8.3 What Are the Structures and Chemistry of Glycerophospholipids? 223 glycerols are normally soluble in benzene, chloroform, ether, and hot ethanol. Al- though triacylglycerols are insoluble in water, monoacylglycerols and diacylglycerols readily form organized structures in water (see Chapter 9), 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 tri- acylglycerols 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 What Are the Structures and Chemistry of 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 and most im- portant classes of natural lipids. They are essential components of cell membranes and are found in small concentrations in other parts of the cell. It should be noted A DEEPER LOOK Polar Bears Prefer Nonpolar Food The polar bear is magnificently adapted to thrive in its harsh Arc- tic environment. Research by Malcolm Ramsay (at the University of Saskatchewan in Canada) and others has shown that polar bears eat only during a few weeks out of the year and then fast for periods of 8 months or more, consuming no food or water during that time. Eating mainly in the winter, the adult polar bear feeds almost exclusively on seal blubber (largely composed of triacylglycerols), thus building up its own triacylglycerol re- serves. Through the Arctic summer, the polar bear maintains normal physical activity, roaming over long distances, but relies entirely on its body fat for sustenance, burning as much as 1 to 1.5 kg of fat per day. It neither urinates nor defecates for ex- tended periods. All the water needed to sustain life is provided from the metabolism of triacylglycerols (because oxidation of fatty acids yields carbon dioxide and water). Ironically, the word Arctic comes from the ancient Greeks, who understood that the northernmost part of the earth lay under the stars of the constellation Ursa Major, the Great Bear. Although un- aware of the polar bear, they called this region Arktikós, which means “the country of the great bear.” © John Shaw/Photo Researchers, Inc. C O O CH 2 C HC O O CH 2 O P O – O O – FIGURE 8.4 Phosphatidic acid, the parent compound for glycerophospholipids. 224 Chapter 8 Lipids 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 phos- phate itself can be referred to either as D-glycerol-1-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. The stereospe- cific numbering system is based on the concept of prochirality. If a tetrahedral cen- ter in a molecule has two identical substituents, it is referred to as prochiral because if either of the like substituents is converted to a different group, the tetrahedral center then becomes chiral. Consider glycerol (Figure 8.5): The central carbon of glycerol is prochiral because replacing either of the ϪCH 2 OH groups would make the central carbon chiral. Nomenclature for prochiral centers is based on the (R,S) system (see Chapter 4). To name the otherwise identical substituents of a prochiral center, imagine increasing slightly the priority of one of them (by substituting a deu- terium for a hydrogen, for example) as shown in Figure 8.5. 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 exer- cise, you should confirm that labeling the other CH 2 OH group with a deuterium produces the (R) configuration at the central carbon so that this latter CH 2 OH group is the pro-R substituent. Now consider the two presentations of glycerol phosphate in Figure 8.5. In the stereospecific numbering 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 glyc- erol phosphate in natural phosphoglycerides is named sn-glycerol-3-phosphate. Glycerophospholipids Are 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 molecule. The phosphate, HOH 2 C H OH CH 2 OH C Glycerol HOH 2 3 C H OH 1 CHOH D 2 C 1-d, 2(S)-Glycerol (S-configuration at C-2) HO C H CH 2 OH CH 2 OPO 3 2 – L-Glycerol-3-phosphate pro-S position pro-R position H C OH CH 2 OH CH 2 OPO 3 2 – D-Glycerol-1-phosphate sn-Glycerol-3-phosphate (a) (b) ACTIVE FIGURE 8.5 (a) The two identi- cal OCH 2 OH groups on the central carbon of glycerol may be distinguished by imagining a slight increase in pri- ority for one of them (by replacement of an H by a D) as shown. (b) The absolute configuration of sn-glycerol-3- phosphate is shown. The pro-R and pro-S positions of the parent glycerol are also indicated.Test yourself on the concepts in this figure at www.cengage.com/login Go to CengageNOW at www .cengage.com/login and click BiochemistryInteractive to learn the structures and names of the glycerophos- pholipids. 