7.7 Do Carbohydrates Provide a Structural Code? 213 Proteoglycans Make Cartilage Flexible and Resilient Cartilage matrix proteoglycan is responsible for the flexibility and resilience of car- tilage tissue in the body. In cartilage, long filaments of hyaluronic acid are studded or coated with proteoglycan molecules, as shown in Figure 7.39. The hyaluronate chains can be as long as 4 m and can coordinate 100 or more proteoglycan units. Cartilage proteoglycan possesses a hyaluronic acid–binding domain on the NH 2 - terminal portion of the polypeptide, which binds to hyaluronate with the assistance of a link protein. The proteoglycan–hyaluronate aggregates can have molecular weights of 2 million or more. The proteoglycan–hyaluronate aggregates are highly hydrated by virtue of strong interactions between water molecules and the polyanionic complex. When cartilage is compressed (such as when joints absorb the impact of walking or running), water is briefly squeezed out of the cartilage tissue and then reab- sorbed when the stress is diminished. This reversible hydration gives cartilage its flexible, shock-absorbing qualities and cushions the joints during physical activi- ties that might otherwise injure the involved tissues. 7.7 Do Carbohydrates Provide a Structural Code? The surprisingly low number of genes in the genomes of complex multicellular or- ganisms has led biochemists to consider other explanations for biological complexity and diversity. Oligosaccharides and polysaccharides, endowed with an unsurpassed variability of structures, are information carriers, and glycoconjugates—complexes of proteins with oligosaccharides and polysaccharides—are the mediators of informa- tion transfer by these carbohydrate structures. Individual sugar units are the “letters” of the sugar code, and the “words” and “sentences” of this code are synthesized by gly- cosyltransferases, glycosidases, and other enzymes. The total number of permutations for a six-unit polymer formed from an alphabet of 20 hexose monosaccharides is a staggering 1.44 ϫ 10 15 , whereas only 6.4 ϫ 10 7 hexamers can be formed from 20 amino acids and only 4096 hexanucleotides can be formed from the four nu- cleotides of DNA. The vast array of possible glycan structures adds a glycomic dimen- sion to the genomic complexity achieved by protein expression in organisms. The processes of cell migration, cell–cell interaction, immune response, and blood clotting, along with many other biological processes, depend on information transfer modulated by glycoconjugates. Many of the proteins involved in glycocon- jugate formation belong to the lectins—a class of proteins that bind carbohydrates with high specificity and affinity. Lectins are the translators of the sugar code. Table 7.1 describes a few of the many known lectins, their carbohydrate affinities, and their functions. A few examples of lectin–carbohydrate complexes and their roles in bio- logical information transfer will illustrate the nature of these important and com- plex interactions. Carbohydrate Lectin Family Specificity Function Calnexins Glucose Ligand-selective molecular chaperones in ER C-type lectins Variable Cell-type specific endocytosis and other functions ERGIC-53 Mannose Intracellular routing of glycoproteins and vesicles Galectins Galactose/lactose Cellular growth regulation and cell–matrix interactions Pentraxins Variable Anti-inflammatory action Selectins Variable Cell migration and routing TABLE 7.1 Specificities and Functions of Some Animal Lectins 214 Chapter 7 Carbohydrates and the Glycoconjugates of Cell Surfaces Selectins, Rolling Leukocytes, and the Inflammatory Response Human bodies are constantly exposed to a plethora of bacteria, viruses, and other inflammatory substances. To combat these infectious and toxic agents, the body has developed a carefully regulated inflammatory response system. Part of that re- sponse is the orderly migration of leukocytes to sites of inflammation. Leukocytes literally roll along the vascular wall and into the tissue site of inflammation. This rolling movement is mediated by reversible adhesive interactions between the leukocytes and the vascular