Androgen formation by cytochrome P450 CYP17. Solvent isotope effect and pL studies suggest a role for protons in the regulation of oxene versus peroxide chemistry
| Autor: | Amy Y. Mak, David C. Swinney |
|---|---|
| Rok vydání: | 1994 |
| Předmět: |
Male
Reaction mechanism Stereochemistry Swine Protonation Cleavage (embryo) Biochemistry Peroxide Catalysis Hydroxylation chemistry.chemical_compound Cytochrome P-450 Enzyme System Isotopes Microsomes Kinetic isotope effect Testis Animals Androstenedione Progesterone Aldehyde-Lyases Chemistry Steroid 17-alpha-Hydroxylase Peroxides Kinetics Androgens Solvents Epoxy Compounds Protons |
| Zdroj: | Biochemistry. 33(8) |
| ISSN: | 0006-2960 |
| Popis: | CYP17 catalyzes the cleavage of the C-17 side chain of progesterone to form androstenedione. The two-step reaction involves an initial 17 alpha-hydroxylation catalyzed by oxene chemistry followed by cleavage of the C-17 side chain. We have recently shown that C-17 side-chain cleavage may involve the rearrangement of a peroxy intermediate via a Baeyer-Villiger rearrangement [Mak, A. Y., & Swinney, D. C. (1992) J. Am. Chem. Soc. 114, 8309]. Accordingly, CYP17 is proposed to catalyze oxidations via both oxene and peroxide chemistry. This study was initiated to investigate the possibility that protons may play a determining role in differentiating between the oxene and peroxide chemistries associated with product formation. The pL dependence of the deuterium solvent isotope effects associated with progesterone oxidation to 17 alpha-hydroxyprogesterone and 17-O-acetyltestosterone and 17 alpha-hydroxyprogesterone oxidation to androstenedione was determined in microsomes from pig testes. The formation of 17 alpha-hydroxyprogesterone is assumed to occur via oxene chemistry and the formation of 17-O-acetyltestosterone and androstenedione by peroxide chemistry. The initial rate of progesterone oxidation to 17 alpha-hydroxyprogesterone was associated with a pL-independent inverse solvent isotope effect (Hk/Dk = 0.75-0.95, in 30% DOD), whereas the rate of oxidation to 17-O-acetyltestosterone was associated with a pL-independent positive solvent isotope effect in the presence of 30% DOD (Hk/Dk approximately 2). In contrast, DOD inhibited the formation of androstenedione from 17 alpha-hydroxyprogesterone in a noncompetitive, pL-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Databáze: | OpenAIRE |
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