Steroid Biosynthesis

Steroid hormones in mammals are biosynthesized from cholesterol, which in turn is made in vivo from acetyl-coenzyme A (acetyl-CoA) via the mevalonate pathway. Although humans do obtain approximately 300 mg of cholesterol per day in their diets, a greater amount (about 1 g) is biosynthesized per day. A schematic outline of these biosynthetic pathways is shown in Figure 25.5.

Conversion of cholesterol to pregnenolone is the rate-limiting step in steroid hormone biosynthesis. It is not the enzymatic transformation itself that is rate limiting; however, the translocation of cholesterol to the inner mito-chondrial membrane of steroid-synthesizing cells is rate limiting.5 A key protein involved in the translocation is the

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Figure 25.1 • Steroid nomenclature and numbering.

Figure 25.1 • Steroid nomenclature and numbering.

Figure 25.2 • Steroid nomenclature—stereochemistry.

Figure 25.2 • Steroid nomenclature—stereochemistry.

5a-Androst-8(14)-ene or 5a_A8(14)-Androstene Figure 25.3 • Steroid nomenclature—double bonds.

5a-Androstane

Figure 25.4 • Alternative representations of steroids.

5a-Androstane

Figure 25.4 • Alternative representations of steroids.

Figure 25.5 • Outline of the biosynthesis of steroid hormones. (3^-HSD, 30-hydroxysteroid dehydrogenase/A5-4-isomerase; 170-HSD, 17^-hydroxysteroid dehydrogenase.)

Figure 25.5 • Outline of the biosynthesis of steroid hormones. (3^-HSD, 30-hydroxysteroid dehydrogenase/A5-4-isomerase; 170-HSD, 17^-hydroxysteroid dehydrogenase.)

Stereochemistry Steroids

Steroidogenic Acute Regulatory protein (StAR). Defects in the StAR gene lead to congenital lipoid adrenal hyperplasia, a rare condition marked by a deficiency of adrenal and gonadal steroid hormones.6 The enzymes involved in the transformation of cholesterol to the hormones are mainly cytochromes P450 and dehydrogenases. The main routes of biosynthesis of the hormones are depicted in Figure 25.5. Estradiol, testosterone, progesterone, aldosterone, and hydrocortisone are representatives of the distinct steroid-receptor ligands that are shown. Further metabolic fates of these compounds are presented under the specific structural class.

An enzyme-denoted cytochrome P450scc (SCC stands for side-chain cleavage) mediates the cleavage of the C17 side chain on the D ring of the sterol to provide preg-nenolone, the C21 precursor of the steroids. This enzyme mediates a three-step process involved in the oxidative metabolism of the side chain. Successive hydroxylations at C20 and C22 are followed by oxidative cleavage of the C20-C22 bond, providing pregnenolone. Pregnenolone can be either directly converted into progesterone or modified for synthesis of GCs, estrogens, and androgens. Introduction of unsaturation into the A ring leads to the formation of progesterone. Specifically, oxidation of the alcohol at C3 to the ketone provides a substrate in which iso-merization of the A5,6-double bond to the A4,5-double bond is facilitated. This transformation is mediated by a bifunc-tional enzyme, 3^-hydroxysteroid dehydrogenase/A5-4 iso-merase (3^-HSD). This enzyme can act on several 3-ol-5-ene steroids in addition to pregnenolone. Hydroxylation at C17 provides the precursor for both sex steroid hormones and GCs. Cytochrome P450c17 hydroxylates pregnenolone and progesterone to provide the corresponding 17a-hy-droxylated compounds. 17a-Hydroxypregnenolone can be converted to 17a-hydroxyprogesterone by 3^-HSD. Cytochrome P450c17 is also a bifunctional enzyme, with lyase activity in addition to the hydroxylase action. The Cl7,20-lyase activity is crucial for the formation of sex hormones. The lyase oxidatively removes the two carbons at C17, providing the C17 ketone. In the case of 17a-hy-droxypregnenolone, the product is dehydroepiandrosterone (DHEA). If 17a-hydroxyprogesterone is the substrate for the lyase, androstenedione results. The conversion of 17a-hydroxyprogesterone to androstenedione is limited in humans, although in other species this is an important pathway. DHEA is converted to androstenedione by the action of 3jS-HSD. Androstenedione can either be converted to testosterone by the action of 17^-hydroxysteroid dehydrogenase (17^-HSD) or be transformed into estrone by aro-matase, a unique cytochrome P450 that aromatizes the A ring of certain steroid precursors. Testosterone is aromatized to 17^-estradiol by the same enzyme. 17^-HSD acts on estrone to form 17^-estradiol. If testosterone is acted on by 5a-reductase, 5a-dihydrotestosterone (DHT), an androgen important in the prostate, is produced.

The major route to GCs diverges at 17a-hydroxypreg-nenolone. Instead of oxidative cleavage at C17, 3^-HSD acts on this substrate to provide 17a-hydroxyprogesterone. Small amounts of 17a-hydroxyprogesterone can be produced directly from progesterone, although this is not a major pathway in humans. Sequential action of 21-hydroxylase (Cyp21) and 11 jS-hydroxylase (Cyp11B1) provides hydrocortisone, the key GC in humans.

If progesterone is directly acted on by 21-hydroxylase (Cyp21), 11-deoxycorticosterone is produced, a precursor to the MC aldosterone. In tissues where aldosterone is syn-thesized,aldosterone synthase (Cyp11B2), the multifunctional enzyme, mediates the hydroxylation at C11, as well as the two-step oxidation of C18 to an aldehyde, providing aldosterone, which exists predominantly in the cyclic-hemiacetal form.

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  • reginald romaine
    What is the rate limiting step in steroid biosynthesis?
    6 months ago

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