Lipids

"The mighty whales which swin in a swa of water, and have a sea of oil swimming in them."
Herman Melville, "Extracts." Moby Dick. New Your: Peguin Books, 1972.
(Humpback whale (Megaptera novaeangliae) breacking, Cape Cod, MA; photo © Steven Morello/Peter Arnold, Inc.)

8.1 · Fatty Acids

A fatty acid is composed of a long hydrocarbon chain (“tail”) and a terminal carboxyl group (or “head”). The carboxyl group is normally ionized under physiological conditions. Fatty acids occur in large amounts in biological systems, but rarely in the free, uncomplexed state. They typically are esterified to glycerol or other backbone structures. Most of the fatty acids found in nature have an even number of carbon atoms (usually 14 to 24). Certain marine organisms, however, contain substantial amounts of fatty acids with odd numbers of carbon atoms. Fatty acids are either saturated (all carbon-carbon bonds are single bonds) or unsaturated (with one or more double bonds in the hydrocarbon chain). If a fatty acid has a single double bond, it is said to be monounsaturated, and if it has more than one, polyunsaturated. Fatty acids can be named or described in at least three ways, as listed in Table 8.1. For example, a fatty acid composed of an 18-carbon chain with no double bonds can be called by its systematic name (octadecanoic acid), its common name (stearic acid), or its shorthand notation, in which the number of carbons is followed by a colon and the number of double bonds in the molecule (18:0 for stearic acid). The structures of several fatty acids are given in Figure 8.1. Stearic acid (18:0) and palmitic acid (16:0) are the most common saturated fatty acids in nature.

      Free rotation around each of the carbon-carbon bonds makes saturated fatty acids extremely flexible molecules. Owing to steric constraints, however, the fully extended conformation (Figure 8.1) is the most stable for saturated fatty acids. Nonetheless, the degree of stabilization is slight, and (as will be seen) saturated fatty acid chains adopt a variety of conformations.

      Unsaturated fatty acids are slightly more abundant in nature than saturated fatty acids, especially in higher plants. The most common unsaturated fatty acid is oleic acid, or 18:1(9), with the number in parentheses indicating that the double bond is between carbons 9 and 10. The number of double bonds in an unsaturated fatty acid varies typically from one to four, but, in the fatty acids found in most bacteria, this number rarely exceeds one.

      The double bonds found in fatty acids are nearly always in the cis configuration. As shown in Figure 8.1, this causes a bend or “kink” in the fatty acid chain. This bend has very important consequences for the structure of biological membranes. Saturated fatty acid chains can pack closely together to form ordered, rigid arrays under certain conditions, but unsaturated fatty acids prevent such close packing and produce flexible, fluid aggregates.
      Some fatty acids are not synthesized by mammals and yet are necessary for normal growth and life. These essential fatty acids include linoleic and g-linolenic acids. These must be obtained by mammals in their diet (specifically from plant sources). Arachidonic acid, which is not found in plants, can only be synthesized by mammals from linoleic acid. At least one function of the essential fatty acids is to serve as a precursor for the synthesis of eicosanoids, such as prostaglandins, a class of compounds that exert hormone-like effects in many physiological processes (discussed in Chapter 25).
      In addition to unsaturated fatty acids, several other modified fatty acids are found in nature. Microorganisms, for example, often contain branched-chain fatty acids, such as tuberculostearic acid (Figure 8.2). When these fatty acids are incorporated in membranes, the methyl group constitutes a local structural perturbation in a manner similar to the double bonds in unsaturated fatty acids (see Chapter 9). Some bacteria also synthesize fatty acids containing cyclic structures such as cyclopropane, cyclopropene, and even cyclopentane rings.

