8.7 What Are Steroids, and What Are Their Cellular Functions? 233 8.7 What Are Steroids, and What Are Their Cellular Functions? Cholesterol A large and important class of terpene-based lipids is the steroids. This molecu- lar family, whose members affect an amazing array of cellular functions, is based on a common structural motif of three 6-membered rings and one 5-membered ring all fused together. Cholesterol (Figure 8.16) 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. Significantly, 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 -orientation. Alkyl groups that extend from the other side of the steroid backbone are in an ␣-orientation. Cholesterol is a principal component of animal cell plasma membranes, and smaller amounts of cholesterol are found in the membranes of intracellular or- ganelles. 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 Are Derived from Cholesterol Steroids derived from cholesterol in animals include five families of hormones (the androgens, estrogens, progestins, glucocorticoids, and mineralocorticoids) and bile acids (Figure 8.17). 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 regu- late salt (Na ϩ , K ϩ , and Cl Ϫ ) 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. HO AB CD 1 2 3 4 5 H 3 C 19 9 10 8 7 6 11 12 H 3 C 18 13 17 14 16 15 CH 2 CH 3 HC CH 2 CH 2 CH 3 CH 3 HC 20 21 22 23 24 25 26 27 Cholesterol FIGURE 8.16 The structure of cholesterol, shown with steroid ring designations and carbon numbering. 234 Chapter 8 Lipids 8.8 How Do Lipids and Their Metabolites Act as Biological Signals? Glycerophospholipids and sphingolipids play important structural roles as the prin- cipal components of biological membranes (see Chapter 9). However, their modi- fication and breakdown also produce an eclectic assortment of substances that act as powerful chemical signals (Figures 8.18 and 8.19). In contrast to the steroid hor- mones (Figure 8.17), which travel from tissue to tissue in the blood to exert their effects, these lipid metabolites act locally, either within the cell in which they are made or on nearby cells. Signal molecules typically initiate a cascade of reactions with multiple possible effects, and the lifetimes of these powerful signals in or near a cell are usually very short. Thus, the creation and breakdown of signal molecules is almost always carefully timed and regulated. HO C CH 2 OH OH O Cortisol OH Testosterone O Progesterone O C CH 3 O HO OH Estradiol O Cholic acid HO OH HO COOH Deoxycholic acid HO HO COOH FIGURE 8.17 The structures of several important sterols derived from cholesterol. Phospholipase D Phospholipase C Phospholipase A 2 Phospholipase A 1 O – OP O OCH 2 CH 2 N + CH 3 CH 3 CH 3 O CH 2 CH 2 CH 2 O O C O C (b) FIGURE 8.18 (a) Phospholipases A 1 and A 2 cleave fatty acids from a glycerophospholipid, producing lyso- phospholipids. Phospholipases C and D hydrolyze on either side of the phosphate in the polar head group. (b) Phospholipases are components of the venoms of many poisonous snakes.The pain and physiological consequences of a snake bite partly result from breakdown of cell membranes by phospholipases. © Joe McDonald/CORBIS © Tom Bean/CORBIS (a) Diamondback rattlesnake Indian cobra 8.8 How Do Lipids and Their Metabolites Act as Biological Signals? 235 Enzymes known as phospholipases hydrolyze the ester bonds of glycerophos- pholipids as shown in Figure 8.18. Phospholipases A 1 and A 2 remove fatty acid chains from the 1- and 2-positions of glycerophospholipids, respectively. Phospholi- pases C and D attack the polar head group of a glycerophospholipid. Hydrolysis of inositol phospholipids by phospholipase C produces a diacylglycerol and inositol- 1,4,5-trisphosphate (IP 3 ) (Figure 8.19), two signal molecules whose combined ac- tions trigger signaling cascades that regulate many cell processes (see Chapter 32). Action of phospholipase A 2 on a phosphatidic acid releases a fatty acid and a lysophosphatidic acid (LPA, Figure 8.19). If the fatty acid is arachidonic acid, fur- ther chemical modifications can produce a family of 20-carbon compounds—that is, eicosanoids. The eicosanoids are local hormones produced as a response to in- jury and inflammation. They exert their effects on