8.3 What Are the Structures and Chemistry of Glycerophospholipids? 225 together with such esterified entities, is referred to as a “head” group. Phos- phatides with choline or ethanolamine are referred to as phosphatidylcholine (known commonly as lecithin) or phosphatidylethanolamine, 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 tis- sues is diphosphatidylglycerol. First observed in heart tissue, it is also called cardiolipin. In cardiolipin, a phosphatidylglycerol is esterified through the C-1 hy- droxyl group of the glycerol moiety of the head group to the phosphoryl group of another phosphatidic acid molecule. Phosphatides exist in many different varieties, depending on the fatty acids ester- ified to the glycerol group. As we shall see, the nature of the fatty acids can greatly Phosphatidylcholine N CH 3 + CH 3 CH 3 CH 2 CH 2 OP O – O CH 2 C CH 2 O HOC O OC O GLYCEROLIPIDS WITH OTHER HEAD GROUPS: NH 3 CH 2 CH 2 OP O – O O + Phosphatidylethanolamine CH NH 3 COO – CH 2 OP O – O O + Phosphatidylserine CH OH CH 2 OP O – O O Phosphatidylglycerol CH 2 OH C CH 2 OP O – O O Diphosphatidylglycerol (Cardiolipin) CH 2 OHH OP O – O O OH OH HOH H H H HH HO OH OP O – O O Phosphatidylinositol ANIMATED FIGURE 8.6 Structures of several glycerophospholipids and space-filling models of phosphatidyl- choline, phosphatidylglycerol, and phos- phatidylinositol. See this figure animated at www.cengage.com/login. 226 Chapter 8 Lipids 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 mem- branes, 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. Cer- tain phospholipids, including phosphatidylinositol and phosphatidylcholine, par- ticipate in complex cellular signaling events. These roles are described in Section 8.8 and Chapter 32. Ether Glycerophospholipids Include PAF and Plasmalogens Ether glycerophospholipids possess an ether linkage instead of an acyl group at the C-1 position of glycerol (Figure 8.8a). One of the most versatile biochemical signal molecules found in mammals is platelet-activating factor, or PAF, a unique ether glycerophospholipid (Figure 8.8b). 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. FIGURE 8.7 A space-filling model of 1-stearoyl-2-oleoyl- phosphatidylcholine. – O P O O O CH 2 CH 2 NH 3 CH 2 CHH 2 C OO CR 1 O R 2 Ester linkage Ether linkage + (a) – O P O O O CH 2 CH 2 N + CH 2 CHH 2 C OO C O CH 3 CH 3 CH 3 CH 3 Platelet- activating factor (b) FIGURE 8.8 (a) A 1-alkyl 2-acyl-phosphatidylethanolamine (an ether glycerophospholipid). (b) The structure of 1-alkyl 2-acetyl-phosphatidylcholine, also known as platelet-activating factor or PAF. 8.4 What Are Sphingolipids, and How Are They Important for Higher Animals? 227 Plasmalogens are ether glycerophospholipids in which the alkyl moiety is cis-␣,␤- unsaturated (Figure 8.9). Common plasmalogen head groups include choline, ethanolamine, and serine. These lipids are referred to as phosphatidal choline, phosphatidal ethanolamine, and phosphatidal serine. 8.4 What Are Sphingolipids, and How Are They Important for Higher Animals? Sphingolipids represent another class of lipids frequently found in biological mem- branes. An 18-carbon amino alcohol, sphingosine (Figure 8.10a), forms the back- bone of these lipids rather than glycerol. Typically, a fatty acid is joined to a sphin- gosine via an amide linkage to form a ceramide (Figure 8.10b). 