A Deeper Look
Fatty Acids in Food: Saturated Versus Unsaturated
Fats consumed in the modern human diet vary widely in their fatty acid compositions. The table below provides a brief summary. The incidence of cardiovascular disease is correlated with diets high in saturated fatty acids. By contrast, a diet that is relatively higher in unsaturated fatty acids (especially polyunsaturated fatty acids) may reduce the risk of heart attacks and strokes. Corn oil, abundant in the United States and high in (polyunsaturated) linoleic acid, is an attractive dietary choice. Margarine made from corn, safflower, or sunflower oils is much lower in saturated fatty acids than is butter, which is made from milk fat. However, margarine may present its own health risks. Its fatty acids contain trans-double bonds (introduced by the hydrogenation process), which may also contribute to cardiovascular disease. (Margarine was invented by a French chemist, H. Mège Mouriès , who won a prize from Napoleon III in 1869 for developing a substitute for butter.)             Although vegetable oils usually contain a higher proportion of unsaturated fatty acids than do animal oils and fats, several plant oils are actually high in saturated fats. Palm oil is low in polyunsaturated fatty acids and particularly high in (saturated) palmitic acid (whence the name palmitic ). Coconut oil is particularly high in lauric and myristic acids (both saturated) and contains very few unsaturated fatty acids. Some of the fatty acids found in the diets of developed nations (often 1	to 10 g of daily fatty acid intake) are  trans  fatty acids — fatty acids with one or more double bonds in the trans  configuration. Some of these derive from dairy fat and ruminant meats, but the bulk are provided by partially hydrogenated vegetable or fish oils. Substantial evidence now exists to indicate that  trans fatty acids may have deleterious health consequences. Numerous studies have shown that trans fatty acids raise plasma LDL cholesterol levels when exchanged for cis-unsaturated fatty acids in the diet and may also lower HDL cholesterol levels and raise triglyceride levels. The effects of  trans fatty acids on LDL, HDL, and cholesterol levels are similar to those of saturated fatty acids, and diets aimed at reducing the risk of coronary heart disease should be low in both trans and saturated fatty acids. Structure of cis and trans monounsaturated C18 fatty acids.
Fatty Acid Compositions of Some Dietary Lipids* Source Lauric and Myristic Palmitic Stearic Oleic Linoleic Beef 5 24-32 20-25 37-43 2-3 Milk   25 12 33 3 Coconut 74 10 2 7 - Corn   8-12 3-4 19-49 34-62 Olive   9 2 84 4 Palm   39 4 40 8 Safflower   6 3 13 78 Soybean   9 6 20 52 Sunflower   6 1 21 66 Data from Merck Index, 10th ed. Rahway, NJ: Merck and Co.; and Wilson, et al., 1967, Principles of Nutrition, 2nd ed. New York: Wiley. *Values are percentages of total fatty acids.

8.2 · Triacylglycerols

A significant number of the fatty acids in plants and animals exist in the form of triacylglycerols (also called triglycerides). Triacylglycerols are a major energy reserve and the principal neutral derivatives of glycerol found in animals. These molecules consist of a glycerol esterified with three fatty acids (Figure 8.3). If all three fatty acid groups are the same, the molecule is called a simple tri-acylglycerol. Examples include tristearoylglycerol (common name tristearin) and trioleoylglycerol (triolein). Mixed triacylglycerols contain two or three different fatty acids. Triacylglycerols in animals are found primarily in the adipose tissue (body fat), which serves as a depot or storage site for lipids. Mono-acylglycerols and diacylglycerols also exist, but are far less common than the triacylglycerols. Most natural plant and animal fat is composed of mixtures of simple and mixed triacylglycerols.

      Acylglycerols can be hydrolyzed by heating with acid or base or by treatment with lipases. Hydrolysis with alkali is called saponification and yields salts of free fatty acids and glycerol. This is how soap (a metal salt of an acid derived from fat) was made by our ancestors. One method used potassium hydroxide (potash) leached from wood ashes to hydrolyze animal fat (mostly triacylglycerols). (The tendency of such soaps to be precipitated by Mg²⁺ and Ca²⁺ ions in hard water makes them less useful than modern detergents.) When the fatty acids esterified at the first and third carbons of glycerol are different, the second carbon is asymmetric. The various acylglycerols are normally soluble in benzene, chloroform, ether, and hot ethanol. Although triacylglycerols are insoluble in water, mono- and diacylglycerols readily form organized structures in water (discussed later), owing to the polarity of their free hydroxyl groups.
      Triacylglycerols are rich in highly reduced carbons and thus yield large amounts of energy in the oxidative reactions of metabolism. Complete oxidation of 1 g of triacylglycerols yields about 38 kJ of energy, whereas proteins and carbohydrates yield only about 17 kJ/g. Also, their hydrophobic nature allows them to aggregate in highly anhydrous forms, whereas polysaccharides and proteins are highly hydrated. For these reasons, triacylglycerols are the molecules of choice for energy storage in animals. Body fat (mainly triacylglycerols) also provides good insulation. Whales and Arctic mammals rely on body fat for both insulation and energy reserves.