surface. These interactions involve adhesion proteins called selectins, which are found both on the rolling leukocytes and on the endothelial cells of the vascular walls. Selectins have a characteristic domain structure, consisting of an N-terminal extra- cellular lectin (LEC) domain, a single epidermal growth factor (E) domain, a series of two to nine short consensus repeat (SCR) domains, a single transmembrane segment, and a short cytoplasmic domain. The lectin domains bind carbohydrates with high affinity and specificity. Selectins of three types are known: E-selectins, L-selectins, and P-selectins. L-Selectin is found on the surfaces of leukocytes, in- cluding neutrophils and lymphocytes, and binds to carbohydrate ligands on endo- thelial cells (Figure 7.40). The presence of L-selectin is a necessary component of leukocyte rolling. P-Selectin and E-selectin are located on the vascular endothelium and bind with carbohydrate ligands on leukocytes. Typical neutrophil cells possess 10,000 to 20,000 P-selectin–binding sites. Selectins are expressed on the surfaces of their respective cells by exposure to inflammatory signal molecules, such as hista- mine, hydrogen peroxide, and bacterial endotoxins. P-Selectins, for example, are stored in intracellular granules and are transported to the cell membrane within seconds to minutes of exposure to a triggering agent. Substantial evidence supports the hypothesis that selectin–carbohydrate ligand interactions modulate the rolling of leukocytes along the vascular wall. Studies with L-selectin–deficient and P-selectin–deficient leukocytes show that L-selectins medi- ate weaker adherence of the leukocyte to the vascular wall and promote faster rolling along the wall. Conversely, P-selectins promote stronger adherence and slower rolling. Thus, leukocyte rolling velocity in the inflammatory response could be modulated by variable exposure of P-selectins and L-selectins at the surfaces of endothelial cells and leukocytes, respectively. P-Selectin LEC E LEC E LEC E E-Selectin L-Selectin SCR repeat SCR repeat SCR repeat Endothelial cell Leukocyte Selectin receptors Selectin receptor L-Selectin E-Selectin P-Selectin (a) (b) FIGURE 7.40 (a) The interactions of selectins with their receptors. (b) The selectin family of adhesion proteins. 7.7 Do Carbohydrates Provide a Structural Code? 215 Galectins—Mediators of Inflammation, Immunity, and Cancer The galectins are a very conserved family of proteins with carbohydrate recognition domains (CRDs) of about 135 amino acids that bind -galactosides specifically. Galectins occur in both vertebrates and invertebrates, and they participate in processes such as cell adhesion, growth regulation, inflammation, immunity, and cancer metastasis. In humans, one galectin is associated with increased risk of heart attacks and another is implicated in inflammatory bowel disease. The structure of human galectin-1 is a dimer of antiparallel beta-sandwich subunits (Figure 7.41a). Lactose binds at opposite ends of the dimer. Structural studies of the protein in the presence and absence of ligand reveal that the amino acid residues implicated in galactose binding are kept in their proper orientation in the absence of ligand by a hydrogen-bonded network of four water molecules (Figure 7.41b). C-Reactive Protein—A Lectin That Limits Inflammation Damage The pentraxins are lectins that adopt an unusual quaternary structure in which five identical subunits combine to form a planar ring with a central hole (Figure 7.42a). C-reactive protein is a pentraxin that functions to limit tissue damage, acute in- flammation, and autoimmune reactions. C-reactive protein acts by binding to phos- phocholine moieties on damaged membranes. Binding of the protein to phospho- choline is apparently mediated through a bound calcium ion and a hydrophobic pocket centered on Phe 66 (Figure 7.42b). (b)(a) FIGURE 7.41 (a) Structure of the human galectin-1 dimer.The lactose-binding sites are at opposite ends of the dimer. (b) The carbohydrate recognition site of human galectin-1, showing the amino acids involved in galactose binding and the network of water molecules (red circles) that orient these residues. (b)(a) FIGURE 7.42 (a) The C-reactive protein pentamer. (b) The phosphocholine-binding site of C-reactive pro- tein contains two bound Ca 2ϩ ions (blue) and a hydrophobic pocket. Phe 66 is shown in purple. PROBLEMS Preparing for an exam? Create your own study path for this chapter at www.cengage.com/login. 