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 8.10c). There is another class of ceramide-based lipids that, 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 HUMAN BIOCHEMISTRY Platelet-Activating Factor: A Potent Glyceroether Mediator Platelet-activating factor (PAF) was first identified by its ability (at low levels) to cause platelet aggregation and dilation of blood ves- sels, but it is now known to be a potent mediator in inflammation, allergic responses, and shock. PAF effects are observed at tissue concentrations as low as 10 Ϫ12 M. PAF causes a dramatic inflam- mation of air passages and induces asthmalike symptoms in labo- ratory animals. Toxic shock syndrome occurs when fragments of destroyed bacteria act as toxins and induce the synthesis of PAF. PAF causes a drop in blood pressure and a reduced volume of blood pumped by the heart, which leads to shock and, in severe cases, death. Beneficial effects have also been attributed to PAF. In repro- duction, PAF secreted by the fertilized egg is instrumental in the implantation of the egg in the uterine wall. PAF is produced in significant quantities in the lungs of the fetus late in pregnancy and may stimulate the production of fetal lung surfactant, a protein–lipid complex that prevents collapse of the lungs in a newborn infant. Choline plasmalogen N CH 3 + CH 3 CH 3 CH 2 CH 2 OP O O – O CH 2 CHCH 2 O C O O C C H H The ethanolamine plasmalogens have ethanolamine in place of choline. FIGURE 8.9 The structure and a space-filling model of a choline plasmalogen. 228 Chapter 8 Lipids residues in a ␤-glycosidic linkage at the 1-hydroxyl moiety. The neutral glyco- sphingolipids contain only neutral (uncharged) sugar residues. When a single glu- cose or galactose is bound in this manner, the molecule is a cerebroside (Figure 8.10d). Another class of lipids is formed when a sulfate is esterified at the 3-position of the galactose to make a sulfatide. Gangliosides (Figure 8.10e) 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 OH C H H C + NH 3 OH CH 2 C C H H Sphingosine (a) (d) (e) (b) (c) R COOH Fatty acid OH C H H H C NH OH CH 2 Ceramide C R O H 2 O C C H O CH 2 OH H OH HOH H HO OH CH H H C NH O CH 2 C R O A cerebroside C C H H N CH 3 + CH 3 CH 3 CH 2 CH 2 OP O – O CH 2 C O O OH CH H C NH Choline sphingomyelin with stearic acid C C H H D-Galactose ␤- D-Galactose O CH 2 OH H OH HOH H HO H H N-Acetyl- D-galactosamine O CH 2 OH H OH HNH H HO H H O CH 3 O O CH 2 OH H HOH H H H O O CH 2 OH H HOH H H H O D-Galactose D-Glucose O O CHOH H OH H H H H N H CHOH CH 2 OH COO – C O CH 3 OH CH H H C NH O CH 2 C R O N-Acetylneuraminidate (a sialic acid) G M3 G M2 G M1 Gangliosides G M1 ,G M2 , and G M3 C C H C Ganglioside G M1 FIGURE 8.10 Sphingolipids are based on the structure of sphingosine. A ceramide with a phosphocholine head group is a choline sphingomyelin. A ceramide with a single sugar is a cerebroside. Gangliosides are cera- mides with three or more sugars esterified, one of which is a sialic acid. 8.6 What Are Terpenes, and What Is Their Relevance to Biological Systems? 229 latter compounds are referred to as acidic glycosphingolipids, and they have a net negative charge at neutral pH. The glycosphingolipids have a number of important cellular functions, despite the fact that they are present only in small amounts in most membranes. Glyco- sphingolipids at cell surfaces appear to determine, at least in part, certain elements of tissue and organ specificity. Cell–cell recognition and tissue immunity depend on specific glycosphingolipids. Gangliosides are present in nerve endings and are im- portant in nerve impulse transmission. A number of genetically transmitted diseases involve the accumulation of specific glycosphingolipids due to an absence of the en- zymes needed for their degradation. Such is the case for ganglioside G M2 in the brains of Tay-Sachs disease victims, a rare but fatal childhood disease characterized by a red spot on the retina, gradual blindness, and self-mutilation. 8.5 What Are Waxes, and How Are They Used? 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 8.11). 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 their mostly hy- drocarbon composition. 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, ob- tained 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, 1 a wool wax, is used as a base for pharmaceutical and cosmetic products because it is rapidly assimilated by human skin. The brand name Oil of Olay ® was coined by Graham Wulff, a South African chemist who developed it. The name refers to lanolin, a key ingredient. 