cells near their sites of synthesis (see Chapter 24). LPA produced outside the cell is a signal that can bind to recep- tor proteins on nearby cells, thereby regulating a host of processes, including brain development, cell proliferation and survival, and olfaction (the “sense of smell”). Sphingolipids can also be modified or broken down to produce chemical signals. Sphingosine itself can be phosphorylated to produce sphingosine-1-phosphate (S1P) inside cells (Figure 8.20). S1P may either exert a variety of intracellular effects or may be excreted from the cell, where it can bind to membrane receptor proteins, either on adjacent cells or on the cell from which the S1P was released. Excreted A DEEPER LOOK Glycerophospholipid Degradation: One of the Effects of Snake Venom 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 A 2 , which catalyzes the hydrolysis of fatty acids at the C-2 position of glyc- erophospholipids (Figure 8.18). The phospholipid breakdown product of this reaction, lysolecithin, acts as a detergent and dis- solves the membranes of red blood cells, causing them to rupture. Indian cobras kill several thousand people each year. Lysophosphatidic acid (LPA) (extracellular) Arachidonic acid EffectsProstaglandins Thromboxanes Leukotrienes Effects Phosphatidic acid PLA 2 + Phosphatidylinositol-4,5-bisphosphate (PIP 2 ) PLC Inositol-1,4,5-trisphosphate (IP 3 )Diacylglycerol Increase in cellular Ca 2 + Activation of protein kinase C Binding and regulation Phosphorylation in signaling pathways Phosphatidylinositol 2 ADP 2 ATP FIGURE 8.19 Modification and breakdown of glycerophospholipids produce a variety of signals and regulatory effects. Phospholipase A 2 cleaves a fatty acid from phosphatidic acid to produce lysophosphatidic acid (LPA), which can act as an extracellular signal. If the fatty acid released is arachidonic acid, it can be the substrate for synthesis of prostaglandins, thromboxanes, and leukotrienes.Phospholipase C action on phosphatidylinositol-4,5-bisphosphate produces diacylglycerol and inositol-1,4,5-trisphosphate, two signal molecules that work together to active protein kinases—enzymes that phosphorylate other proteins in signaling pathways. 236 Chapter 8 Lipids HUMAN BIOCHEMISTRY Plant Sterols and Stanols—Natural Cholesterol Fighters Dietary guidelines for optimal health call for reducing the choles- terol intake. One strategy involves eating plant sterols and stanols in place of cholesterol-containing fats such as butter (figure). De- spite their structural similarity to cholesterol, minor isomeric dif- ferences and the presence of methyl and ethyl groups in the side chains of these substances result in their poor absorption by in- testinal mucosal cells. Interestingly, stanols are even less well ab- sorbed than their sterol counterparts. Both sterols and stanols bind to cholesterol receptors on intestinal cells and block the ab- sorption of cholesterol itself. Stanols esterified with long-chain fatty acids form micelles (see page 244) that are more effectively distributed in the fat phase of the food digest and provide the most effective blockage of cholesterol uptake. (Stanols are fully re- duced sterols.) Raisio Group, a Finnish company, has developed Benecol, a stanol ester spread that can lower LDL cholesterol by up to 14% if consumed daily (see graph). McNeil Nutritionals has partnered with Raisio Group to market Benecol in the United States. Cholesterol (mg/dL) Ϫ202468101214 Study period (mo) Sitostanol-ester margarine 200 240 230 220 210 250 H 3 C H 3 C CH 3 CH 3 CH 2 CH 3 Stigmasterol HO H 3 C H 3 C H 3 C CH 3 CH 3 CH 2 CH 3 Stigmastanol -Sitosterol HO H 3 C H 3 C H 3 C CH 3 CH 3 CH 3 -Sitostanol HO H 3 C H 3 C H 3 C CH 3 CH 3 CH 3 HO H 3 C H H ᮤ Serum cholesterol levels before and after the con- sumption of margarine with and without sitostanol ester for 12 months. Green circles: 0 g/day. Red squares: 2.6 g/day. Blue triangles: 1.8 g/day. Note: The y-axis begins at 200 mg cholesterol/dL. (Adapted from Miettinen, T. A., et al., 1995. Reduction of serum cholesterol with sitostanol-ester margarine in a mildly hypercholesterolemic population. New England Journal of Medicine 333:1308–1312.) 8.9 What Can Lipidomics Tell Us about Cell,Tissue, and Organ Physiology? 