8.3 · Glycerophospholipids

A 1,2-diacylglycerol that has a phosphate group esterified at carbon atom 3 of the glycerol backbone is a glycerophospholipid, also known as a phosphoglyceride or a glycerol phosphatide (Figure 8.4). These lipids form one of the largest classes of natural lipids and one of the most important. They are essential components of cell membranes and are found in small concentrations in other parts of the cell. It should be noted that all glycerophospholipids are members of the broader class of lipids known as phospholipids.

      The numbering and nomenclature of glycerophospholipids present a dilemma in that the number 2 carbon of the glycerol backbone of a phospholipid is asymmetric. It is possible to name these molecules either as D- or L-isomers. Thus, glycerol phosphate itself can be referred to either as D-glycerol-L-phosphate or as L-glycerol-3-phosphate (Figure 8.5). Instead of naming the glycerol phosphatides in this way, biochemists have adopted the stereospecific numbering or sn-system. In this system, the pro-S position of a prochiral atom is denoted as the 1-position, the prochiral atom as the 2-position, and so on. When this scheme is used, the prefix sn- precedes the molecule name (glycerol phosphate in this case) and distinguishes this nomenclature from other approaches. In this way, the glycerol phosphate in natural phosphoglycerides is named sn-glycerol-3-phosphate.

Figure 8.5  ·  The absolute configuration of sn-glycerol-3-phosphate. The pro-(R) and pro-(S) positions of the parent glycerol are also indicated.

A Deeper Look
Prochirality
If a tetrahedral center in a molecule has two identical substituents, it is referred to as prochiral since, if either of the like substituents is converted to a different group, the tetrahedral center then becomes chiral . Consider glycerol: the central carbon of glycerol is prochiral since replacing either of the -CH2OH groups would make the central carbon chiral. Nomenclature for prochiral centers is based on the (R,S ) system (in Chapter 3). To name the otherwise identical substituents of a prochiral center, imagine	increasing slightly the priority of one of them (by substituting a deuterium for a hydrogen, for example) as shown: the resulting molecule has an (S)-configuration about the (now chiral) central carbon atom. The group that contains the deuterium is thus referred to as the pro-S   group. As a useful exercise, you should confirm that labeling the other CH2OH group with a deuterium produces the (R)-configuration at the central carbon, so that this latter CH2OH group is the pro-substituent .

The Most Common Phospholipids

Phosphatidic acid, the parent compound for the glycerol-based phospholipids (Figure 8.4), consists of sn-glycerol-3-phosphate, with fatty acids esterified at the 1- and 2-positions. Phosphatidic acid is found in small amounts in most natural systems and is an important intermediate in the biosynthesis of the more common glycerophospholipids (Figure 8.6). In these compounds, a variety of polar groups are esterified to the phosphoric acid moiety of the mole-cule. The phosphate, together with such esterified entities, is referred to as a “head” group. Phosphatides with choline or ethanolamine are referred to as phosphatidylcholine (known commonly as lecithin) or phosphatidyleth- anolamine, respectively. These phosphatides are two of the most common constituents of biological membranes. Other common head groups found in phosphatides include glycerol, serine, and inositol (Figure 8.6). Another kind of glycerol phosphatide found in many tissues is diphosphatidylglycerol. First observed in heart tissue, it is also called cardiolipin. In cardiolipin, a phosphatidylglycerol is esterified through the C-1 hydroxyl group of the glycerol moiety of the head group to the phosphoryl group of another phosphatidic acid molecule.

Figure 8.6  ·  Structures of several glycerophospholipids and space-filling models of phosphatidylcholine, phosphatidylglycerol, and phosphatidylinositol.

     Phosphatides exist in many different varieties, depending on the fatty acids esterified to the glycerol group. As we shall see, the nature of the fatty acids can greatly affect the chemical and physical properties of the phosphatides and the membranes that contain them. In most cases, glycerol phosphatides have a saturated fatty acid at position 1 and an unsaturated fatty acid at position 2 of the glycerol. Thus, 1-stearoyl-2-oleoyl-phosphatidylcholine (Figure 8.7) is a common constituent in natural membranes, but 1-linoleoyl-2-palmitoylphosphatidylcholine is not.
      Both structural and functional strategies govern the natural design of the many different kinds of glycerophospholipid head groups and fatty acids. The structural roles of these different glycerophospholipid classes are described in Chapter 9. Certain phospholipids, including phosphatidylinositol and phosphatidylcholine, participate in complex cellular signaling events. These roles, appreciated only in recent years, are described in Chapter 34.

