Pregnenolone biosynthesis

Fig. 4. An example of a sequential hydroxylation sequence for pregnenolone biosynthesis. f22)indicates hydroxylation position.

Strushkevich N, MacKenzie F, Cherkesova T, Grab-ovec I, Usanov S, Park HW (2011) Structural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase system. Proc Natl Acad Sci U S A 108 10139-10143... 

NADPH), oxygen, and a specific cytochrome P450. The rate-limiting step in steroid biosynthesis is the conversion of cholesterol to pregnenolone (Fig. 60.1). 

Testosterone synthesis from pregnenolone can occur along two distinct metabolic pathways (Fig. 63.1). The names given to these two routes of metabolism refer to the position in the steroid molecule where an unsaturated bond is maintained. Thus, in the delta-4 pathway an unsaturated position is between C4 and C5 of ring A, whereas in the delta-5 pathway, the unsaturated position is between C5 and C6 of ring B. In the human testis, the delta-5 pathway is the predominant (but not exclusive) one used for the biosynthesis of testosterone. 

The steroid Ci7(20)lyase is an enzyme that is involved in the biosynthesis of andro-stenedione and of dehydroepiandrosterone from progesterone and pregnenolone, respectively. As androgen and estrogen hormones are necessary for the growth of tumors, this enzyme is a potential therapeutic target for the treatment of prostate cancer and in hormone-dependent breast cancers. 

Eur J Neuropsychopharmacol 6 (suppl 3) 207, 1996 Julius D, McDermott AB, Axel R, et al Molecular characterization of a functional cDNA encoding the serotonin 1C receptor. Science 241 558-564, 1988 Jung-Testas 1, Hu ZY, Beaulieu EE, et al Neurosteroids biosynthesis of pregnenolone and progesterone in primary cultures of rat glial cells. Endocrinology 125 2083-2091, 1989... 

Outline of major pathways in adrenocortical hormone biosynthesis. The major secretory products are underlined. Pregnenolone is the major precursor of corticosterone and aldosterone, and 17-hydroxypregnenolone is the major precursor of cortisol. The enzymes and cofactors for the reactions progressing down each column are shown on the left and across columns at the top of the figure. When a particular enzyme is deficient, hormone production is blocked at the points indicated by the shaded bars. 

Fig. 2. Biosynthesis of testosterone (a) Pregnenolone (b) 17-hydroxy pregneno-line (c) dehydrois-oandrosterone (d) progesterone (e) 17-hydroxypro ges terone If androstenedione (g) testosterone...

The initial reaction in steroid hormone biosynthesis is catalyzed by desmolase (side-chain cleavage complex), which is found in the mitochondria of steroid-producing tissues (e.g., adrenals, gonads). The reaction is shown in figure 20.22. The product, pregnenolone, is subsequently transferred to the endoplasmic reticulum, where an oxidation of... 

The step-by-step synthesis of the steroid hormones pregnenolone and progesterone from cholesterol (C27) was presented in chapter 20 (see fig 20.22). Note that pregneno-lone (C2i) and progesterone (table 20.4) (C2 ) are intermediates in the biosynthesis of all of the major adrenal steroids, including cortisol (C2i), corticosterone (C21), and aldosterone (C21). The same two compounds are intermediates in the synthesis of the gonadal steroid hormones, testosterone (C,9) and 17/3-estradiol (CI8). Because the synthesis of all these hormones follows a common pathway, a defect in the activity or amount of an enzyme along that pathway can lead to both a deficiency in the hormones beyond the affected step and an excess of the hormones, or metabolites, prior to that step. 

Outline of major pathways in adrenocortical hormone biosynthesis. The major secretory products are underlined. Pregnenolone is the major precursor of corticosterone and aldosterone, and 17-... 

The rate-limiting step in progestin biosynthesis is the side-chain cleavage of cholesterol to pregnenolone taking place in the mitochondria. At least three steps in the cholesterol side-chain cleavage (SSC) reaction may be under hormonal regulation [72,73]. FSH stimulates the synthesis of the SSC cytochrome P-450 which results in the stimulation of SSC activity [74]. 

Fig. 2. Pathway of biosynthesis of the glucocorticoid, cortisol, in the adrenal cortex. Cholesterol, from stores in cholesteryl esters or from other sources (see text) is converted via mitochondrial cytochrome P-450SCC (cholesterol side-chain cleavage enzyme) to pregnenolone, which then is successively converted by the microsomal enzymes cytochrome P-450,7 (17a-hydroxylase), 3 j8-hydroxysteroid dehydrogenase/ isomerase and cytochrome P-450c2, (21-hydroxylase) to 11-deoxycortisol, followed by conversion by the mitochondrial cytochrome P-450ll(3 (11/3-hydroxylase) to cortisol. The short-term action of ACTH in stimulation of steroidogenesis is to increase the availability of cholesterol for conversion by cytochrome P-450scc. From Ref. 9.

A symposium213 deals with the methodology of steroid biochemistry and the biosynthesis of trophic hormones. Side-chain cleavage that converts cholesterol into pregnenolone is catalysed, in the rat, by a mitochondrial enzyme complex that... 

The side chain cleavage of cholesterol, producing pregnenolone, is catalyzed by cytochrome P450JCC. This is the initial step in the biosynthesis of several steroid hormones. In this assay, the initial product, pregnenolone, is quantitatively converted to progesterone by treatment with cholesterol oxidase, which increases by about 10-fold the sensitivity of the assay. 

Caspi, E., Lewis, D.O., Piatak, D.M., Thimann, K.V. and Winter, A. (1966) Biosynthesis of plant sterols. Conversion of cholesterol to pregnenolone in Digitalis purpurea. Experientia, 12, 506-7. 

Duport, C., Spagnoli, R., Degryse, E. and Rompon, D. (1998) Self-sufficient biosynthesis of pregnenolone and progesterone in engineered yeast. Nat. Biotechnol, 16, 186-9. 

G-12) (G-13) 21-bydroxylase deficiency. This is the most common hereditary enzyme defect in steroid biosynthesis. There is decreased glucocorticoid and mineralocorticoid production, as the enzyme is common to both pathways. This leads to increased ACTH production, which in turn causes adrenal hyperplasia and increased pregnenolone production. This results in increased androgen production and virilization. Therapy consists in administering glucocorticoids. This decreases ACTH production by negative feedback. 

The intermediates employed in the biosynthesis of androgens belong to two structurally different chemical classes, a,)3-unsaturated ketones (progesterone) and /3,y-unsatui ated alcohols (pregnenolone and dehydroepiandrosterone). The biosynthetic pathways in the production of androgens are also different [390]. 

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