Natural Mutagenesis Study of the Human Steroid 5.alpha.-Reductase 2 Isoenzyme
Autor: | James S. Prihoda, I. Mowszowicz, Maria I. New, David W. Russell, Berenice B. Mendonca, Jean D. Wilson, W. Christian Wigley |
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Rok vydání: | 1994 |
Předmět: |
Male
chemistry.chemical_classification Mutation Cofactor binding Base Sequence Molecular Sequence Data Mutagenesis (molecular biology technique) DNA Biology medicine.disease_cause Biochemistry Isozyme Isoenzymes Enzyme 3-Oxo-5-alpha-Steroid 4-Dehydrogenase chemistry Mutagenesis SRD5A2 Dihydrotestosterone medicine Humans Female Gene medicine.drug |
Zdroj: | Biochemistry. 33:1265-1270 |
ISSN: | 1520-4995 0006-2960 |
Popis: | The enzyme steroid 5 alpha-reductase utilizes NADPH to reduce the double bonds of a variety of steroid substrates with generalized 3-oxo, delta 4,5 structures. One substrate for this membrane-bound enzyme is testosterone, whose reduction to dihydrotestosterone is required for the embryonic differentiation of the external male genitalia and prostate. There are two 5 alpha-reductase isozymes, designated types 1 and 2, which have different biochemical and pharmacological properties. Inherited deficiencies of 5 alpha-reductase type 2 result in a form of male pseudohermaphroditism in which the external genitalia fail to develop normally. Here, nine additional mutations in the 5 alpha-reductase 2 gene in subjects with 5 alpha-reductase deficiency are described. The biochemical consequences of these mutations, as well as 13 previously identified missense mutations, were characterized by recreating the mutations in an expressible cDNA and transfecting into mammalian cells. Twelve of the 22 mutations inactivated the enzyme. The remaining 10 mutations impaired enzyme function by affecting either substrate or cofactor binding. Almost all mutations decreased the half-life of the protein, and all but one of the impaired enzymes had an altered pH optimum. The mutations provide insight into functional domains in the protein as well as an unusual acidic pH optimum characteristic of the 5 alpha-reductase type 2 isozyme. |
Databáze: | OpenAIRE |
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