Four-amino acid segment in steroid 5 alpha-reductase 1 confers sensitivity to finasteride, a competitive inhibitor.

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Thigpen AE, Russell DW

Four-amino acid segment in steroid 5 alpha-reductase 1 confers sensitivity to finasteride, a competitive inhibitor.

J Biol Chem. 1992 Apr 25;267(12):8577-83.

PubMed ID

1314830 [ View in PubMed

]

Abstract

The 4-azasteroid 17 beta-(N-t-butyl)carbamoyl-4-aza-5 alpha-androst-1-en-3-one (finasteride) is 100-fold more potent as a competitive inhibitor of the rat NADPH:delta 4-3-oxosteroid-5-alpha- oxidoreductase (steroid 5 alpha-reductase) type 1 enzyme (Ki = 3-5 nM) than of the human type 1 enzyme (Ki greater than or equal to 300 nM). In this study, we exploit this differential sensitivity to map a major determinant of finasteride sensitivity in steroid 5 alpha-reductase. Chimeric steroid 5 alpha-reductase cDNAs composed of different combinations of rat and human exon sequences were created by genetic engineering, expressed in human embryonic kidney 293 cells, and assayed for their sensitivity to finasteride. Hybrid proteins containing sequences encoded by rat exon 1 were found to be as sensitive to finasteride as the parental enzyme. The exchange of progressively smaller protein segments encoded within exon 1 identified a tetrapeptide sequence (Val-Ser-Ile-Val) in the rat enzyme that conferred sensitivity to finasteride. The analogous sequence in the human enzyme (Ala-Val-Phe-Ala) conferred partial resistance to the drug. Finasteride was a competitive inhibitor of the native and all chimeric enzymes tested, suggesting that the tetrapeptide segments form a portion of the substrate-binding domain of steroid 5 alpha-reductase.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Finasteride	3-oxo-5-alpha-steroid 4-dehydrogenase 1	Protein	Humans	Unknown	Inhibitor	Details