8.6 What Are Terpenes, and What Is Their Relevance to Biological Systems? The terpenes are a class of lipids formed from combinations of two or more mole- cules of 2-methyl-1,3-butadiene, better known as isoprene (a five-carbon unit that is abbreviated C 5 ). A monoterpene (C 10 ) consists of two isoprene units, a sesquiterpene A DEEPER LOOK Moby Dick and Spermaceti: A Valuable Wax from Whale Oil When oil from the head of the sperm whale is cooled, spermaceti, a translucent wax with a white, pearly luster, crystallizes from the mixture. Spermaceti, which makes up 11% of whale oil, is com- posed mainly of the wax cetyl palmitate: CH 3 (CH 2 ) 14 OCOOO(CH 2 ) 15 CH 3 as well as smaller amounts of cetyl alcohol: HOO(CH 2 ) 15 CH 3 Spermaceti and cetyl palmitate have been widely used in the mak- ing of cosmetics, fragrant soaps, and candles. In the literary classic Moby Dick, Herman Melville describes Ishmael’s impressions of spermaceti, when he muses that the waxes “discharged all their opulence, like fully ripe grapes their wine; as I snuffed that uncontaminated aroma—literally and truly, like the smell of spring violets.”* * Melville, H., 1984. Moby Dick. London: Octopus Books, p. 205. (Adapted from Waddell, T. G., and Sanderlin, R. R., 1986. Chemistry in Moby Dick. Journal of Chemical Education 63:1019–1020.) 1 Lanolin is a complex mixture of waxes with 33 different alcohols esterified to 36 different fatty acids. 230 Chapter 8 Lipids C O O CH 2 CH 3 (CH 2 ) 14 (CH 2 ) 16 CH 3 Stearyl palmitate C O O CH 2 CH 3 (CH 2 ) 14 (CH 2 ) 28 CH 3 Triacontanol palmitate C O O R 2 R 1 General forumula of a wax OC O Stearic acidOleoyl alcohol Oleo y l stearate FIGURE 8.11 Waxes consist of long-chain alcohols esterified to long-chain fatty acids.Triacontanol palmitate is the principal component of beeswax. Waxes are components of the waxy coating on the leaves of plants, such as jade plants (shown here). Such species typically contain dozens of different waxy esters. © Steven Lunetta Photography, 2007 C C CH 2 CH 3 H 2 C H Isoprene Geraniol Head-to-tail linkage OH Tail-to-tail linkage R R FIGURE 8.12 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 iso- prene units. O C OH Gibberellic acid HO COOH H H CH 3 DITERPENES CH 2 OH Phytol O Camphene ␣-Pinene HO Eudesmol CHO HO H Lanosterol TRITERPENES Lycopene MONOTERPENES Limonene Citronellal Menthol OH CHO Squalene SESQUITERPENES Bisabolene TETRATERPENES All-trans-retinal ACTIVE FIGURE 8.13 Many monoterpenes are readily recognized by their characteristic flavors or odors (limonene in lemons; citronellal in roses, geraniums, and some perfumes; and menthol from peppermint, used in cough drops and nasal inhalers).The diterpenes, which are C 20 terpenes, include retinal (the essential light-absorbing pigment in rhodopsin, the photoreceptor protein of the eye), and phytol (a constituent of chlorophyll).The triterpene lanosterol is a constituent of wool fat. Lycopene is a carotenoid found in ripe fruit, especially tomatoes. Test yourself on the concepts in this figure at www.cengage.com/login 8.6 What Are Terpenes, and What Is Their Relevance to Biological Systems? 231 (C 15 ) consists of three isoprene units, a diterpene (C 20 ) has four isoprene units, and so on. Isoprene units can be linked in terpenes to form straight-chain or cyclic mol- ecules, and the usual method of linking isoprene units is head to tail (Figure 8.12). Monoterpenes occur in all higher plants, whereas sesquiterpenes and diterpenes are less widely known. Several examples of these classes of terpenes are shown in Figure 8.13. The triterpenes are C 30 terpenes and include squalene and lanosterol, two of the precursors of cholesterol and other steroids (discussed later). Tetraterpenes (C 40 ) are less common but include the carotenoids, a class of colorful photosynthetic pigments. ␤-Carotene is the precursor of vitamin A, whereas lycopene, similar to ␤-carotene, is a pigment found in tomatoes. Long-chain polyisoprenoid molecules with a terminal alcohol moiety are called polyprenols. The dolichols, one class of polyprenols (Figure 8.14), consist of 16 to 22 isoprene units and, in the form of dolichyl phosphates, function to carry carbo- hydrate units in the biosynthesis of glycoproteins in animals. Polyprenyl groups serve to anchor certain proteins to biological membranes (discussed in Chapter 9). The Membranes of Archaea Are Rich