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Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th edition. New York: W H Freeman; 2002.

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Biochemistry. 5th edition.

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Section 26.4Important Derivatives of Cholesterol Include Bile Salts and Steroid Hormones

Cholesterol is a precursor for other important steroid molecules: the bile salts, steroid hormones, and vitamin D.

Bile Salts

As polar derivatives of cholesterol, bile salts are highly effective detergents because they contain both polar and nonpolar regions. Bile salts are synthesized in the liver, stored and concentrated in the gall bladder, and then released into the small intestine. Bile salts, the major constituent of bile, solubilize dietary lipids (Section 22.1.1). Solubilization increases in the effective surface area of lipids with two consequences: more surface area is exposed to the digestive action of lipases and lipids are more readily absorbed by the intestine. Bile salts are also the major breakdown products of cholesterol.

Cholesterol is converted into trihydroxycoprostanoate and then into cholyl CoA, the activated intermediate in the synthesis of most bile salts (Figure 26.23). The activated carboxyl carbon of cholyl CoA then reacts with the amino group of glycine to form glycocholate or it reacts with the amino group of taurine (H2NCH2CH2SO3-), derived from cysteine, to form taurocholate. Glycocholate is the major bile salt.

Figure 26.23. Synthesis of Bile Salts.

Figure 26.23

Synthesis of Bile Salts. Pathways for the formation of bile salts from cholesterol.

Steroid Hormones

Cholesterol is the precursor of the five major classes of steroid hormones: progestagens, glucocorticoids, mineralocorticoids, androgens, and estrogens (Figure 26.24). These hormones are powerful signal molecules that regulate a host of organismal functions. Progesterone, a progestagen, prepares the lining of the uterus for implantation of an ovum. Progesterone is also essential for the maintenance of pregnancy. Androgens of male secondary sex characteristics, whereas estrogens (such as estrone) are required for the development of female secondary sex characteristics. Estrogens, along with progesterone, also participate in the ovarian cycle. Glucocorticoids (such as cortisol) promote gluconeogenesis and the formation of glycogen, enhance the degradation of fat and protein, and inhibit the inflammatory response. They enable animals to respond to stress—indeed, the absence of glucocorticoids can be fatal. Mineralocorticoids (primarily aldosterone) act on the distal tubules of the kidney to increase the reabsorption of Na+ and the excretion of K+ and H+, which leads to an increase in blood volume and blood pressure. The major sites of synthesis of these classes of hormones are the corpus luteum, for progestagens; the ovaries, for estrogens; the testes, for androgens; and the adrenal cortex, for glucocorticoids and mineralocorticoids.

Figure 26.24. Biosynthetic Relations of Classes of Steroid Hormones and Cholesterol.

Figure 26.24

Biosynthetic Relations of Classes of Steroid Hormones and Cholesterol.

Steroid hormones bind to and activate receptor molecules that serve as transcription factors to regulate gene expression (Section 31.3.1). These small, relatively similar molecules are able to have greatly differing effects because the slight structural differences among them allow interactions with specific receptor molecules.

26.4.1. The Nomenclature of Steroid Hormones

Carbon atoms in steroids are numbered as shown for cholesterol in (Figure 26.25). The rings in steroids are denoted by the letters A, B, C, and D. Cholesterol contains two angular methyl groups: the C-19 methyl group is attached to C-10, and the C-18 methyl group is attached to C-13. The C-18 and C-19 methyl groups of cholesterol lie above the plane containing the four rings. A substituent that is above the plane is termed β oriented, whereas a substituent that is below the plane is α oriented.

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Figure 26.25. Cholesterol Carbon Numbering.

Figure 26.25

Cholesterol Carbon Numbering. The numbering scheme for the carbon atoms in cholesterol and other steroids.

If a hydrogen atom is attached to C-5, it can be either α or β oriented. The A and B steroid rings are fused in a trans conformation if the C-5 hydrogen is < oriented, and cis if it is < oriented. The absence of a Greek letter for the C-5 hydrogen atom on the steroid nucleus implies a trans fusion. The C-5 hydrogen atom is α oriented in all steroid hormones that contain a hydrogen atom in that position. In contrast, bile salts have a β-oriented hydrogen atom at C-5. Thus, a cis fusion is characteristic of the bile salts, whereas a trans fusion is characteristic of all steroid hormones that possess a hydrogen atom at C-5. A trans fusion yields a nearly planar structure, whereas a cis fusion gives a buckled structure.