1. Draw Haworth structures for the two possible isomers of D-altrose (Figure 7.2) and D-psicose (Figure 7.3). 2. (Integrates with Chapters 4 and 5.) Consider the peptide DGNILSR, where N has a covalently linked galactose and S has a covalently linked glucose. Draw the structure of this glycopeptide, and also draw titration curves for the glycopeptide and for the free peptide that would result from hydrolysis of the two sugar residues. 3. (Integrates with Chapters 5 and 6.) Human hemoglobin can react with sugars in the blood (usually glucose) to form covalent adducts. The ␣-amino groups of N-terminal valine in the Hb -subunits react with the C-1 (aldehyde) carbons of monosaccharides to form aldimine adducts, which rearrange to form very stable ketoamine products. Quantitation of this “glycated hemoglobin” is important clinically, especially for diabetic individuals. Suggest at least three methods by which glycated Hb could be separated from normal Hb and quantitated. SUMMARY Carbohydrates are a versatile class of molecules of the formula (CH 2 O) n . They are a major form of stored energy in organisms, and they are the metabolic precursors of virtually all other biomolecules. Carbohydrates linked to lipids (glycolipids) are components of biological membranes. Carbohydrates linked to proteins (glycoproteins) are important compo- nents of cell membranes and function in recognition between cell types and recognition of cells by other molecules. Recognition events are im- portant in cell growth, differentiation, fertilization, tissue formation, transformation of cells, and other processes. 7.1 How Are Carbohydrates Named? Carbohydrates are classified into three groups: monosaccharides, oligosaccharides, and polysaccha- rides. Monosaccharides cannot be broken down into smaller sugars un- der mild conditions. Oligosaccharides consist of from two to ten simple sugar molecules. Polysaccharides are polymers of simple sugars and their derivatives and may be branched or linear. Their molecular weights range up to 1 million or more. 7.2 What Is the Structure and Chemistry of Monosaccharides? Mono- saccharides consist typically of three to seven carbon atoms and are de- scribed as either aldoses or ketoses. Aldoses with at least three carbons and ketoses with at least four carbons contain chiral centers. The pre- fixes D- and L- are often used to indicate the configuration of the high- est numbered asymmetric carbon. The D- and L-forms of a monosac- charide are mirror images of each other, called enantiomers. Pairs of isomers that have opposite configurations at one or more chiral centers, but are not mirror images of each other, are called diastereomers. Sug- ars that differ in configuration at only one chiral center are epimers. An interesting feature of carbohydrates is their ability to form cyclic struc- tures with formation of an additional asymmetric center. Aldoses and ketoses with five or more carbons can form either furanose or pyranose rings, and the more stable form depends on structural factors. A variety of chemical and enzymatic reactions produce derivatives of simple sug- ars, such as sugar acids, sugar alcohols, deoxy sugars, sugar esters, amino sugars, acetals, ketals, and glycosides. 7.3 What Is the Structure and Chemistry of Oligosaccharides? The complex array of oligosaccharides in higher organisms is formed from relatively few different monosaccharide units, particularly glucose, fruc- tose, mannose, galactose, ribose, and xylose. Disaccharides consist of two monosaccharide units linked by a glycosidic bond, and each indi- vidual unit is termed a residue. The most common disaccharides in na- ture are sucrose, maltose, and lactose. The anomeric carbons of oligo- saccharides may be substituted or unsubstituted. Disaccharides with a free, unsubstituted anomeric carbon can reduce oxidizing agents and thus are termed reducing sugars. 