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J. Biol. Chem., Vol. 278, Issue 49, 48563-48569, December 5, 2003

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CYP17 Mutation E305G Causes Isolated 17,20-Lyase Deficiency by Selectively Altering Substrate Binding^*

Daniel P. Sherbet¶, Dov Tiosano, Kerri M. Kwist, Zeev Hochberg, and Richard J. Auchus||

From the Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8857 and the Division of Endocrinology, Meyer Children's Hospital, Rambam Medical Center, Haifa 31096, Israel

Cytochrome P450c17 (CYP17) converts the C₂₁ steroids pregnenolone and progesterone to the C₁₉ androgen precursors dehydroepiandrosterone (DHEA) and androstenedione, respectively, via sequential 17-hydroxylase and 17,20-lyase reactions. Disabling mutations in CYP17 cause combined 17-hydroxylase/17,20-lyase deficiency, but rare missense mutations cause isolated loss of 17,20-lyase activity by disrupting interactions of redox partner proteins with CYP17. We studied an adolescent male with clinical and biochemical features of isolated 17,20-lyase deficiency, including micropenis, hypospadias, and gynecomastia, who is homozygous for CYP17 mutation E305G, which lies in the active site. When expressed in HEK-293 cells or Saccharomyces cerevisiae, mutation E305G retains 17-hydroxylase activities, converting pregnenolone and progesterone to 17-hydroxysteroids. However, mutation E305G lacks 17,20-lyase activity for the conversion of 17-hydroxypregnenolone to DHEA, which is the dominant pathway to C₁₉ steroids catalyzed by human CYP17 (the ⁵-steroid pathway). In contrast, mutation E305G exhibits 11-fold greater catalytic efficiency (k_cat/K_m) for the cleavage of 17-hydroxyprogesterone to androstenedione compared with wild-type CYP17. We conclude that mutation E305G selectively impairs 17,20-lyase activity for DHEA synthesis despite an increased capacity to form androstenedione. Mutation E305G provides genetic evidence that androstenedione formation from 17-hydroxyprogesterone via the minor ⁴-steroid pathway alone is not sufficient for complete formation of the male phenotype in humans.

Received for publication, July 14, 2003 , and in revised form, September 16, 2003.

^* This work was supported by NIDDK Grants K08DK02387 and R03DK56641 from the National Institutes of Health (to R. J. A.). 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.

^¶ University of Texas Southwestern Summer Research Fellow.

^|| To whom correspondence should be addressed: Div. of Endocrinology and Metabolism, Dept. of Internal Medicine, UT Southwestern Medical Center, P. O. Box 8857, 5323 Harry Hines Blvd., Dallas, TX 75390-8857. Tel.: 214-648-6751; Fax: 214-648-8917; E-mail: richard.auchus{at}UTSouthwestern.edu.

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