In all species, the first step in androgen biosynthesis is the conversion of cholesterol to pregnenolone, which is catalyzed by P450scc located in the inner mitochondrial membrane. This reaction also requires a mitochondrial electron transfer system, consisting of adrenodoxin and adrenodoxin reductase, to convey electrons from NAPDH to P450scc (40). The P450scc enzyme catalyzes three sequential oxidation reactions of cholesterol, with each reaction requiring 1 molecule of O2 and one molecule of nicotinamide adenine dinucleotide phosphate (NAPDH). The first reaction is hydroxylation at C22, followed by hydroxylation at C20 to yield (20,22) R-hydroxycholesterol, which is cleaved between C20 and C22 to yield the C21 steroid pregnenolone and isocaproalde-hyde (41,42). Isocaproaldehyde is unstable and quickly oxidized to isocaproic acid (43).
The rate-limiting step in the synthesis of steroid hormones is not the first enzymatic reaction catalyzed by P450scc but rather the transport of precursor cholesterol from intracellular sources to the inner mitochondrial membrane and subsequent loading of cholesterol into the catalytic site of P450scc (44,45). Hydrophobic cholesterol cannot traverse the aqueous intermembrane space of mitochondria and reach the P450scc rapidly enough by simple diffusion to support acute steroid synthesis (46). Thus, cholesterol is mobilized by carrier proteins. Both steroidogenic acute response (StAR) protein and peripheral benzodiazepine receptor (PBR) are believed to participate in cholesterol delivery to the mitochondria, with StAR being primarily involved in gonadotropin-stimulated transfer.
Cholesterol, the raw material for steroidogenesis, is obtained from (1) lipoprotein in circulation, with low-density lipoprotein (LDL) being the primary source in humans; (2) de novo synthesis from acetate in the SER; and (3) free cholesterol liberated by cholesterol esterase from less directly available esters in lipid droplets (47).
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