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J. Biol. Chem., Vol. 280, Issue 14, 13265-13271, April 8, 2005

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Regulation of 17,20 Lyase Activity by Cytochrome b₅ and by Serine Phosphorylation of P450c17^*

Amit V. Pandey and Walter L. Miller

From the Department of Pediatrics and The Metabolic Research Unit, University of California San Francisco, San Francisco, California 94143-0978

Cytochrome P450c17 catalyzes the 17-hydroxylase activity required for glucocorticoid synthesis and the 17,20 lyase activity required for sex steroid synthesis. Most P450 enzymes have fixed ratios of their various activities, but the ratio of these two activities of P450c17 is regulated post-translationally. We have shown that serine phosphorylation of P450c17 and the allosteric action of cytochrome b₅ increase 17,20 lyase activity, but it has not been apparent whether these two post-translational mechanisms interact. Using purified enzyme systems, we now show that the actions of cytochrome b₅ are independent of the state of P450c17 phosphorylation. Suppressing cytochrome b₅ expression in human adrenal NCI-H295A cells by >85% with RNA interference had no effect on 17-hydroxylase activity but reduced 17,20 lyase activity by 30%. Increasing P450c17 phosphorylation could compensate for this reduced activity. When expressed in bacteria, human P450c17 required either cytochrome b₅ or phosphorylation for 17,20 lyase activity. The combination of cytochrome b₅ and phosphorylation was not additive. Cytochrome b₅ and phosphorylation enhance 17,20 lyase activity independently of each other, probably by increasing the interaction between P450c17 and NADPH-cytochrome P450 oxidoreductase.

Received for publication, December 30, 2004 , and in revised form, January 28, 2005.

^* This work was supported by National Institutes of Health Grant HD41958 (to W. L. M.). 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.

To whom correspondence should be addressed: Dept. of Pediatrics, Bldg. MR4 Rm. 209, University of California San Francisco, San Francisco, CA 94143-0978. Tel.: 415-476-2598; Fax: 415-476-6286; E-mail: wlmlab{at}itsa.ucsf.edu.

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