7.4 What Is the Structure and Chemistry of Polysaccharides? Poly- saccharides are formed from monosaccharides and their derivatives. If a polysaccharide consists of only one kind of monosaccharide, it is a homopolysaccharide, whereas those with more than one kind of mono- saccharide are heteropolysaccharides. Polysaccharides may function as energy storage materials, structural components of organisms, or pro- tective substances. Starch and glycogen are readily metabolizable and provide energy reserves for cells. Chitin and cellulose provide strong support for the skeletons of arthropods and green plants, respectively. Mucopolysaccharides such as hyaluronic acid form protective coats on animal cells. Peptidoglycan, the strong protective macromolecule of bacterial cell walls, is composed of peptide-linked glycan chains. 7.5 What Are Glycoproteins, and How Do They Function in Cells? Glycoproteins are proteins that contain covalently linked oligosaccha- rides and polysaccharides. Carbohydrate groups may be linked to pro- teins via the hydroxyl groups of serine, threonine, or hydroxylysine residues (in O-linked saccharides) or via the amide nitrogen of an as- paragine residue (in N-linked saccharides). O-Glycosylated stems of cer- tain proteins raise the functional domain of the protein above the mem- brane surface and the associated glycocalyx, making these domains accessible to interacting proteins. N-Glycosylation confers a variety of functions to proteins. N-linked oligosaccharides promote the proper folding of newly synthesized polypeptides in the endoplasmic reticulum of eukaryotic cells. 7.6 How Do Proteoglycans Modulate Processes in Cells and Organ- isms? Proteoglycans are a family of glycoproteins whose carbohydrate moieties are predominantly glycosaminoglycans. Proteoglycans may be soluble and located in the extracellular matrix, as for serglycin, versican, and cartilage matrix proteoglycans, or they may be integral transmem- brane proteins, such as syndecan. Both types appear to function by in- teracting with a variety of other molecules through their glycosamino- glycan components and through specific receptor domains in the polypeptide itself. Proteoglycans modulate cell growth processes and are also responsible for the flexibility and resilience of cartilage tissue in the body. 7.7 Do Carbohydrates Provide a Structural Code? Oligosaccharides and polysaccharides are information carriers, and glycoconjugates are the mediators of information transfer by these carbohydrate structures. The vast array of possible glycan structures adds a glycomic dimension to the genomic complexity achieved by protein expression in organ- isms. The processes of cell migration, cell–cell interaction, immune re- sponse, and blood clotting, along with many other biological processes, depend on information transfer modulated by glycoconjugates. Many of the proteins involved in glycoconjugate formation belong to the lectins—a class of proteins that bind carbohydrates with high specificity and affinity. 216 Chapter 7 Carbohydrates and the Glycoconjugates of Cell Surfaces Problems 217 4. Trehalose, a disaccharide produced in fungi, has the following structure: a. What is the systematic name for this disaccharide? b. Is trehalose a reducing sugar? Explain. 5. Draw a Fischer projection structure for L-sorbose (D-sorbose is shown in Figure 7.3). 6. ␣- D-Glucose has a specific rotation, [␣] D 20 , of ϩ112.2°, whereas - D-glucose has a specific rotation of ϩ18.7°. What is the composi- tion of a mixture of ␣- D- and -D-glucose, which has a specific rota- tion of 83.0°? 7. Use the information in the Critical Developments in Biochemistry box titled “Rules for Description of Chiral Centers in the (R,S) Sys- tem” (Chapter 4) to name D-galactose using (R,S) nomenclature. Do the same for L-altrose. 