A Deeper Look
Glycerophospholipid Degradation: One of the Effects of Snake Venoms
The venoms of poisonous snakes contain (among other things) a class of enzymes known as phospholipases, enzymes that cause the breakdown of phospholipids. For example, the venoms of the eastern diamondback rattlesnake (Crotalus adamanteus) and the Indian cobra (Naja naja) both contain phospholipase A2, which catalyzes the hydrolysis of fatty acids at the C-2 position of glycerophospholipids.	The phospholipid breakdown product of this reaction, lysolecithin, acts as a detergent and dissolves the membranes of red blood cells, causing them to rupture. Indian cobras kill several thousand people each year. Eastern diamondback rattlesnake. (Dr. E.R. Degginger) Indian cobra. (Dr. E.R. Degginger)

Figure 8.7  ·  A space-filling model of 1-stearoyl-2-oleoyl-phosphatidylcholine.

Ether Glycerophospholipids

Ether glycerophospholipids possess an ether linkage instead of an acyl group at the C-1 position of glycerol (Figure 8.8).

One of the most versatile biochemical signal molecules found in mammals is platelet activating factor, or PAF, a unique ether glycerophospholipid (Figure 8.9). The alkyl group at C-1 of PAF is typically a 16-carbon chain, but the acyl group at C-2 is a 2-carbon acetate unit. By virtue of this acetate group, PAF is much more water-soluble than other lipids, allowing PAF to function as a soluble messenger in signal transduction.

      Plasmalogens are ether glycerophospholipids in which the alkyl moiety is cis-a ,b-unsaturated (Figure 8.10). Common plasmalogen head groups include choline, ethanolamine, and serine. These lipids are referred to as phosphatidal choline, phosphatidal ethanolamine, and phosphatidal serine.

8.4 · Sphingolipids

Sphingolipids represent another class of lipids found frequently in biological membranes. An 18-carbon amino alcohol, sphingosine (Figure 8.11), forms the backbone of these lipids rather than glycerol. Typically, a fatty acid is joined to a sphingosine via an amide linkage to form a ceramide.

Figure 8.11  ·  Formation of an amide linkage between a fatty acid and sphingosine produces a ceramide.

Sphingomyelins represent a phosphorus-containing subclass of sphingolipids and are especially important in the nervous tissue of higher animals. A sphingomyelin is formed by the esterification of a phosphorylcholine or a phosphorylethanolamine to the 1-hydroxy group of a ceramide (Figure 8.12).

Figure 8.12  ·  A structure and a space-filling model of a choline sphingomyelin formed from stearic acid.

      There is another class of ceramide-based lipids which, like the sphingomyelins, are important components of muscle and nerve membranes in animals. These are the glycosphingolipids, and they consist of a ceramide with one or more sugar residues in a b-glycosidic linkage at the 1-hydroxyl moiety. The neutral glycosphingolipids contain only neutral (uncharged) sugar residues. When a single glucose or galactose is bound in this manner, the molecule is a cerebroside (Figure 8.13). Another class of lipids is formed when a sulfate is esterified at the 3-position of the galactose to make a sulfatide.

Figure 8.13  ·  The structure of a cerebroside. Note the sphingosine backbone.

Gangliosides (Figure 8.14) are more complex glycosphingolipids that consist of a ceramide backbone with three or more sugars esterified, one of these being a sialic acid such as N-acetylneuraminic acid. These latter compounds are referred to as acidic glycosphingolipids, and they have a net negative charge at neutral pH.

Figure 8.14  ·  The structures of several important gangliosides. Also shown is a space-filling model of ganglioside G_M1.

      The glycosphingolipids have a number of important cellular functions, despite the fact that they are present only in small amounts in most membranes. Glycosphingolipids at cell surfaces appear to determine, at least in part, certain elements of tissue and organ specificity. Cell-cell recognition and tissue immunity appear to depend upon specific glycosphingolipids. Gangliosides are present in nerve endings and appear to be important in nerve impulse transmission. A number of genetically transmitted diseases involve the accumulation of specific glycosphingolipids due to an absence of the enzymes needed for their degradation. Such is the case for ganglioside G_{M 2} in the brains of Tay-Sachs disease victims, a rare but fatal disease characterized by a red spot on the retina, gradual blindness, and loss of weight, especially in infants and children.

