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Steroidogenesis Steroid hormones • Cholesterol derivative – Dietary source • Carried in blood as a part of lipoproteins – Synthesized by liver – Receptor-mediated uptake by the cell – De novo synthesis • Cells produce their own cholesterol • Acetate as a source Acetate HMG-CoA HMG-CoA Reductase Mevalonic acid Cholesterol Steroidogenesis • Modification of cholesterol – Changes in the number of carbons – Location of double bond – Redox reaction • Location of steroidogenesis – Mitochondria – Cytoplasm • Mitochondria – Site of side-chain cleavage • Reduction in the number of carbons – Transport of cholesterol • First rate-limiting step • Regulated by steroid acute transport regulate protein (StAR) – Channel protein • StAR protein – Transport channel – Regulation of activity • cAMP dependent – Phospholyration – Synthesis – Loss of StAR • 86 % reduction in steroid hormone synthesis – Basal steroidogenesis Side-chain cleavage • From 27-C molecule to 21-C molecule – Mitochondira – Synthesis of pregnenolone (P5) – Done by the P450scc • Cytochrome C P450 enzyme superfamily • Pregnenolone – Universal substrate for synthesis of steroids • Ovarian steroids • Testicular steroids • Adrenal steroids • Synthesis of progesterone (P4) from P5 – Cytosol • Isomer formation • Reduction of ketone to alcohol • Done by 3b-HSD (3b-hydroxysteroid dehydrogenase) and ∆5,4isomerase • Alternative to synthesis of P4 – Synthesis of 17-hydorxypregnenolone • Addition of hydroxyl group on C-17 • Done by Cytochrome C P 450C17 (17ahydroxylase) – Conversion of 17-hydroxypregnenolone to dehydroepiandrosterone • Cleavage of side-chain on C17 – Formation of C-19 steroid – Done by Cytochrome C P 450C17 (17a- hydroxylase) • Conversion of progesterone – 17hydroxyprogesterone • Addition of hydroxyl group on C-17 • Done by Cytochrome C P 450C17 (17ahydroxylase) • Synthesized from 17hydroxypregnenolone – 3b-HSD • Conversion of progestigens to androstenedione – Androgen precursor – Done by 3b-HSD (3bhydroxysteroid dehydrogenase) • Same in both 17 hydroxyprogesteone and dehydroepiandrosterone • Synthesis of androgens – Conversion of androstenedione • Testosterone • Done by 17b-HSD – Conversion of testosterone • Dihydrotestosterone – Occurs in peripheral tissues by 5a-reductase – More biologically active • Synthesis of estorgen – C-19 to C-18 steroid – Aromatization • A ring of the sterol ring • Done by P450arom (aromatase/CYP 19) – Side-chain on C-17 • Hydroxyl group – Estradiol • Ketone group – Estrone • Key components of steroidogenesis – StAR • Rate-limiting step of the entire process – Enzymes • • • • • P450scc 3b-HSD P 450C17 17b-HSD P450arom Biological activity of steoroids • Major products – Most potent form • Progesterone • Estradiol • Testosterone – DHT • Intermediates – Very low biological activity • Need to be converted