8. A 0.2-g sample of amylopectin was analyzed to determine the frac- tion of the total glucose residues that are branch points in the struc- ture. The sample was exhaustively methylated and then digested, yielding 50 mol of 2,3-dimethylglucose and 0.4 mol of 1,2,3,6- tetramethylglucose. a. What fraction of the total residues are branch points? b. How many reducing ends does this sample of amylopectin have? 9. (Integrates with Chapters 5, 6, and 9.) Consider the sequence of gly- cophorin (see Figure 9.10), and imagine subjecting glycophorin, and also a sample of glycophorin treated to remove all sugars, to treatment with trypsin and chymotrypsin. Would the presence of sugars in the native glycophorin make any difference to the results? 10. (Integrates with Chapters 4, 5, and 23.) The caloric content of protein and carbohydrate are quite similar, at approximately 16 to 17 kJ/g, whereas that of fat is much higher, at 38 kJ/g. Discuss the chemical basis for the similarity of the values for carbohydrate and for protein. 11. Write a reasonable chemical mechanism for the starch phosphory- lase reaction (Figure 7.22). 12. Laetrile is a glycoside found in bitter almonds and peach pits. Laetrile treatment is offered in some countries as a cancer therapy. This procedure is dangerous, and there is no valid clinical evidence of its efficacy. Look up the structure of laetrile and suggest at least one reason that laetrile treatment could be dangerous for human patients. 13. Treatment with chondroitin and glucosamine is offered as one pop- ular remedy for arthritis pain. Suggest an argument for the efficacy of this treatment, and then comment on its validity, based on what you know of polysaccharide chemistry. 14. Certain foods, particularly beans and leg umes, contain substances that are indigestible (at least in part) by the human stomach, but which are metabolized readily by intestinal microorganisms, produc- ing flatulence. One of the components of such foods is stachyose. OH OH OH OH OH H H H H H H H H H O HO CH 2 OH HOCH 2 O O Beano is a commercial product that can prevent flatulence. Describe the likely breakdown of stachyose in the human stomach and in- testines and how Beano could contribute to this process. What would be an appropriate name for the active ingredient in Beano? 15. Give the systematic name for stachyose. 16. Prolonged exposure of amylopectin to starch phosphorylase yields a substance called a limit dextrin. Describe the chemical composi- tion of limit dextrins, and draw a mechanism for the enzyme- catalyzed reaction that can begin the breakdown of a limit dextrin. 17. Biochemist Joseph Owades revolutionized the production of beer in the United States by developing a simple treatment with an en- zyme that converted regular beer into “light beer,” which was mar- keted aggressively as a beverage that “tastes great,” even though it is “less filling.” What was the enzyme-catalyzed reaction that Owades used to modify the fermentation process so cleverly, and how is reg- ular beer different from light beer? 18. Amateur brewers of beer, who do not have access to the enzyme de- scribed in problem 17, have nonetheless managed to brew light beers using a readily available commercial product. What is that product, and how does it work? 19. Kudzu is a vine that grows prolifically in the southern and south- eastern United States. A native of Japan, China, and India, kudzu was brought to the United States in 1876 at the Centennial Exposi- tion in Philadelphia. During the Great Depression of the 1930s, the Soil Conservation Service promoted kudzu for erosion control, and farmers were paid to plant it. Today, however, kudzu is a universal nuisance, spreading rapidly, and covering and destroying trees in large numbers. Already covering 7 to 10 million acres in the U.S., kudzu grows at the rate of a foot per day. Assume that the kudzu vine consists almost entirely of cellulose fibers, and assume that the fibers lie parallel to the vine axis. Calculate the rate of the cellulose synthase reaction that adds glucose units to the growing cellulose molecules. Use the structures in your text to make a reasonable es- timate of the unit length of a cellulose molecule (from one glucose monomer to the next). Preparing for the MCAT Exam 20. Heparin has a characteristic pattern of hydroxy and anionic func- tions. What amino acid side chains on antithrombin III might be the basis for the strong interactions between this protein and the anticoagulant heparin? 