tailieunhanh - Báo cáo khoa học: Assessment of porcine and human 16-ene-synthase, a third activity of P450c17, in the formation of an androstenol precursor

Recently, we have shown that the biosynthesis of androste-nol, a potential endogenous ligand for the orphan receptors constitutive androstane receptor and pregnane-X-receptor, requires the presence of enzymes of the steroidogenic path-way, such as 3b-hydroxysteroid dehydrogenase, 5a-reduc-tase and 3a-hydroxysteroid dehydrogenase. | Eur. J. Biochem. 270 1349-1355 2003 FEBS 2003 doi Assessment of porcine and human 16-ene-synthase a third activity of P450C17 in the formation of an androstenol precursor Role of recombinant cytochrome b5 and P450 reductase Penny Soucy Lucille Lacoste and Van Luu-The Molecular Endocrinology and Oncology Research Center Laval University Medical Center CHUL and Laval University Quebec Canada Recently we have shown that the biosynthesis of androste-nol a potential endogenous ligand for the orphan receptors constitutive androstane receptor and pregnane-X-receptor requires the presence of enzymes of the steroidogenic pathway such as 3b-hydroxysteroid dehydrogenase 5a-reduc-tase and 3a-hydroxysteroid dehydrogenase. In this report we examine at the molecular level whether the enzyme 17a-hydroxylase 17 20-lyase P450c17 which possesses dual 17a-hydroxylase and 17 20-lyase activities and catalyzes the production of precursors for glucocorticoids and sex steroids is also able to catalyze the formation of a third class of active steroids 16-ene steroids including androstenol . The role of components of the P450 complex is also assessed. We transfected human embryonic kidney HEK-293 cells with various amounts of vectors expressing P450c17 NADPH- cytochrome P450 reductase and cytochrome b5. Our results showed that P450c17 possesses a 16-ene-synthase activity able to transform pregnenolone into 5 16-androstadien-3 -ol. without the formation of the precursor 17-hydroxy-pregnenolone. Cytochrome b5 has a much stronger effect on the 16-ene-synthase activity than on the 17a-hydroxylase 17 20-lyase activities. On the other hand P450reductase has a drastic effect on the latter but a negligible one on 5 16-androstadien-3b-ol synthesis. Our results therefore demonstrate that human P450c17 as other enzymes of the classical steroidogenic pathway is involved in the biosynthetic pathway leading to the formation of androstenol. Keywords 16-ene-synthase .

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