The first step in classical steroid hormone biosynthesis involves the conversion of cholesterol into pregnenolone by the cholesterol side chain cleavage enzyme P450scc (see Figure 1 and Table 1, entry #1). Although the side chain cleavage reaction is known to be the rate-limiting enzyme for adrenal and gonadal steroid hormones, it is not the catalytic process of the cholesterol side chain cleavage enzyme that is rate limiting.
Fig1. Cholesterol side chain cleavage to generate the intermediate pregnenolone followed by its separate conversion to either progesterone or to 17αOH-progesterone. The cholesterol side chain cleavage enzyme (csc) carries out three distinct enzymatic steps, comprising two successive hydroxylations on C-20 and C-22 (shown in green) followed by scission of the C-20–C-22 carbon–carbon bond that releases as products pregnenolone and the rest of the steroid side chain as isocaproaldehyde. Pregnenolone, depending upon the cell type (adrenals, ovary, or testes) can ultimately be converted into aldosterone, cortisol, estradiol, or testosterone. The two immediate fates of prenenolone are its conversion either by the P450c17 enzyme into 17αOH-pregnenolone or by the 3βHSD2 enzyme into progesterone or 17αOH-progesterone. The 3βHSD2 enzyme carries out two distinct catalytic steps : first a dehydrogenation of the 3β-hydroxyl (shown in blue) followed by isomerization of the Δ5,Δ6 double bond to become a Δ4,Δ5 double bond (shown in blue) for both progesterone and 17αOH-progesterone.
Table1. a Key Human Enzymes Concerned with the Production of Steroid Hormones
A specific cholesterol transport protein, known as the steroidogenic acute regulatory protein (StAR), has been implicated as being the essential mediator of cholesterol delivery to the mitochondria and the consequent activation of P450scc. StAR is biosynthesized as an ~300-amino acid protein with a binding pocket for a single cholesterol molecule. StAR has a mitochondrial targeting sequence of 25 amino acid residues, which is cleaved from the NH2-terminus after it is transported into the mitochondria. More specifically, the rate limiting step in classical steroid hormone biosynthesis is the presence and properties of the StAR at the outer mitocondrial membrane (OMM) where it facilitates the movement of cholesterol across the OMM to the IMM site of the P450scc. It is known that the adrenal tropic ACTH hormone can rapidly stimulate the gene transcription of StAR in the adrenal cortex which then is the exclusive mediator of the trans port of cholesterol from the OMM to the IMM.
The most convincing evidence for the essential nature of StAR in facilitating the actions of cholesterol side chain cleavage and the resultant production in the adrenals of mineralocorticoids and glucocorticoids, and in the gonads, but not the placenta, of estrogens or androgens is that mutations of the StAR gene can result in a defect associated with the disease known as lipoid congenital adrenal hyperplasia (CAH). (See Chapter 10, section V.C, “Congenital Adrenal Hyperplasia and Others.”) In lipoid congenital adrenal hyperplasia, which is characterized by a deficiency of both adrenal and gonadal steroid hormones, there is a mutation in the StAR gene, so that the StAR protein is nonfunctional due to premature stop codons.
