The hydrocarbon chain of cholesterol is shortened and the steroid nucleus is hydroxylated during synthesis. The cholesterol side-chain cleavage enzyme, also known as P450scc and desmolase, catalyzes the initial and rate-limiting reaction that converts cholesterol to pregnenolone, a 21-carbon compound. This enzyme is a cytochrome P450 mixed function oxidase located in the inner mitochondrial membrane. The reaction requires NADPH and O2. Cholesterol can be synthesized de novo, obtained from lipoproteins, or released from stored cholesteryl esters in the cytosol of steroidogenic tissues by an esterase. Afterward, cholesterol moves to the outer mitochondrial membrane. The movement from the outer to the inner mitochondrial membrane is facilitated by the steroidogenic acute regulatory (StAR) protein. Pregnenolone serves as the precursor for all steroid hormones. It undergoes oxidation and isomerization to progesterone, which is further modified into other steroid hormones through CYP protein-catalyzed hydroxylation reactions taking place in the smooth endoplasmic reticulum (SER) and mitochondria. Deficiencies in enzymes within this pathway can result in a deficiency in hormone synthesis beyond the affected step and an excess of hormones or metabolites prior to that step. Due to the potent biological activity of all pathway members, enzyme deficiencies lead to serious metabolic imbalances. These disorders are collectively referred to as congenital adrenal hyperplasias (CAH), which cause adrenal enlargement. It is important to note that Addison disease, characterized by adrenocortical insufficiency, is caused by autoimmune destruction of the adrenal cortex. The adrenal cortical steroid hormones are produced through this process.
Synthesis involves shortening the hydrocarbon chain of cholesterol and hydroxylating the steroid nucleus. The initial and rate-limiting reaction converts cholesterol to the 21-carbon pregnenolone. It is catalyzed by the cholesterol side-chain cleavage enzyme, a cytochrome P450 (CYP) mixed function oxidase of the inner mitochondrial membrane (see p. 149) that is also known as P450scc and desmolase. NADPH and O2 are required for the reaction. The cholesterol substrate can be newly synthesized, taken up from lipoproteins, or released by an esterase from cholesteryl esters stored in the cytosol of steroidogenic tissues. The cholesterol moves to the outer mitochondrial membrane. An important control point is the subsequent movement from the outer to the inner mitochondrial membrane. This process is mediated by StAR (steroidogenic acute regulatory) protein. Pregnenolone is the parent compound for all steroid hormones (see Fig. 18.25). It is oxidized and then isomerized to progesterone, which is further modified to the other steroid hormones by CYP protein–catalyzed hydroxylation reactions in the SER and mitochondria. A defect in the activity or amount of an enzyme in this pathway can lead to a deficiency in the synthesis of hormones beyond the affected step and to an excess in the hormones or metabolites before that step. Because all members of the pathway have potent biologic activity, serious metabolic imbalances occur with enzyme deficiencies (see Fig. 18.25). Collectively, these disorders are known as the congenital adrenal hyperplasias (CAH), because they result in enlarged adrenals. [Note: Addison disease, due to autoimmune destruction of the adrenal cortex, is characterized by adrenocortical insufficiency.]
B. Adrenal cortical steroid hormones