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26.4.2. Steroids Are Hydroxylated by Cytochrome P450 Monooxygenases That Utilize NADPH and O2

Hydroxylation reactions play a very important role in the synthesis of cholesterol from squalene and in the conversion of cholesterol into steroid hormones and bile salts. All these hydroxylations require NADPH and O2. The oxygen atom of the incorporated hydroxyl group comes from O2 rather than from H2O. While one oxygen atom of the O2 molecule goes into the substrate, the other is reduced to water. The enzymes catalyzing these reactions are called monooxygenases (or mixed-function oxygenases). Recall that a monooxygenase also participates in the hydroxylation of aromatic amino acids (Section 23.5.7).

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Hydroxylation requires the activation of oxygen. In the synthesis of steroid hormones and bile salts, activation is accomplished by a cytochrome P450, a family of cytochromes that absorb light maximally at 450 nm when complexed in vitro with exogenous carbon monoxide. These membraneanchored proteins (~50 kd) contain a heme prosthetic group. Because the hydroxylation reactions promoted by P450 enzymes are oxidation reactions, it is at first glance surprising that they also consume the reductant NADPH. NADPH transfers its high-potential electrons to a flavoprotein, which transfers them, one at a time, to adrenodoxin, a nonheme iron protein. Adrenodoxin transfers one electron to reduce the ferric (Fe3+) form of P450 to the ferrous (Fe2+) form (Figure 26.26). Without the addition of this electron, P450 will not bind oxygen. Recall that only the ferrous form of hemoglobin binds oxygen (Section 10.2.1). The binding of O2 to the heme is followed by the acceptance of a second electron from adrenodoxin. The acceptance of this second electron leads to cleavage of the O–O bond. One of the oxygen atoms is then protonated and released as water. The remaining oxygen atom forms a highly reactive ferryl (Fe ═ O) intermediate. This intermediate abstracts a hydrogen atom from the substrate RH to form R•. This transient free radical captures the OH group from the iron atom to form ROH, the hydroxylated product, returning the iron atom to the ferric state.

Figure 26.26. Cytochrome P450 Mechanism.

Figure 26.26

Cytochrome P450 Mechanism. These enzyme-bind O2 and use one oxygen atom to hydroxylate their substrates.

26.4.3. The Cytochrome P450 System Is Widespread and Performs a Protective Function

The cytochrome P450 system, which in mammals is located primarily in the endoplasmic reticulum of the liver and small intestine, is also important in the detoxification of foreign substances (xenobiotic compounds) by oxidative metabolism. For example, the hydroxylation of phenobarbital, a barbiturate, increases its solubility and facilitates its excretion. Likewise, polycyclic aromatic hydrocarbons are hydroxylated by P450, providing sites for conjugation with highly polar units (e.g., glucuronate or sulfate), which markedly increase the solubility of the modified aromatic molecule. One of the most relevant functions of the cytochrome P450 system to human beings is its role in drug metabolism. Drugs such as caffeine and ibuprofen are oxidatively metabolized by these monooxygenases. Indeed, the duration of action of many medications depends on their rate of inactivation by the P450 system. Despite its general protective role in the removal of foreign chemicals, the action of the P450 system is not always beneficial. Some of the most powerful carcinogens are generated from harmless compounds by the P450 system in vivo in the process of metabolic activation. In plants, the cytochrome P450 system plays a role in the synthesis of toxic compounds as well as the pigments of flowers.

Image tree.jpg The cytochrome P450 system is a ubiquitous superfamily of monooxygenases that is present in plants, animals, and prokaryotes. The human genome encodes more than 50 members of the family, whereas the genome of the plant Arabidopsis encodes more than 250 members. All members of this large family arose by gene duplication followed by subsequent divergence that generated a range of substrate specificity. Indeed, the specificity of these enzymes is encoded in delimited regions of the primary structure, and the substrate specificity of closely related members is often defined by a few critical residues or even a single amino acid.