237 S1P binds to many different receptor proteins and provokes many different cell and tissue effects, among them inflammation in allergic reactions, heart rate, and move- ment and migration of certain cells. Sphingolipid signal molecules are carefully bal- anced and regulated in organisms, and chemical agents that disturb this balance can be highly toxic. For example, fumonisin is a common fungal contaminant of corn and corn-based products that inhibits sphingolipid biosynthesis (Figure 8.20; see also Chapter 24). Fumonisin can trigger esophageal cancer in humans and leu- coencephalomalacia, a fatal neurological disease in horses. 8.9 What Can Lipidomics Tell Us about Cell, Tissue, and Organ Physiology? The crucial role of lipids in cells is demonstrated by the large number of human diseases that involve the disruption of lipid metabolic enzymes and pathways. Ex- amples of such diseases include atherosclerosis, diabetes, cancer, infectious dis- eases, and neurodegenerative diseases. Emerging analytical techniques are making possible the global analysis of lipids and their interacting protein partners in organs, cells, and organelles—an approach termed lipidomics. A typical cell may contain more than a thousand different lipids, each with a polar head and a hydro- phobic tail or tails. Despite this general similarity, proteins recognize lipids with exquisite specificity. Local concentrations of lipids vary between organelles and be- tween specific areas of cellular membranes. Complete understanding of lipid function, as well as alteration of such function in disease states, will require the determination of which lipids are present and in OH C H H C + NH 3 OPO 3 2 – CH 2 C C H H Sphingosine-1-phosphate (S1P) CH 3 CH 3 CH 3 CH 3 NH 2 O O OH OH OH OHOOC OHOOC HOOC HOOC Fumonisin B 1 FIGURE 8.20 Structures of sphingosine-1-phosphate (S1P) and fumonisin B 1 . 238 Chapter 8 Lipids what concentrations in every intracellular location. The same knowledge will be needed about each lipid’s interaction partners. Mass spectrometric analyses of rat heart muscle reveal that the onset of diabetes results in dramatic changes in triglyc- eride levels, an increase in phosphatidylinositol levels, and a decrease in phos- phatidylethanolamine. On the other hand, mass spectrometric analyses of brain white matter in the very early stages of Alzheimer’s disease show a dramatic decrease in one type of plasmalogen and a threefold increase in ceramide levels. Cellular lipidomics provides a framework for understanding the myriad roles of lipids, which include (but are not limited to) membrane transport (see Chapter 9), metabolic regulation (see Chapters 18–27), and cell signaling (see Chapter 32). For example, six different classes of lipids have been shown to modulate systems im- portant in the regulation of pain responses. Each of these classes of lipids exerts its action by interacting with one or more receptor proteins. True understanding of the molecular basis for diseases and metabolic and physiologic conditions may re- quire comprehensive and simultaneous analyses of many lipid species and their re- spective receptors. HUMAN BIOCHEMISTRY 17-Hydroxysteroid Dehydrogenase 3 Deficiency Testosterone, the principal male sex steroid hormone, is synthe- sized in five steps from cholesterol, as shown in the following fig- ure. In the last step, five isozymes catalyze the 17-hydroxysteroid dehydrogenase reaction that interconverts 4-androstenedione and testosterone. Defects in the synthesis or action of testosterone can impair the development of the male phenotype during embryoge- nesis and cause the disorders of human sexuality termed male pseudohermaphroditism. Specifically, mutations in isozyme 3 of the 17-hydroxysteroid dehydrogenase in the fetal testes impair the formation of testosterone and give rise to genetic males with female external genitalia and blind-ending vaginas. Such individ- uals are typically raised as females but virilize at puberty, due to an increase in serum testosterone, and develop male hair growth pat- terns. Fourteen different mutations of 17-hydroxysteroid dehy- drogenase 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. HO HO C H O O