Cholesterol is an essential component of many cellular and developmental processes and is the precursor for all adrenal and gonadal steroid hormones, bile acids, and neurosteroids. The cholesterol molecule (27 carbons) is synthesized from lanosterol through a series of approximately 30 enzymatic reactions (see Chapter 23).
Adrenals can synthesize cholesterol de novo from acetate and coenzyme A, but most cholesterol is of dietary origin, provided by plasma low-density lipoproteins (LDLs). Two families of enzymes play a leading role in the conversion of cholesterol to adrenal steroid hormones: cytochrome P450s and hydroxysteroid dehydrogenases.
Most of the enzymes involved in the synthesis of adrenal steroids belong to the cytochrome P450 enzyme family, which are membrane-bound proteins associated with either mitochondria or the endoplasmic reticulum (microsomal). P450 enzymes function as monooxygenases using reduced nicotinamide adenine dinucleotide phosphate (NADPH) as the electron donor for the reduction of the molecular oxygen.1
The mitochondrial P450scc enzyme and P450c11 isozymes, P450c11β and P450c11AS, respectively, receive electrons from the NADPH through a sequential electron shuttle transfer involving two proteins, adrenodoxin reductase (a flavoprotein)2 and adrenodoxin (a non heme iron–sulfur protein).3 The microsomal P450c17, P450c21, P450arom enzymes, receive electrons from the reduced form of NADPH using only one membrane-bound flavoprotein, P450 oxidoreductase (POR), to transfer the electrons from NADPH to POR to P450 enzymes.
The hydroxysteroid dehydrogenases, which include 3β-HSD and 17β-HSD isozymes, are involved in the reduction and oxidation of adrenal and gonadal steroids in the presence of NAD+/NADP+ or their reducing equivalents as cofactors (Table 29-1).
TABLE 29-1Steroidogenic Enzymes ||Download (.pdf) TABLE 29-1 Steroidogenic Enzymes
|Enzyme ||Gene ||Locus ||Cellular Site ||Electron Transfer/Target Tissue ||Coenzymes ||Enzymatic Activity |
|Cytochrome P450 |
|P450scc ||CYP11A1 ||15q23-q24 ||Mitochondrial ||Adrenal cortex, placenta, testes, ovaries ||Adrenodoxin/adrenodoxin reductase/NADPH/O2 ||Converts cholesterol to pregnenolone via 20α-hydroxylation, 22-hydroxylation, and cleavage of the cholesterol chain bond at position 20–22 |
|P450c11β ||CYP11B1 ||8q21 ||Mitochondrial ||Zona fasciculata and reticularis ||Adrenodoxin/adrenodoxin reductase/NADPH/O2 ||Converts 11-deoxycortisol to cortisol in the zona fasciculata and 11-deoxycorticosterone (DOC) to corticosterone (B) in the zona glomerulosa via 11β-hydroxylase activity |
|P450c11AS ||CYP11B2 ||8q21-q22 ||Mitochondrial ||Zona glomerulosa ||Adrenodoxin/adrenodoxin reductase/NADPH/O2 ||Through three sequential enzymatic steps converts DOC to B via 11β-hydroxylase activity, B to 18-OHB through 18-hydroxylase or corticosterone methyl oxidase I (CMOI) activity, and 18-OHDOC to aldosterone through 18-oxidase (CMOII) activity |
|P450c17 ||CYP17 ||10q24.3 ||Microsomal ||Leydig and theca cells, zonae fasciculata and reticularis ||P450 oxidoreductase/b5 cytochrome/NADPH/O2 ||Through two subsequent enzymatic steps converts pregnenolone to 17α-hydroxypregnenolone and progesterone to 17α-hydroxyprogesterone (17-OHP) through 17α-hydroxylase activity; 17-hydroxyperegnenolone, and, to a lesser degree, 17-OHP are converted to DHEA and Δ4A, respectively, through 17,20-lyase activity |
|P450arom ||CYP19 ||15q21.1 ||Microsomal ||Leydig and ...|