8.5 · Waxes

Waxes are esters of long-chain alcohols with long-chain fatty acids. The resulting molecule can be viewed (in analogy to the glycerolipids) as having a weakly polar head group (the ester moiety itself) and a long, nonpolar tail (the hydrocarbon chains) (Figure 8.15). Fatty acids found in waxes are usually saturated. The alcohols found in waxes may be saturated or unsaturated and may include sterols, such as cholesterol (see later section). Waxes are water-insoluble due to the weakly polar nature of the ester group. As a result, this class of molecules confers water-repellant character to animal skin, to the leaves of certain plants, and to bird feathers. The glossy surface of a polished apple results from a wax coating. Carnauba wax, obtained from the fronds of a species of palm tree in Brazil, is a particularly hard wax used for high gloss finishes, such as in automobile wax, boat wax, floor wax, and shoe polish. Lanolin, a component of wool wax, is used as a base for pharmaceutical and cosmetic products because it is rapidly assimilated by human skin.

Figure 8.15  ·  An example of a wax. Oleoyl alcohol is esterified to stearic acid in this case.

8.6 · Terpenes

The terpenes are a class of lipids formed from combinations of two or more molecules of 2-methyl-1,3-butadiene, better known as isoprene (a five-carbon unit that is abbreviated C₅). A monoterpene (C₁₀) consists of two isoprene units, a sesquiterpene (C₁₅) consists of three isoprene units, a diterpene (C₂₀) has four isoprene units, and so on. Isoprene units can be linked in terpenes to form straight chain or cyclic molecules, and the usual method of linking isoprene units is head to tail (Figure 8.16).

Figure 8.16  ·  The structure of isoprene (2-methyl-1,3-butadiene) and the structure of head-to-tail and tail-to-tail linkages. Isoprene itself can be formed by distillation of natural rubber, a linear head-to-tail polymer of isoprene units.

Monoterpenes occur in all higher plants, while sesquiterpenes and diterpenes are less widely known. Several examples of these classes of terpenes are shown in Figure 8.17. The triterpenes are C₃₀ terpenes and include squalene and lanosterol, two of the precursors of cholesterol and other steroids (discussed later). Tetraterpenes (C₄₀) are less common but include the carotenoids, a class of colorful photosynthetic pigments. b-Carotene is the precursor of vitamin A, while lycopene, similar to b-carotene but lacking the cyclopentene rings, is a pigment found in tomatoes.

Figure 8.17  ·  Many monoterpenes are readily recognized by their characteristic flavors or odors (limonene in lemons; citronellal in roses, geraniums, and some perfumes; pinene in turpentine; and menthol from peppermint, used in cough drops and nasal inhalers). The diterpenes, which are C₂₀ terpenes, include retinal (the essential light-absorbing pigment in rhodopsin, the photoreceptor protein of the eye), phytol (a constituent of chlorophyll), and the gibberellins (potent plant hormones). The triterpene lanosterol is a constituent of wool fat. Lycopene is a carotenoid found in ripe fruit, especially tomatoes.

      Long-chain polyisoprenoid molecules with a terminal alcohol moiety are called polyprenols. The dolichols, one class of polyprenols (Figure 8.18), consist of 16 to 22 isoprene units and, in the form of dolichyl phosphates, function to carry carbohydrate units in the biosynthesis of glycoproteins in animals. Polyprenyl groups serve to anchor certain proteins to biological membranes (discussed in Chapter 9).

Figure 8.18  ·  Dolichol phosphate is an initiation point for the synthesis of carbohydrate polymers in animals. The analogous alcohol in bacterial systems, undecaprenol, also known as bactoprenol, consists of 11 isoprene units. Undecaprenyl phosphate delivers sugars from the cytoplasm for the synthesis of cell wall components such as peptidoglycans, lipopolysaccharides, and glycoproteins. Polyprenyl compounds also serve as the side chains of vitamin K, the ubiquinones, plastoquinones, and tocopherols (such as vitamin E).

A Deeper Look

Why Do Plants Emit Isoprene? The Blue Ridge Mountains of Virginia are so-named for the misty blue vapor or haze that hangs over them through much of the summer season. This haze is composed in part of isoprene that is produced and emitted by the plants and trees of the mountains. Global emission of isoprene from vegetation is estimated at 3 x 1014 g/yr. Plants frequently emit as much as 15% of the carbon fixed in photosynthesis as isoprene, and Thomas Sharkey, a botanist at the University of Wisconsin, has shown that the kudzu plant can emit as much as 67% of its fixed carbon as isoprene as the result of water stress. Why should plants and trees emit large amounts of isoprene and other hydrocarbons? Sharkey has shown that an isoprene atmosphere or “blanket” can protect leaves from irreversible damage induced by high (summer-like) temperatures. He hypothesizes that isoprene in the air around plants dissolves into leaf-cell membranes, altering the lipid bilayer and/or lipid-protein and protein-protein interactions within the membrane to increase thermal tolerance.

