Steroid hormones from biosynthesis

Biosynthesis of steroid hormones from cholesterol. The different pathways occur to varying extent in adrenals, gonads, and placenta. The systematic names for cytochrome P-450 enzymes, namely CYP followed by a number, are given in parentheses. CYPI1B2 and CYP17 possess multiple enzyme activities. [Reproduced with permission from P. C. White and P. W. Speiser, Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocrine Reviews 21,245 (2000).]... 

Cholesterol is a major constituent of the cell membranes of animal cells (see p. 216). It would be possible for the body to provide its full daily cholesterol requirement (ca. 1 g) by synthesizing it itself However, with a mixed diet, only about half of the cholesterol is derived from endogenous biosynthesis, which takes place in the intestine and skin, and mainly in the liver (about 50%). The rest is taken up from food. Most of the cholesterol is incorporated into the lipid layer of plasma membranes, or converted into bile acids (see p. 314). A very small amount of cholesterol is used for biosynthesis of the steroid hormones (see p. 376). In addition, up to 1 g cholesterol per day is released into the bile and thus excreted. 

The cholesterol required for biosynthesis of the steroid hormones is obtained from various sources, it is either taken up as a constituent of LDL lipoproteins (see p. 278) into the hormone-synthesizing glandular cells, or synthesized by glandular cells themselves from acetyl-CoA (see p. 172). Excess cholesterol is stored in the form of fatty acid esters in lipid droplets. Hydrolysis allows rapid mobilization of the cholesterol from this reserve again. 

Congenital defects in the biosynthesis of steroid hormones can lead to severe developmental disturbances, in the adrenogenital syndrome (AGS), which is relatively common, there is usually a defect in 21-hydroxylase, which is needed for synthesis of cortisol and aldosterone from progesterone. Reduced synthesis of this hormone leads to increased formation of testosterone, resulting in masculin-ization of female fetuses. With early diagnosis, this condition can be avoided by providing the mother with hormone treatment before birth. 

The biosynthesis of steroids is complex, as one wonld expect since all the compounds in this group must be derived from a single precnrsor (cholesterol (5.4)). The primary sonrce of all the compounds involved in steroid synthesis is acetate, in the form of acetyl-coenzyme A. Cholesterol, besides being ingested in food, is synthesized in large amounts, and an adnlt human contains about 250 g of cholesterol. In contrast, the steroid hormones are produced at the milligram level or lower. 

Cholesterol is a soft waxy substance that is a steroidal alcohol or sterol. It is the most abundant steroid in the human body and is a component of every cell. Cholesterol is essential to life and most animals and many plants contain this compound. Cholesterol biosynthesis occurs primarily in the liver, but it may be produced in other organs. A number of other substances are synthesized from cholesterol including vitamin D, steroid hormones (including the sex hormones), and bile salts. Cholesterol resides mainly in cell membranes. 

We begin with an account of the main steps in the biosynthesis of cholesterol from acetate, then discuss the transport of cholesterol in the blood, its uptake by cells, the normal regulation of cholesterol synthesis, and its regulation in those with defects in cholesterol uptake or transport. We next consider other cellular components derived from cholesterol, such as bile acids and steroid hormones. Finally, an outline of the biosynthetic pathways to some of the many compounds derived from isoprene units, which share early steps with the pathway to cholesterol, illustrates the extraordinary versatility of isoprenoid condensations in biosynthesis. 

Ascorbic acid may be required for steroid hormone biosynthesis depleted from adrenal cortex on cortical secretion Biotin adrenocortical insufficiency noted in biotin deficiency... 

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. 

Steroid hormones are produced in the adrenal cortex and the sex glands. All such hormones originate from cholesterol. Figure 16.4 shows the overall scheme for steroid hormone biosynthesis that is applicable to all tissues. The final products may be divided into the following groups mineralocorticoids (e.g., aldosterone), produced by the zona glomerulosa of the adrenal cortex glucocorticoids (e.g., cortisol), produced by the zona fasciculata of the adrenal cortex and the... 

Figure 16.4 Biosynthesis of various classes of steroid hormones. Reaction (A) is catalyzed by a cholesterol desmolase, which oxidizes the cholesterol side chain. Reactions (D) are catalyzed by 21-hydroxylases, which are defective in congenital adrenal hyperplasia. (Reproduced by permission from Schwarz V. A Clinical Companion to Biochemical Studies. Reading Freeman, 1978, p. 94.)...

Figure 17.8 Typical hydroxylation reaction involving cytochrome P450. Ad, adrenodoxin. The substrate is a steroid hormone biosynthesis intermediate. The location of the reaction is in the mitochondria of adrenal cortex. (Reproduced by permission from Bezkorovainy A. Biochemistry of Nonheme Iron. New York Plenum Press, 1980, p. 380.)...

Our study on the distribution of electron transferring proteins in animal sources is still in progress. From present knowledge, adrenodoxin can be found in adrenal cortexes from pig, beef, and rat. Further, a similar protein was isolated from pig testis (see II-A-2), and it was also found in the ovary. However, brain, heart, liver, kidney, and pancreas appear to lack adrenodoxin-like protein. If this is correct, the proteins of the ferredoxin family are located solely in the glands which directly act in the biosynthesis of steroid hormones. It is of interest that adrenodoxin-like protein does not participate in the steroid hydroxylation involved in cholesterol and cholic acid biosyntheses. All of these reactions without the participation of adrenodoxin are similar to enzymes responsible for microsomal non-specific hydroxylation, which consist of the following sequence of electron transfer ... 

HMG-CoA reductase is the rate-limiting step of cholesterol biosynthesis, and is subject to complex regulatory controls. A relatively constant level of cholesterol in the body (150-200 mg/dl) is maintained primarily by controlling the level of de novo synthesis. The level of cholesterol synthesis is regulated in part by the dietary intake of cholesterol. Cholesterol from both diet and synthesis is utilised in the formation of membranes and in the synthesis of the steroid hormones and bile acids. The greatest proportion of cholesterol is used in bile acid synthesis. 

This chapter examines the biosynthesis of three important components of biological membranes—phospholipids, sphingolipids, and cholesterol (Chapter 12). Triacylglycerols also are considered here because the pathway for their synthesis overlaps that of phospholipids. Cholesterol is of interest both as a membrane component and as a precursor of many signal molecules, including the steroid hormones progesterone, testosterone, estrogen, and cortisol. The biosynthesis of cholesterol exemplifies a fundamental mechanism for the assembly of extended carbon skeletons from five-carbon units. 

The human body tunts over about 800 mg of cholesterol per day. Most of this turnover (synthesis, degradation, or loss from the body) inv olves bile salts. More specifically, about 400 mg cholesterol is used to manufacture new bile salts to replace those that have been lost in the feces. About 80 mg cholesterol is lost through the skin about 50 mg is used for synthesis of steroid hormones. Cholestyramine can stimulate the loss of much more than the equivalent of 400 mg, and can produce clinically significant decreases in serum cholesterol Cholestyramine alone does not drastically lower serum cholesterol, because the liver senses any depletion and responds by increasing its rate of cholesterol biosynthesis. However, use of the drug in combination with other drugs that Inhibit... 

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