21. What properties of hyaluronate, chondroitin sulfate, and keratan sulfate make them ideal components of cartilage? Stachyose CH 2 OH HO OH OH O O CH 2 HO OH OH O O CH 2 HO OH OH O O O HO OH CH 2 OH CH 2 OH FURTHER READING Carbohydrate Structure and Chemistry Collins, P. M., 1987. Carbohydrates. London: Chapman and Hall. Davison, E. A., 1967. Carbohydrate Chemistry. New York: Holt, Rinehart and Winston. Pigman, W., and Horton, D., 1972. The Carbohydrates. New York: Aca- demic Press. Sharon, N., 1980. Carbohydrates. Scientific American 243:90–102. Polysaccharides Aspinall, G. O., 1982. The Polysaccharides, Vols. 1 and 2. New York: Aca- demic Press. Höfte, H., 2001. A baroque residue in red wine. Science 294:795–797. McNeil, M., Darvill, A. G., Fry, S. C., and Albersheim, P., 1984. Structure and function of the primary cell walls of plants. Annual Review of Bio- chemistry 53:625–664. O’Neill, M. A., Eberhard, S., Albersheim, P., and Darvill, A. G., 2002. Requirements of borate cross-linking of cell wall rhamnogalacturo- nan II for Arabidopsis growth. Science 294:846–849. Glycoproteins Feeney, R. E., Burcham, T. S., and Yeh, Y., 1986. Antifreeze glycoproteins from polar fish blood. Annual Review of Biophysical Chemistry 15:59–78. Helenius, A., and Aebi, M., 2001. Intracellular functions of N-linked gly- cans. Science 291:2364–2369. Jentoft, N., 1990. Why are proteins O-glycosylated? Trends in Biochemical Sciences 155:291–294. Sharon, N., 1984. Glycoproteins. Trends in Biochemical Sciences 9:198–202. Proteoglycans Day, A. J., and Prestwich, G. D., 2002. Hyaluronan-binding proteins: Tying up the giant. Joournal of Biological Chemistry 277:4585–4588. Kjellen, L., and Lindahl, U., 1991. Proteoglycans: Structures and inter- actions. Annual Review of Biochemistry 60:443–475. Lennarz, W. J., 1980. The Biochemistry of Glycoproteins and Proteoglycans. New York: Plenum Press. Ruoslahti, E., 1989. Proteoglycans in cell regulation. Journal of Biological Chemistry 264:13369–13372. Glycobiology Bertozzi, C. R., and Kiessling, L. L., 2001. Chemical glycobiology. Science 291:2357–2363. Lodish, H. F., 1991. Recognition of complex oligosaccharides by the multisubunit asialoglycoprotein receptor. Trends in Biochemical Sci- ences 16:374–377. Maeder, T., 2002. Sweet medicines. Scientific American 287:40–47. Miyamoto, S., 2006. Clinical applications of glycomic approaches for the detection of cancer and other diseases. Current Opinion in Molecular Therapies 8:507–513. Rademacher, T. W., Parekh, R. B., and Dwek, R. A., 1988. Glycobiology. Annual Review of Biochemistry 57: 785–838. Timmer , M., Stocker, B., and Seeburger, P., 2007. Probing glycomics. Current Opinion in Chemical Biology 11:59–65. 218 Chapter 7 Carbohydrates and the Glycoconjugates of Cell Surfaces © Brandon D. Cole/CORBIS 8 Lipids The lipids found in biological systems are either hydrophobic (containing only non- polar groups) or amphipathic (possessing both polar and nonpolar groups). The hydrophobic nature of lipid molecules allows membranes to act as effective barriers to more polar molecules. In this chapter, we discuss the chemical and physical prop- erties of the various classes of lipid molecules. The following chapter considers membranes, whose properties depend intimately on their lipid constituents. 8.1 What Are the Structures and Chemistry of Fatty Acids? A fatty acid is composed of a long hydrocarbon chain (“tail”) and a terminal car- boxyl group (or “head”). The carboxyl group is normally ionized under physio- logical conditions. Fatty acids occur in large amounts in biological systems but only rarely in the free, uncomplexed state. They typically are esterified to glyc- erol 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 de- scribed in at least three ways, as shown in Table 8.1. For example, a fatty acid composed of an 18-carbon chain with no double bonds can be called by its sys- tematic name (octadecanoic acid), its common name (stearic acid), or its short- hand 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 common 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 Δ9 , 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 typically varies 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 “The mighty whales which swim in a sea of water, and have a sea of oil swimming in them.”Herman Melville, “Extracts.” Moby Dick.New York: Penguin Books, 1972. (Humpback whale [Megaptera novaeangliae] breach- ing,Cape Cod, MA) A feast of fat things, a feast of wines on the lees. Isaiah 25:6 KEY QUESTIONS 8.1 What Are the Structures and Chemistry of Fatty Acids? 