Another enzyme that carries out both a hydroxylation reaction and cleavage of a carbon–carbon bond is the P450c17 that is present in three locations. These include in the adrenal zona reticularis (Figure 1), the testicular Leydig cells (see entries 5 and 6 in Table 1 and Figure 2), and the ovarian theca and granulosa cells (see Figure3). The P450c17 enzymes from both the adrenals and testes have been cloned and expressed and found to be identical proteins.
Fig1. Adrenal cortex pathways for production of three classes of steroid hormones. Cholesterol and the presence of the cholesterol side chain cleavage enzyme are the starting point of separate steroid hormone(s) biosynthesis for the three classes. The zona glomerulosa (mineralocorticoids) produces aldosterone. A structural hallmark of aldosterone is the presence of both a C-11 hydroxyl and a C-18 aldehyde. The C-18 aldehyde can form either a five member hemiacetal ring, which uses the C-11 hydroxyl group or a six member hemiacetal ring, which uses the C-21 hydroxyl group. These are reminiscent of carbohydrate chemistry. The zona fasciculata (glucocorticoids) produces both cortisol and corticosterone. The zona reticularis produces limited amounts (represented by the dashed arrow) of the androgens, dehydroepiandrosterone (DHEA), androst-4-ene-3,17-dione and testosterone. DHEA can be converted to DHEA-sulfate via a sulfotransferase, which forms a mixed ester with the 3β-hydroxyl group. For each of the steroid enzyme transformations, the 3-7 letter/number acronymn is shown in magenta next to the arrow. The enzyme’s full name for each acronymn is tabulated in Table 1.
Table1. a Key Human Enzymes Concerned with the Production of Steroid Hormones
Fig2. Pathways of androgen biosynthesis in testicular Leydig cells. Cholesterol is the starting point for production of the principal androgen, testosterone (shown in blue color). The conversion of cholesterol to DHEA is in a manner similar to that of the adrenal cortex zona reticularis. The conversion of testosterone to the more potent dihydrotestosterone (DHT; shown in green color; also see black dashed arrow) by the 5α-reductase (see entry #11 in Table 1) occurs in androgen target glands such as the prostate, epididymis, seminal vesicles, and certain regions of the brain. For each of the steroid enzyme transformations, the 3–7 letter/number acronym is shown in magenta next to the arrow. The enzyme full name for each acronym is listed in Table1.
Fig3. Pathway of the production of progesterone by the corpus luteum and estradiol by the theca and granulosa cells. Cholesterol is the starting point for the production of both progesterone (shown in green color) and estradiol (shown in blue color). There are two pathways from dehydroepiandrosterone (DHEA) to estradiol-17. The major pathway is via androst-4-ene-3, 17dione and estrone. The second pathway via androste-5-ene-3β, 17β-diol and testosterone is only a minor pathway (see three magenta dashed lines). The chemical details of the aromatization of estradiol are described in Figure 4. For each of the steroid enzyme transformations, the seven letter/number acronym is shown in magenta next to the arrow. The enzyme full name for each acronym is tabulated in Table 1.
Fig4. Proposed mechanism of aromatization of estradiol. The aromatase belongs to the cytochrome P450 super family of enzymes. The aromatase is located in the endoplasmic reticulum and is specifically responsible for the production of the steroid hormone estradiol (shown in blue color). The reaction requires one molecule of testosterone (shown in green color), three molecules of NADPH, and three molecules of O2. The initial step is hydroxylation of carbon 19 (the CH3) followed immediately by a second hydroxylation of carbon-19 to yield a gem-diol, which fragments into a C-19 aldehyde. The third oxidative attack (O2) results in the conversion of the C-19 aldehyde into a C-19 carboxyl group that is followed by an immediate elimination of the C-19 methyl group as formic acid which completes the aromatization of the A-ring. Aromatization of estradiol as described by W.L. Miller & R.J. Auchus in Endocrine Rev. 32, 81–151 (2001).