26.4.4. Pregnenolone, a Precursor for Many Other Steroids, Is Formed from Cholesterol by Cleavage of Its Side Chain

Steroid hormones contain 21 or fewer carbon atoms, whereas cholesterol contains 27. Thus, the first stage in the synthesis of steroid hormones is the removal of a six-carbon unit from the side chain of cholesterol to form pregnenolone. The side chain of cholesterol is hydroxylated at C-20 and then at C-22, and the bond between these carbon atoms is subsequently cleaved by desmolase. Three molecules of NADPH and three molecules of O2 are consumed in this remarkable six-electron oxidation.

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Adrenocorticotropic hormone (ACTH, or corticotropin), a polypeptide synthesized by the anterior pituitary gland, stimulates the conversion of cholesterol into pregnenolone, the precursor of all steroid hormones.

26.4.5. The Synthesis of Progesterone and Corticosteroids from Pregnenolone

Progesterone is synthesized from pregnenolone in two steps. The 3-hydroxyl group of pregnenolone is oxidized to a 3-keto group, and the Δ5 double bond is isomerized to a Δ4 double bond (Figure 26.27). Cortisol, the major glucocorticoid, is synthesized from progesterone by hydroxylations at C-17, C-21, and C-11; C-17 must be hydroxylated before C-21 is, whereas C-11 can be hydroxylated at any stage. The enzymes catalyzing these hydroxylations are highly specific, as shown by some inherited disorders. The initial step in the synthesis of aldosterone, the major mineralocorticoid, is the hydroxylation of progesterone at C-21. The resulting deoxycorticosterone is hydroxylated at C-11. The oxidation of the C-18 angular methyl group to an aldehyde then yields aldosterone.

Figure 26.27. Pathways for the Formation of Progesterone, Cortisol, and Aldosterone.

Figure 26.27

Pathways for the Formation of Progesterone, Cortisol, and Aldosterone.

26.4.6. The Synthesis of Androgens and Estrogens from Pregnenolone

Androgens and estrogens also are synthesized from pregnenolone through the intermediate progesterone. Androgens contain 19 carbon atoms. The synthesis of androgens (Figure 26.28) starts with the hydroxylation of progesterone at C-17. The side chain consisting of C-20 and C-21 is then cleaved to yield androstenedione, an androgen. Testosterone, another androgen, is formed by the reduction of the 17-keto group of androstenedione. Testosterone, through its actions in the brain, is paramount in the development of male sexual behavior. It is also important for maintenance of the testes and development of muscle mass. Owing to the latter activity, testosterone is referred to as an anabolic steroid. Testosterone is reduced by 5a-reductase to yield dihydrotestosterone (DHT), a powerful embryonic androgen that instigates the development and differentiation of the male phenotype. Estrogens are synthesized from androgens by the loss of the C-19 angular methyl group and the formation of an aromatic A ring. Estrone, an estrogen, is derived from androstenedione, whereas estradiol, another estrogen, is formed from testosterone.

Figure 26.28. Pathways for the Formation for Androgens and Estrogens.

Figure 26.28

Pathways for the Formation for Androgens and Estrogens.

26.4.7. Vitamin D Is Derived from Cholesterol by the Ring-Splitting Activity of Light

Cholesterol is also the precursor of vitamin D, which plays an essential role in the control of calcium and phosphorus metabolism. 7-Dehydrocholesterol (provitamin D3) is photolyzed by the ultraviolet light of sunlight to previtamin D3, which spontaneously isomerizes to vitamin D3 (Figure 26.29). Vitamin D3 (cholecalciferol) is converted into calcitriol (1,25-dihydroxycholecalciferol), the active hormone, by hydroxylation reactions in the liver and kidneys. Although not a steroid, vitamin D acts in an analogous fashion. It binds to a receptor, structurally similar to the steroid receptors, to form a complex that functions as a transcription factor, regulating gene expression.

Figure 26.29. Vitamin D Synthesis.