8.2 What Are the Structures and Chemistry of Triacylglycerols? 8.3 What Are the Structures and Chemistry of Glycerophospholipids? 8.4 What Are Sphingolipids, and How Are They Important for Higher Animals? 8.5 What Are Waxes, and How Are They Used? 8.6 What Are Terpenes, and What Is Their Relevance to Biological Systems? 8.7 What Are Steroids, and What Are Their Cellular Functions? 8.8 How Do Lipids and Their Metabolites Act as Biological Signals? 8.9 What Can Lipidomics Tell Us about Cell, Tissue, and Organ Physiology? ESSENTIAL QUESTION Lipids are a class of biological molecules defined by low solubility in water and high solubility in nonpolar solvents. As molecules that are largely hydrocarbon in nature, lipids represent highly reduced forms of carbon and, upon oxidation in metabolism, yield large amounts of energy. Lipids are thus the molecules of choice for metabolic energy storage. What are the structure, chemistry, and biological function of lipids? Create your own study path for this chapter with tutorials, simulations, animations, and Active Figures at www.cengage.com/ login 220 Chapter 8 Lipids has very important consequences for the structure of biological membranes. Satu- rated fatty acid chains can pack closely together to form ordered, rigid arrays un- der 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 nor- mal growth and life. These essential fatty acids include linoleic and ␥-linolenic acids. These must be obtained by mammals in their diet (specifically from plant sources). Arachidonic acid, which is not found in plants, can be synthesized by mammals only 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 hormonelike effects in many physiological processes (discussed in Chapter 24). Fats in the modern human diet vary widely in their fatty acid composition (Table 8.2). The incidence of cardiovascular disease is correlated with diets high in satu- rated fatty acids. By contrast, a diet relatively higher in unsaturated fatty acids (es- pecially polyunsaturated fatty acids) may reduce the risk of heart attacks and strokes. Although vegetable oils usually contain a higher proportion of unsatu- rated 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 (hence the name palmitic). Coconut oil is particularly high in lauric and myristic acids (both saturated) and contains little unsaturated fatty acid. Canola oil has been promoted as a healthy dietary oil because it consists primar- ily of oleic acid (60%), linoleic acid (20%), and α-linolenic acid (9%) with very low saturated fat content (7%). Canola oil is actually rapeseed oil, from the seeds of the rape plant Brassica rapa (from the Latin rapa, meaning “turnip”), a close relative of mustard, kale, cabbage, and broccoli. Asians and Europeans used rapeseed oil in lamps for hundreds of years, but it was not usually considered edible because of its high erucic acid content, a 22:1 ⌬13 monounsaturated fatty acid (often 20% to 60%). In the first half of the 20th century, it was used as a steam engine lubricant (espe- cially in World War II). Conventional breeding techniques have reduced the erucic acid content to less than 1%, producing the “canola oil” (the name is derived from Canadian oil, low acid) now used so commonly for cooking and baking. Number of Carbons Common Name Systematic Name Symbol Structure Saturated fatty acids 12 Lauric acid Dodecanoic acid 12:0 CH 3 (CH 2 ) 10 COOH 14 Myristic acid Tetradecanoic acid 14:0 CH 3 (CH 2 ) 12 COOH 16 Palmitic acid Hexadecanoic acid 16:0 CH 3 (CH 2 ) 14 COOH 18 Stearic acid Octadecanoic acid 18:0 CH 3 (CH 2 ) 16 COOH 20 Arachidic acid Eicosanoic acid 20:0 CH 3 (CH 2 ) 18 COOH 22 Behenic acid Docosanoic acid 22:0 CH 3 (CH 2 ) 20 COOH 24 Lignoceric acid Tetracosanoic acid 