O O O O OH O O O OH Cholesterol Pregnenolone 17␣-Hydroxyprogesterone 4-Androstenedione Testosterone Progesterone Desmolase (Mitochondria) (Endoplasmic reticulum) 17␣-Hydroxylase 17,20-Lyase (Gonads) 17-Hydroxysteroid dehydrogenase Isocaproic aldehyde H 3 C H 3 C H 3 C H 3 C H 3 C H 3 C H 3 C H 3 C H 3 C H 3 C H 3 C H 3 C SUMMARY 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 meta- bolic energy storag e. The lipids found in biological systems are either hydrophobic (containing only nonpolar groups) or amphipathic (containing both polar and nonpolar groups). The hydrophobic na- ture of lipid molecules allows membranes to act as effective barriers to more polar molecules. 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 carboxyl group (“head”). The carboxyl group is normally ionized un- der physiological conditions. Fatty acids occur in large amounts in bi- ological systems but only rarely in the free, uncomplexed state. They typically are esterified to glycerol or other backbone structures. 8.2 What Are the Structures and Chemistry of Triacylglycerols? A sig- nificant 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. Triacylglycerols in animals are found primarily in the adipose tis- sue (body fat), which serves as a depot or storage site for lipids. Monoa- cylglycerols and diacylglycerols also exist, but they are far less common than the triacylglycerols. 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. These lipids form one of the largest and most important classes of natural lipids. They are essen- tial components of cell membranes and are found in small concentra- tions in other parts of the cell. All glycerophospholipids are members of the broader class of lipids known as phospholipids. 8.4 What Are Sphingolipids, and How Are They Important for Higher Animals? Sphingolipids represent another class of lipids in biological membranes. An 18-carbon amino alcohol, sphingosine, forms the back- bone of these lipids rather than glycerol. Typically, a fatty acid is joined to a sphingosine via an amide linkage to form a ceramide. Sphingo- myelins are a phosphorus-containing subclass of sphingolipids espe- cially important in the nervous tissue of higher animals. A sphingo- myelin is formed by the esterification of a phosphorylcholine or a phosphorylethanolamine to the 1-hydroxy group of a ceramide. Glyco- sphingolipids are another class of ceramide-based lipids that, like the sphingomyelins, are important components of muscle and nerve mem- branes in animals. Glycosphingolipids consist of a ceramide with one or more sugar residues in a -glycosidic linkage at the 1-hydroxyl moiety. 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). 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. Waxes are water insoluble due to their predominantly hydrocarbon nature. 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 molecules of 2-methyl-1,3-butadiene, better known as isoprene (a five-carbon unit abbreviated C 5 ). A monoterpene (C 10 ) con- sists of two isoprene units, a sesquiterpene (C 15 ) consists of three iso- prene units, a diterpene (C 20 ) has four isoprene units, and so on. Iso- prene 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. Monoterpenes occur in all higher plants, whereas sesquiterpenes and diterpenes are less widely known. 8.7 What Are Steroids, and What Are Their Cellular Functions? A large and important class of terpene-based lipids is the steroids. This molecular family, whose members affect an amazing array of cellular functions, is based on a common structural motif of three 6-membered rings and one 5-membered ring all fused together. Cholesterol is the most common steroid in animals and the precursor for all other animal steroids. The numbering system for cholesterol applies to all such mol- ecules. The polyprenyl nature of this compound is particularly evident in the side chain. Many steroids contain an oxygen at C-3, either a hy- droxyl group in sterols or a carbonyl group in other steroids. The methyl groups at positions 10 and 13 and the alkyl group at position 17 are usually oriented on the same side of the steroid nucleus, the -orientation. Alkyl groups that extend from the other side of the steroid backbone are in an ␣-orientation. Cholesterol is a principal com- ponent of animal cell plasma membranes. Steroids derived from cho- lesterol in animals include five families of hormones (the androgens, estrogens, progestins, glucocorticoids, and mineralocorticoids) and bile acids. 