:chemistry* / Q000502:physiology; D006973:Hypertension / Q000201:enzymology*; D008958:Models, Molecular; D009369:Neoplasms / Q000201:enzymology*; D010946:Plants, Medicinal; D011487:Protein Conformation
D000450:Aldosterone; D006913:Hydroxysteroid Dehydrogenases; C035507:3(17)-hydroxysteroid dehydrogenase; D003349:Cortisone Reductase; D006854:Hydrocortisone