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Steroidogenesis

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. HMG-CoA. Acetate. HMG-CoA Reductase.

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Steroidogenesis

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  1. Steroidogenesis

  2. 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

  3. HMG-CoA Acetate HMG-CoA Reductase Mevalonic acid Cholesterol

  4. Steroidogenesis • Modification of cholesterol • Changes in the number of carbons • Location of double bond • Redox reaction • Location of steroidogenesis • Mitochondria • Cytoplasm

  5. 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

  6. StAR protein • Transport channel • Regulation of activity • cAMP dependent • Phospholyration • Synthesis • Loss of StAR • 86 % reduction in steroid hormone synthesis • Basal steroidogenesis

  7. 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

  8. Pregnenolone • Universal substrate for synthesis of steroids • Ovarian steroids • Testicular steroids • Adrenal steroids

  9. Synthesis of progesterone (P4) from P5 • Cytosol • Isomer formation • Reduction of ketone to alcohol • Done by 3b-HSD (3b-hydroxysteroid dehydrogenase) and ∆5,4isomerase

  10. Alternative to synthesis of P4 • Synthesis of 17-hydorxypregnenolone • Addition of hydroxyl group on C-17 • Done by Cytochrome C P 450C17 (17a- hydroxylase) • Conversion of17-hydroxypregnenolone to dehydroepiandrosterone • Cleavage of side-chain on C17 • Formation of C-19 steroid • Done by Cytochrome C P 450C17 (17a- hydroxylase)

  11. Conversion of progesterone • 17-hydroxyprogesterone • Addition of hydroxyl group on C-17 • Done by Cytochrome C P 450C17 (17a- hydroxylase) • Synthesized from 17-hydroxypregnenolone • 3b-HSD

  12. Conversion of progestigens to androstenedione • Androgen precursor • Done by 3b-HSD (3b-hydroxysteroid dehydrogenase) • Same in both 17 hydroxyprogesteone and dehydroepiandrosterone

  13. 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

  14. 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

  15. Key components of steroidogenesis • StAR • Rate-limiting step of the entire process • Enzymes • P450scc • 3b-HSD • P 450C17 • 17b-HSD • P450arom

  16. Biological activity of steoroids • Major products • Most potent form • Progesterone • Estradiol • Testosterone • DHT • Intermediates • Very low biological activity • Need to be converted

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