8.8 How Do Lipids and Their Metabolites Act as Biological Signals? Modification and breakdown of cellular lipids produce an eclectic as- sortment of substances that act as powerful chemical signals. Signal mol- ecules typically initiate a cascade of reactions with multiple possible ef- fects. The creation and breakdown of signal molecules is almost always carefully timed and regulated. Phospholipases initiate the production of a variety of lipid signals, including arachidonic acid (the precursor to eicosanoids), lysophosphatidic acid, inositol-1,4,5-trisphosphate, and diacylglycerol. 8.9 What Can Lipidomics Tell Us about Cell, Tissue, and Organ Physi- ology? The comprehensive analysis of lipids and their interacting protein partners in organs, cells, and organelles is termed lipidomics. A typical cell may contain more than a thousand different lipids. Com- plete understanding of lipid function, as well as alteration of such func- tion in disease states, will require the determination of which lipids are present and in what concentrations in every intracellular location. The same knowledge will be needed about each lipid’s interaction partners. Problems 239 PROBLEMS Preparing for an exam? Create your own study path for this chapter at www.cengage.com/login 1. Draw the structures of (a) all the possible triacylglycerols that can be formed from glycerol with stearic and arachidonic acid and (b) all the phosphatidylserine isomers that can be formed from palmitic and linolenic acids. 2. Describe in your own words the structural features of a. a ceramide and how it differs from a cerebroside. b. a phosphatidylethanolamine and how it differs from a phos- phatidylcholine. c. an ether glycerophospholipid and how it differs from a plas- malogen. 240 Chapter 8 Lipids d. a ganglioside and how it differs from a cerebroside. e. testosterone and how it differs from estradiol. 3. From your memory of the structures, name a. the glycerophospholipids that carry a net positive charge. b. the glycerophospholipids that carry a net negative charge. c. the glycerophospholipids that have zero net charge. 4. Compare and contrast two individuals, one whose diet consists largely of meats containing high levels of cholesterol and the other whose diet is rich in plant sterols. Are their risks of cardiovascular disease likely to be similar or different? Explain your reasoning. 5. James G. Watt, Secretary of the Interior (1981–1983) in Ronald Rea- gan’s first term, provoked substantial controversy by stating publicly that trees cause significant amounts of air pollution. Based on your reading of this chapter, evaluate Watt’s remarks. 6. In a departure from his usual and highly popular westerns, author Louis L’Amour wrote a novel in 1987, Last of the Breed (Bantam Press), in which a military pilot of Native American ancestry is shot down over the former Soviet Union and is forced to use the survival skills of his ancestral culture to escape his enemies. On the rare occasions when he is able to trap and kill an animal for food, he selectively eats the fat, not the meat. Based on your reading of this chapter, what is his reasoning for doing so? 7. As you read Section 8.7, you might have noticed that phospholipase A 2 , the enzyme found in rattlesnake venom, is also the enzyme that produces essential and beneficial lipid signals in most organisms. Ex- plain the differing actions of phospholipase A 2 in these processes. 8. Visit a grocery store near you, stop by the rodent poison section, and examine a container of warfarin or a related product. From what you can glean from the packaging, how much warfarin would a typical dog (40 lbs) have to consume to risk hemorrhages and/or death? 9. Refer to Figure 8.13 and draw each of the structures shown and try to identify the isoprene units in each of the molecules. (Note that there may be more than one correct answer for some of these mol- ecules, unless you have the time and facilities to carry out 14 C la- beling studies with suitable organisms.) 