in Isoprene-Based Lipids Archaea are found primarily in harsh environments. Some thrive in the high temperatures of geysers and ocean steam vents, whereas others are found in extremely acidic, cold, or salty environments. Archaea also live in extremes of pH in the digestive tracts of cows, termites, and humans. Archaea are ideally adapted to their harsh CH 2 CCH CH 3 O H CH 2 CH 2 CH CH 3 CH 2 CH 2 O P O – O – Dolichol phosphate H 3 C C H C CH 3 CH 2 9 CH 2 Undecaprenyl alcohol (bactoprenol) CH 2 CCH CH 3 CH 2 CCH CH 3 CH 2 OH 13 – 23 FIGURE 8.14 Dolichol phosphate is an initiation point for the synthesis of carbohydrate polymers in animals. The analogous alcohol in bacterial systems, undeca- prenol, also known as bactoprenol, consists of 11 iso- prene units. Undecaprenyl phosphate delivers sugars from the cytoplasm for the synthesis of cell wall compo- nents such as peptidoglycans, lipopolysaccharides, and glycoproteins. 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 moun- tains. Global emission of isoprene from vegetation is estimated at 3 ϫ 10 14 g/yr. Plants frequently emit as much as 15% of the car- bon 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 (summerlike) temperatures. He hypothesizes that isoprene in the air around plants dissolves into leaf-cell membranes, altering the lipid bi- layer and/or lipid–protein and protein–protein interactions within the membrane to increase thermal tolerance. ᮡ Blue Ridge Mountains Randy Wells/Getty Images 232 Chapter 8 Lipids environments, and one such adaptation is found in their cell membranes, which contain isoprene-based lipids (Figure 8.15). These isoprene chains are linked at both ends by ether bonds to glycerols. Ether bonds are more stable to hydrolysis than the ester linkages of glycerophospholipids (Figure 8.6). With a length twice that of typical glycerophospholipids, these molecules can completely span a cell membrane, providing additional stability. Interestingly, the glycerols in archaeal lipids are in the (R) configuration, whereas glycerolipids of animals, plants, and eu- bacteria are almost always in the (S) configuration. HUMAN BIOCHEMISTRY Coumadin or Warfarin—Agent of Life or Death The isoprene-derived molecule whose structure is shown here is known alternately as Coumadin and warfarin. By the former name, it is a widely prescribed anticoagulant. By the latter name, it is a component of rodent poisons. How can the same chemi- cal species be used for such disparate purposes? The key to both uses lies in its ability to act as an antagonist of vitamin K in the body. Vitamin K is necessary for the carboxylation of glutamate residues on certain proteins, including some proteins in the blood- clotting cascade (including prothrombin, factor VII, factor IX, and factor X, which undergo a Ca 2ϩ -dependent conformational change in the course of their biological activity, as well as protein C and protein S, two regulatory proteins in coagulation). Carboxylation of these coagulation factors is catalyzed by a carboxylase that re- quires the reduced form of vitamin K (vitamin KH 2 ), molecular oxygen, and carbon dioxide. KH 2 is oxidized to vitamin K epoxide, which is recycled to KH 2 by the enzymes vitamin K epoxide reduc- tase (1) and vitamin K reductase (2, 3). Coumadin/warfarin exerts its anticoagulant effect by inhibiting vitamin K epoxide reductase and possibly also vitamin K reductase. This inhibition depletes vit- amin KH 2 and reduces the activity of the carboxylase. Coumadin/warfarin, given at a typical dosage of 4 to 5 mg/day, prevents the deleterious formation in the bloodstream of small blood clots and thus reduces the risk of heart attacks and strokes for individuals whose arteries contain sclerotic plaques. Taken in much larger doses, as for example in rodent poisons, Coumadin/warfarin can cause massive hemorrhages and death. KH 2 KO K K 1 2 3 Warfarin resistant CH HO O O CH 3 CH 2 C Warfarin (Coumadin) N C CH O H O - O C CH 2 Glu O H 2 C O O CH 2 CO 2 CH C O C N C CH O - - O H ␥-carboxy-Glu Warfarin inhibits CH 2 OH C HO CH 2 O H 2 CO C OH HOCH 2 Isoprene units Caldarchaeol Glycerol Glycerol FIGURE 8.15 The structure of caldarchaeol, an isoprene-based lipid found in archaea.