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 Mevalonic acid Cholesterol HMG-CoA Reductase

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 (P 5 ) –Done by the P450 scc Cytochrome C P450 enzyme superfamily

Pregnenolone –Universal substrate for synthesis of steroids Ovarian steroids Testicular steroids Adrenal steroids

Synthesis of progesterone (P 4 ) from P 5 –Cytosol Isomer formation Reduction of ketone to alcohol Done by 3  -HSD (3b-hydroxysteroid dehydrogenase) and ∆ 5,4 isomerase

Alternative to synthesis of P4 –Synthesis of 17-hydorxypregnenolone Addition of hydroxyl group on C-17 Done by Cytochrome C P 450 C17 (17  hydroxylase) –Conversion of 17-hydroxypregnenolone to dehydroepiandrosterone Cleavage of side-chain on C17 –Formation of C-19 steroid –Done by Cytochrome C P 450 C17 (17  hydroxylase)

Conversion of progesterone –17- hydroxyprogesterone Addition of hydroxyl group on C-17 Done by Cytochrome C P 450 C17 (17  hydroxylase) Synthesized from 17- hydroxypregnenolone – 3  -HSD

Conversion of progestigens to androstenedione –Androgen precursor –Done by 3  -HSD (3  - hydroxysteroid dehydrogenase) Same in both 17 hydroxyprogesteone and dehydroepiandrosterone

Synthesis of androgens –Conversion of androstenedione Testosterone Done by 17  -HSD –Conversion of testosterone Dihydrotestosterone –Occurs in peripheral tissues by 5  -reductase –More biologically active

Synthesis of estorgen –C-19 to C-18 steroid –Aromatization A ring of the sterol ring Done by P450 arom (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 P450 scc 3  -HSD P 450 C17 17  -HSD P450 arom

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