10. (Integrates with Chapter 3.) As noted in the Deeper Look box on polar bears, a polar bear may burn as much as 1.5 kg of fat resources per day. What weight of seal blubber would you have to ingest if you were to obtain all your calories from this energy source? 11. If you are still at the grocery store working on problem 8, stop by the cookie shelves and choose your three favorite cookies from the shelves. Estimate how many calories of fat, and how many other calories from other sources, are contained in 100 g of each of these cookies. Survey the ingredients listed on each package, and describe the contents of the package in terms of (a) satu- rated fat, (b) cholesterol, and (c) trans fatty acids. (Note that food makers are required to list ingredients in order of decreas- ing amounts in each package.) 12. Describe all of the structural differences between cholesterol and stigmasterol. 13. Describe in your own words the functions of androgens, glucocorti- coids, and mineralocorticoids. 14. Look through your refrigerator, your medicine cabinet, and your cleaning solutions shelf or cabinet, and find at least three commer- cial products that contain fragrant monoterpenes. Identify each one by its scent and then draw its structure. 15. Our ancestors kept clean with homemade soap (page 222), often called “lye soap.” Go to http://www.wikihow.com/Make-Your-Own-Soap and read the procedure for making lye soap from vegetable oils and lye (sodium hydroxide). What chemical process occurs in the mak- ing of lye soap? Draw reactions to explain. How does this soap work as a cleaner? 16. Mayonnaise is mostly vegetable oil and vinegar. So what’s the essen- tial difference between oil and vinegar salad dressing and mayon- naise? Learn for yourself: Combine a half cup of pure vegetable oil (olive oil will work) with two tablespoons of vinegar in a bottle, cap it securely, and shake the mixture vigorously. What do you see? Now let the mixture sit undisturbed for an hour. What do you see now? Add one egg yolk to the mixture, and shake vigorously again. Let the mixture stand as before. What do you see after an hour? After two hours? Egg yolk is rich in phosphatidylcholine. Explain why the egg yolk caused the effect you observed. 17. The cholesterol-lowering benefit of stanol-ester margarine is only achieved after months of consumption of stanol esters (see graph, page 236). Suggest why this might be so. Suppose dietary sources represent approximately 25% of total serum cholesterol. Based on the data in the graph, how effective are stanol esters at preventing uptake of dietary cholesterol? 18. Statins are cholesterol-lowering drugs that block cholesterol syn- thesis in the human liver (see Chapter 24). Would you expect the beneficial effects of stanol esters and statins to be duplicative or ad- ditive? Explain. 19. If most plant-derived food products contain plant sterols and stanols, would it be as effective (for cholesterol-lowering purposes) to simply incorporate plant fats in one’s diet as to use a sterol- or stanol-fortified spread like Benecol? Consult a suitable reference (for example, http://lpi.oregonstate.edu/infocenter/phytochemicals/sterols/ #sources at the Linus Pauling Institute) to compose your answer. 20. Tetrahydrogestrinone is an anabolic steroid. It was banned by the U.S. Food and Drug Administration in 2003, but it has been used il- legally since then by athletes to increase muscle mass and strength. Nicknamed “The Clear,” it has received considerable attention in high-profile steroid-abuse cases among athletes such as baseball player Barry Bonds and track star Marion Jones. Use your favorite Web search engine to learn more about this illicit drug. How is it synthesized? Who is “the father of prohormones” who first synthe- sized it? Why did so many prominent athletes use The Clear (and its relative, “The Cream”) when less expensive and more commonly available anabolic steroids are in common use? (Hint: There are at least two answers to this last question.) Preparing for the MCAT Exam 21. Make a list of the advantages polar bears enjoy from their nonpolar diet. Why wouldn’t juvenile polar bears thrive on an exclusively nonpolar diet? 22. Snake venom phospholipase A 2 causes death by generating membrane-soluble anionic fragments from glycerophospholipids. Predict the fatal effects of such molecules on membrane proteins and lipids. OH O Tetrahydrogestrinone H H FURTHER READING General Robertson, R. N., 1983. The Lively Membranes. Cambridge: Cambridge University Press. Seachrist, L., 1996. A fragrance for cancer treatment and prevention. The Journal of NIH Research 8:43. Vance, D. E., and Vance, J. E. (eds.), 1985. Biochemistry of Lipids and Mem- branes. Menlo Park, CA: Benjamin/Cummings. Sterols Anderson, S., Russell, D. W., and Wilson, J. D., 1996. 