Structure and mechanism of action and inhibition of steroid dehydrogenase enzymes involved in hypertension.
Members of the NADPH-dependent short chain dehydrogenase/reductase (SDR) family control blood pressure, fertility, and natural and neoplastic growth. Despite the fact that only one amino acid residue is strictly conserved in the 100 known members of the family, all appear to have a dinucleotide-binding Rossmann fold and homologous catalytic residues including the conserved tyrosine. Variation in the binding pocket creates specificity for steroids, prostaglandins, sugars and alcohols. The critically important tyrosine appears to maintain a fixed position relative to the scaffolding of the Rossmann fold and the cofactor position, while the substrate-binding pocket alters in such a way that the dehydrogenation/reduction reaction site is brought into bonding distance of the tyrosine hydroxyl group. Licorice induces high blood pressure by inhibiting an SDR in the kidney. The crystal structure of the complex of 3alpha,20beta-hydroxysteroid dehydrogenase and carbenoxolone reveals the mechanism of enzyme inhibition by licorice. The most potent dehydrogenase enzyme inhibitors are those that displace substrate and cofactor and form strong hydrogen bonds to one or more amino acid residues involved in catalysis.
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Hauptman-Woodward Medical Research Inst., Inc., Buffalo, New York 14203, USA.
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D042842:11-beta-Hydroxysteroid Dehydrogenases; D015089:20-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D002229:Carbenoxolone / Q000494:pharmacology; D006035:Glycyrrhiza; D019695:Glycyrrhizic Acid / Q000494:pharmacology; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D006973:Hypertension / Q000201:enzymology*; D008968:Molecular Conformation; D010449:Peptide Mapping; D010946:Plants, Medicinal
D019695:Glycyrrhizic Acid; D006913:Hydroxysteroid Dehydrogenases; D015089:20-Hydroxysteroid Dehydrogenases; C115140:3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase; D042842:11-beta-Hydroxysteroid Dehydrogenases; D002229:Carbenoxolone