Blue Ridge Mountains. (Randy Wells/Tony Stone Images)

8.7 · Steroids

Cholesterol

A large and important class of terpene-based lipids is the steroids. This molecular family, whose members effect an amazing array of cellular functions, is based on a common structural motif of three six-membered rings and one five-membered ring all fused together. Cholesterol (Figure 8.19) is the most common steroid in animals and the precursor for all other animal steroids. The numbering system for cholesterol applies to all such molecules. Many steroids contain methyl groups at positions 10 and 13 and an 8- to 10-carbon alkyl side chain at position 17. The polyprenyl nature of this compound is particularly evident in the side chain. Many steroids contain an oxygen at C-3, either a hydroxyl group in sterols or a carbonyl group in other steroids. Note also that the carbons at positions 10 and 13 and the alkyl group at position 17 are nearly always oriented on the same side of the steroid nucleus, the b-orientation. Alkyl groups that extend from the other side of the steroid backbone are in an a-orientation.

      Cholesterol is a principal component of animal cell plasma membranes, and much smaller amounts of cholesterol are found in the membranes of intracellular organelles. The relatively rigid fused ring system of cholesterol and the weakly polar alcohol group at the C-3 position have important consequences for the properties of plasma membranes. Cholesterol is also a component of lipoprotein complexes in the blood, and it is one of the constituents of plaques that form on arterial walls in atherosclerosis.

Steroid Hormones

Steroids derived from cholesterol in animals include five families of hormones (the androgens, estrogens, progestins, glucocorticoids and mineralocorticoids) and bile acids (Figure 8.20). Androgens such as testosterone and estrogens such as estradiol mediate the development of sexual characteristics and sexual function in animals. The progestins such as progesterone participate in control of the menstrual cycle and pregnancy. Glucocorticoids (cortisol, for example) participate in the control of carbohydrate, protein, and lipid metabolism, whereas the mineralocorticoids regulate salt (Na⁺, K⁺, and Cl^-) balances in tissues. The bile acids (including cholic and deoxycholic acid) are detergent molecules secreted in bile from the gallbladder that assist in the absorption of dietary lipids in the intestine.

Human Biochemistry
Plant Sterols—Natural Cholesterol Fighters
Dietary guidelines for optimal health call for reducing the intake of cholesterol. One strategy for doing so involves the plant sterols, including sitosterol, stigmasterol, stigmastanol, and campesterol, shown in the figure. Despite their structural similarity to cholesterol, minor isomeric differences and/or the presence of methyl and ethyl groups in the side chains of these substances result in their poor absorption by intestinal mucosal cells. Interestingly, although plant sterols are not effectively absorbed by the body, they nonetheless are highly effective in blocking the absorption of cholesterol itself by intestinal cells.       The practical development of plant sterol drugs as	cholesterol-lowering agents will depend both on structural features of the sterols themselves and on the form of the administered agent. For example, the unsaturated sterol sitosterol is poorly absorbed in the human intestine, whereas sitostanol, the saturated analog, is almost totally unabsorbable. In addition, there is evidence that plant sterols administered in a soluble, micellar form (see page 261 for a description of micelles) are more effective in blocking cholesterol absorption than plant sterols administered in a solid, crystalline form.

Human Biochemistry
17b-Hydroxysteroid Dehydrogenase 3 Deficiency
Testosterone, the principal male sex steroid hormone, is synthesized in five steps from cholesterol, as shown below. In the last step, five isozymes catalyze the 17b-hydroxysteroid dehydrogenase reactions that interconvert 4-androstenedione and testosterone. Defects in the synthesis or action of testosterone can impair the development of the male phenotype during embryogenesis and cause the disorders of human sexuality termed male pseudohermaphroditism. Specifically, mutations in isozyme 3 of the 17b-hydroxysteroid dehydrogenase in the fetal testis impair the	formation of testosterone and give rise to genetic males with female external genitalia and blind-ending vaginas. Such individuals are typically raised as females but virilize at puberty, due to an increase in serum testosterone, and develop male hair growth patterns. Fourteen different mutations of 17b-hydroxysteroid dehydrogenase 3 have been identified in 17 affected families in the United States, the Middle East, Brazil , and Western Europe. These families account for about 45% of the patients with this disorder reported in scientific literature.