17-Hydroxysteroid dehydrogenase 3 deficiency. Trends in Endocrinology and Metabolism 7:121–126. DeLuca, H. F., and Schneos, H. K., 1983. Vitamin D: Recent advances. Annual Review of Biochemistry 52:411–439. Denke, M. A., 1995. Lack of efficacy of low-dose sitostanol therapy as an adjunct to a cholesterol-lowering diet in men with moderate hyper- cholesterolemia. American Journal of Clinical Nutrition 61:392–396. Thompson, G., and Grundy, S., 2005. History and development of plant sterol and stanol esters for cholesterol-lowering purposes. American Journal of Cardiology 96:3D–9D. Vanhanen, H. T., Blomqvist, S., Ehnholm, C., et al., 1993. Serum cho- lesterol, cholesterol precursors, and plant sterols in hypercholes- terolemic subjects with different apoE phenotypes during dietary sitostanol ester treatment. Journal of Lipid Research 34:1535–1544. Isoprenes and Prenyl Derivatives Dowd, P., Ham, S W., Naganathan, S., and Hershline, R., 1995. The mechanism of action of vitamin K. Annual Review of Nutrition 15: 419–440. Hirsh, J., Dalen, J. E., Deykin, D., Poller, L., and Bussey, H., 1995. Oral anticoagulants: Mechanism of action, clinical effectiveness, and op- timal therapeutic range. Chest 108:231S–246S. Sharkey, T. D., 1995. Why plants emit isoprene. Nature 374:769. Sharkey, T. D., 1996. Emission of low molecular-mass hydrocarbons from plants. Trends in Plant Science 1:78–82. Eicosanoids Chakrin, L. W., and Bailey, D. M., 1984. The Leukotrienes—Chemistry and Biology. Orlando: Academic Press. Keuhl, F. A., and Egan, R. W., 1980. Prostaglandins, arachidonic acid and inflammation. Science 210:978–984. Sphingolipids Hakamori, S., 1986. Glycosphingolipids. Scientific American 254:44–53. Trans Fatty Acids Katan, M. B., Zock, P. L., and Mensink, R. P., 1995. Trans fatty acids and their effects on lipoproteins in humans. Annual Review of Biochem- istry 15:473–493. Lipids of Archaea Hanford, M., and Peebles, T., 2002. Archaeal tetraetherlipids: Unique structures and applications. Applied Biochemistry and Biotechnology 97: 45–62. Lipid Alterations in Disease States Malan, T. P., and Porreca, F., 2005. Lipid mediators regulating pain sen- sitivity. Prostaglandins and Other Lipid Mediators 77:123–130. Smith, L. E. H., and Connor, K. M., 2005. A radically twisted lipid regu- lates vascular death. Nature Medicine 11:1275–1276. Lipidomics Ferrari, C., and Chatgilialoglu, C., 2005. Geometrical trans lipid isomers: A new target for lipidomics. Chembiochem 6:1722–1734. German, J., Gillies, L., Smilowitz, J., Zivkovic, A., and W atkins, S., 2007. Lipidomics and lipid profiling in metabolomics. Current Opinion in Lipidology 18:66–71. Muralikrishna, R., Hatcher, J., and Dempsey, R., 2006. Lipids and lipidomics in brain injury and diseases. AAPS Journal 8:E314–E321. Van Meer, G., 2005. Cellular lipidomics. EMBO Journal 24:3159–3165. Weak, M. R., 2005. The emerging field of lipidomics. Nature Reviews Drug Discovery 4:594–610. Lipids as Signaling Molecules Eyster, K., 2007. The membrane and lipids as integral participants in sig- nal transduction: Lipid signal transduction for the non-lipid bio- chemist. Advances in Physiology Education 31:5–16. Fernandis, A., and Wenk, M., 2007. Membrane lipids as signaling mole- cules. Current Opinion in Lipidology 18:121–128. Rosen, H., and Goetzl, E., 2005. Sphingosine-1-phosphate and its re- ceptors: An autocrine and paracrine network. Nature Reviews Immu- nology 5:560–570. Further Reading 241 © Sven Peter/iStockphoto.com 9 Membranes and Membrane Transport Membranes are key structural and functional elements of cells. All cells have