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J. Biol. Chem., Vol. 280, Issue 11, 10196-10201, March 18, 2005

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Xenopus laevis CYP17 Regulates Androgen Biosynthesis Independent of the Cofactor Cytochrome b₅^*

Wei-Hsiung Yang and Stephen R Hammes

From the Department of Internal Medicine, Division of Endocrinology and Metabolism, and Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390

The enzyme CYP17 primarily regulates androgen production by mediating four reactions: conversion of pregnenolone and progesterone to 17-hydroxypregnenolone and 17-hydroxyprogesterone, respectively (17-hydroxylase activity), followed by conversion of the 17-hydroxylated steroids to dehydroepiandrosterone and androstenedione, respectively (17,20-lyase activity). Most mammalian CYP17 isoforms have high 17-hydroxylase relative to 17,20-lyase activities and preferentially mediate one of the two 17,20-lyase reactions. In contrast, Xenopus laevis CYP17 potently regulates all four reactions in the frog ovary. CYP17 isoforms generally rely on the cofactor cytochrome b₅ for the 17,20-lyase reaction, suggesting that the high lyase activity of Xenopus CYP17 might be due to a lesser dependence on b₅. The kinetics of Xenopus CYP17 expressed in yeast microsomes were therefore examined in the absence and presence of Xenopus on human b₅. Xenopus CYP17 mediated both 17,20-lyase reactions in the absence of b₅, confirming that the activity did not require b₅. However, both Xenopus and human b₅ slightly enhanced Xenopus CYP17-mediated lyase activity, indicating that the enzyme was still at least partially responsive to b₅. Surprisingly, only the human b₅ cofactor enhanced human CYP17-mediated lyase activity, implying that the human enzyme had more specific cofactor requirements than Xenopus CYP17. Studies using human/Xenopus chimeric b₅ proteins revealed that human b₅ residues 16–41 were important for the specific regulation of the lyase activity of HuCYP17, possibly serving as an interacting domain with the enzyme. CYP17 may therefore have evolved from a general producer of sex steroids in lower vertebrates to a more tightly regulated producer of both sex steroids and glucocorticoids in mammals.

Received for publication, October 19, 2004 , and in revised form, January 7, 2005.

^* This work was supported by grants from the National Institutes of Health (Grant DK59913) and the Welch Foundation (Grant I-1506). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplementary table.

The nucleotide sequence reported in this paper has been submitted to the DDBJ/GenBank^TM/EBI Data Bank with accession number(s) AY775052.

A W. W. Caruth, Jr. Scholar in Biomedical Research. To whom correspondence should be addressed. University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8857. Tel.: 214-648-3749; Fax: 214-648-7934; E-mail: stephen.hammes{at}utsouthwestern.edu.

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