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Natural mutagenesis study of the human steroid 5 alpha-reductase 2 isozyme.

Abstract：

: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.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Wigley WC,Prihoda JS,Mowszowicz I,Mendonca BB,New MI,Wilson JD,Russell DW

doi

10.1021/bi00171a029

subject

Has Abstract

pub_date

1994-02-08 00:00:00

pages

1265-70

issue

5

eissn

0006-2960

issn

1520-4995

journal_volume

33

pub_type

杂志文章

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