a cyto- plasmic membrane, or plasma membrane, that functions (in part) to separate the cytoplasm from the surroundings. The plasma membrane is also responsible for (1) the exclusion of certain toxic ions and molecules from the cell, (2) the accu- mulation of cell nutrients, and (3) energy transduction. It functions in (4) cell loco- motion, (5) reproduction, (6) signal transduction processes, and (7) interactions with molecules or other cells in the vicinity. Even the plasma membranes of prokaryotic cells are complex (Figure 9.1). With no intracellular organelles to divide and organize the work, bacteria carry out processes either at the plasma membrane or in the cytoplasm itself. Eukaryotic cells, however, contain numerous intracellular organelles that perform specialized tasks. Nucleic acid biosynthesis is handled in the nucleus; mitochondria are the site of electron transport, oxidative phosphorylation, fatty acid oxidation, and the tricar- boxylic acid cycle; and secretion of proteins and other substances is handled by the endoplasmic reticulum (ER) and the Golgi apparatus. This partitioning of labor is not the only contribution of the membranes in these cells. Many of the processes occurring in these organelles (or in the prokaryotic cell) actively involve mem- branes. Thus, some of the enzymes involved in nucleic acid metabolism are mem- brane associated. The electron transfer chain and its associated system for ATP syn- thesis are embedded in the mitochondrial membrane. Many enzymes responsible for aspects of lipid biosynthesis are located in the ER membrane. This chapter discusses the composition, structure, and dynamic processes of biological membranes. 9.1 What Are the Chemical and Physical Properties of Membranes? Water’s tendency to form hydrogen bonds and share in polar interactions, and the hydrophobic effect, which promotes self-association of lipids in water to maximize entropy, are the basis for the interactions of lipids and proteins to form membranes. These forces drive amphiphilic glycerolipids, sphingolipids, and sterols to form membrane structures in water, and these forces facilitate the association of proteins (and thus myriad biological functions) with membranes. A symphony of molecular events over a range of times from picoseconds to many seconds results in the move- ment of lipids and proteins across and between membranes; catalyzes reactions at Frog eggs are macroscopic facsimiles of microscopic cells. All cells are surrounded by a thin, ephemeral yet stable membrane. It takes a membrane to make sense out of disorder in biology. Lewis Thomas The World’s Biggest Membrane, The Lives of a Cell (1974) KEY QUESTIONS 9.1 What Are the Chemical and Physical Properties of Membranes? 9.2 What Are the Structure and Chemistry of Membrane Proteins? 9.3 How Are Biological Membranes Organized? 9.4 What Are the Dynamic Processes That Modulate Membrane Function? 9.5 How Does Transport Occur Across Biological Membranes? 9.6 What Is Passive Diffusion? 9.7 How Does Facilitated Diffusion Occur? 9.8 How Does Energy Input Drive Active Transport Processes? 9.9 How Are Certain Transport Processes Driven by Light Energy? 9.10 How Is Secondary Active Transport Driven by Ion Gradients? ESSENTIAL QUESTION Membranes serve a number of essential cellular functions.They constitute the boundaries of cells and intracellular organelles, and they provide a surface where many important biological reactions and processes occur. Membranes have proteins that mediate and regulate the transport of metabolites, macromolecules, and ions. Hormones and many other biological signal molecules and regulatory agents exert their effects via interactions with membranes. Photosynthesis, electron transport, oxidative phosphorylation, muscle contraction, and electrical activity all depend on membranes and membrane proteins. For example, 30 percent of the genes of Mycoplasma genitalium are thought to encode membrane proteins. What are the properties and characteristics of biological membranes that ac- count for their broad influence on cellular processes and transport? Create your own study path for this chapter with tutorials, simulations, animations, and Active Figures at www.cengage.com/ login