Figure 26.29

Vitamin D Synthesis. The pathway for the conversion of 7-dehydrocholesterol into vitamin D3 and then into calcitriol, the active hormone.

Image caduceus.jpg Vitamin D deficiency in childhood produces rickets, a disease characterized by inadequate calcification of cartilage and bone. Rickets was so common in seventeenth-century England that it was called the “children's disease of the English.” The 7-dehydrocholesterol in the skin of these children was not photolyzed to previtamin D3, because there was little sunlight for many months of the year. Furthermore, their diets provided little vitamin D, because most naturally occurring foods have a low content of this vitamin. Fish-liver oils are a notable exception. Cod-liver oil, abhorred by generations of children because of its unpleasant taste, was used in the past as a rich source of vitamin D. Today, the most reliable dietary sources of vitamin D are fortified foods. Milk, for example, is fortified to a level of 400 international units per quart (10 μg per quart). The recommended daily intake of vitamin D is 400 international units, irrespective of age. In adults, vitamin D deficiency leads to softening and weakening of bones, a condition called osteomalacia. The occurrence of osteomalacia in Bedouin Arab women who are clothed so that only their eyes are exposed to sunlight is a striking reminder that vitamin D is needed by adults as well as by children.

26.4.8. Isopentenyl Pyrophosphate Is a Precursor for a Wide Variety of Biomolecules

Before this chapter ends, we will revisit isopentenyl pyrophosphate, the activated precursor of cholesterol. The combination of isopentenyl pyrophosphate (C5) units to form squalene (C30) exemplifies a fundamental mechanism for the assembly of carbon skeletons of biomolecules. A remarkable array of compounds is formed from isopentenyl pyrophosphate, the basic five-carbon building block. The fragrances of many plants arise from volatile C10 and C15 compounds, which are called terpenes. For example, myrcene (C10H16) from bay leaves consists of two isoprene units, as does limonene (C10H15) from lemon oil (Figure 26.30). Zingiberene (C15H24), from the oil of ginger, is made up of three isoprene units. Some terpenes, such as gera-niol from geraniums and menthol from peppermint oil, are alcohols; others, such as citronellal, are aldehydes. We shall see later (Chapter 32) how specialized sets of 7-TM receptors are responsible for the diverse and delightful odor and taste sensations that these molecules induce.

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Figure 26.30. Three Isoprenoids from Familiar Sources.

Figure 26.30

Three Isoprenoids from Familiar Sources.

We have already encountered several molecules that contain isoprenoid side chains. The C30 hydrocarbon side chain of vitamin K2, an important molecule in clotting (Section 10.5.7), is built from 6 isoprene (C5) units. Coenzyme Q10 in the mitochondrial respiratory chain (Section 18.3) has a side chain made up of 10 isoprene units. Yet another example is the phytol side chain of chlorophyll (Section 19.2), which is formed from 4 isoprene units. Many proteins are targeted to membranes by the covalent attachment of a farnesyl (C15) or a geranylgeranyl (C20) unit to the carboxyl-terminal cysteine residue of the protein (Section 12.5.3). The attachment of isoprenoid side chains confers hydrophobic character.

Isoprenoids can delight by their color as well as by their fragrance. The color of tomatoes and carrots comes from carotenoids. These compounds absorb light because they contain extended networks of single and double bonds and are important pigments in photosynthesis (Section 19.5.2). Their C40 carbon skeletons are built by the successive addition of C5 units to form geranylgeranyl pyrophosphate, a C20 intermediate, which then condenses tail-to-tail with another molecule of geranylgeranyl pyrophosphate.

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Phytoene, the C40 condensation product, is dehydrogenated to yield lycopene. Cyclization of both ends of lycopene gives β-carotene, which is the precursor of retinal, the chromophore in all known visual pigments (Section 32.3.2). These examples illustrate the fundamental role of isopentenyl pyrophosphate in the assembly of extended carbon skeletons of biomolecules. It is evident that isoprenoids are ubiquitous in nature and have diverse significant roles, including the enhancement of the sensuality of life.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2002, W. H. Freeman and Company.
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