24:0 CH 3 (CH 2 ) 22 COOH Unsaturated fatty acids (all double bonds are cis) 16 Palmitoleic acid 9-Hexadecenoic acid 16:1* CH 3 (CH 2 ) 5 CHPCH(CH 2 ) 7 COOH 18 Oleic acid 9-Octadecenoic acid 18:1 CH 3 (CH 2 ) 7 CHPCH(CH 2 ) 7 COOH 18 Linoleic acid 9,12-Octadecadienoic acid 18:2 CH 3 (CH 2 ) 4 (CHPCHCH 2 ) 2 (CH 2 ) 6 COOH 18 ␣-Linolenic acid 9,12,15-Octadecatrienoic acid 18:3 CH 3 CH 2 (CHPCHCH 2 ) 3 (CH 2 ) 6 COOH 18 ␥-Linolenic acid 6,9,12-Octadecatrienoic acid 18:3 CH 3 (CH 2 ) 4 (CHPCHCH 2 ) 3 (CH 2 ) 3 COOH 20 Arachidonic acid 5,8,11,14-Eicosatetraenoic acid 20:4 CH 3 (CH 2 ) 4 (CHPCHCH 2 ) 4 (CH 2 ) 2 COOH 24 Nervonic acid 15-Tetracosenoic acid 24:1 CH 3 (CH 2 ) 7 CHPCH(CH 2 ) 13 COOH TABLE 8.1 Common Biological Fatty Acids *Palmitoleic acid can also be described as 16:1 Δ9 , in a convention used to indicate the position of the double bond. 8.1 What Are the Structures and Chemistry of Fatty Acids? 221 H 2 C O C OH CH 2 H 2 C CH 2 H 2 C CH 2 H 2 C CH 2 H 2 C CH 2 H 2 C CH 2 H 2 C CH 2 CH 3 O C OH Palmitic acid O C OH Linoleic acid O C OH Stearic acid O C OH ␣-Linolenic acid O C OH Oleic acid O C OH Arachidonic acid ANIMATED FIGURE 8.1 The structures of some typical fatty acids. Note that most natural fatty acids contain an even number of carbon atoms and that the double bonds are nearly always cis and rarely conjugated. See this figure animated at www.cengage.com/login. Lauric and Source 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, E. D., et al., 1979, Principles of Nutrition, 4th ed. New York:Wiley. *Values are percentages of total fatty acids. TABLE 8.2 Fatty Acid Compositions of Some Dietary Lipids* 222 Chapter 8 Lipids Although most unsaturated fatty acids in nature are cis fatty acids, trans fatty acids are formed by some bacteria via double-bond migration and isomerization. These bacterial reactions produce trans fats in ruminant animals (which carry essential bacteria in their rumen), and butter, milk, cheese and the meat of these animals contain modest quantities of trans fats (typically 2% to 8% by weight), such as those in Figure 8.2. Margarine and other “processed fats,” made by partial hydrogenation of polyunsaturated oils (for example, corn, safflower, and sunflower) contain sub- stantial levels of various trans fats, and clinical research has shown that chronic con- sumption of processed foods containing partially hydrogenated vegetable oils can contribute to cardiovascular disease. Diets high in trans fatty acids raise plasma low- density lipoprotein (LDL) cholesterol levels and triglyceride levels while lowering high-density lipoprotein (HDL) cholesterol levels. The effects of trans fatty acids on LDL, HDL, and cholesterol levels are similar to those of saturated fatty acids. Diets aimed at reducing the risk of coronary heart disease should be low in both trans and saturated fatty acids. 8.2 What Are the Structures and Chemistry of Triacylglycerols? A significant number of the fatty acids in plants and animals exist in the form of tri- acylglycerols (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 triacylglycerol. Examples in- clude 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. Monoacylglycerols and diacylglycerols also exist, but they 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 our ancestors made soap (a metal salt of an acid de- rived from fat). 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 Mg 2ϩ and Ca 2ϩ ions in hard water makes them less use- ful 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 acyl- C O OH H H Elaidic acid trans double bond at 9,10 position C O OH H H Vaccenic acid trans double bond at 11,12 position FIGURE 8.2 Structures of elaidic acid and vaccenic acid, two trans fatty acids. H 2 C CH CH 2 OHHO OH Glycerol H 2 C CH CH 2 CC COOO OOO Tristearin (a simple triacylglycerol) H 2 C CH CH 2 O OO CC COOO Myristic Stearic Palmitoleic A mixed triacylglycerol FIGURE 8.3 Triacylglycerols are formed from glycerol and fatty acids. . Index, 10th ed. Rahway, NJ:Merck and Co.; and Wilson, E. D., et al., 1979, Principles of Nutrition, 4th ed. New York:Wiley. *Values are percentages of total fatty acids. TABLE 8.2 Fatty Acid Compositions