Garrett R.H., Grisham C.M. - Biochemistry (1999)(2nd ed.)(en)

● Both ATP and NADPH (as well as NADH) can be produced by this version of the pentose phosphate and glycolytic pathways.

3 CO2

TK

Glyceraldehyde-3-P Sedoheptulose-7-P

TA

Fructose-6-P Erythrose-4-P

TK

2 ATP

PFK

Fructose-6-P Glyceraldehyde-3-P

2 ADP

Fructose-1,6-bisP

DHAP Glyceraldehyde-3-P

5 NAD+

1.Consider the balanced equation for gluconeogenesis in Section 23.1. Account for each of the components of this equation and the indicated stoichiometry.

2.Calculate G° and G for gluconeogenesis in the erythrocyte, using data in Table 19.2 (assume NAD /NADH 20, [GTP]

[ATP], and [GDP] [ADP]). See how closely your values match those in Section 23.1.

3.Use the data of Figure 23.12 to calculate the percent inhibition of fructose-1,6-bisphosphatase by 25 M fructose-2,6- bisphosphate when fructose-1,6-bisphosphate is (a) 25 M and

(b) 100 M.

4.Suggest an explanation for the exergonic nature of the glycogen synthase reaction ( G° 13.3 kJ/mol). Consult Chapter 3 to review the energetics of high-energy phosphate compounds if necessary.

5.Using the values in Table 24.1 for body glycogen content and the data in part b of the illustration for A Deeper Look (page 759), calculate the rate of energy consumption by muscles in heavy exercise (in J/sec). Use the data for fast-twitch muscle.

6.What would be the distribution of carbon from positions 1, 3, and 6 of glucose after one pass through the pentose phosphate

772

pathway if the primary need of the organism is for ribose-5-P and the oxidative steps are bypassed (Figure 23.38)?

7.What is the fate of carbon from positions 2 and 4 of glucose- 6-P after one pass through the scheme shown in Figure 23.40?

8.Which reactions of the pentose phosphate pathway would be inhibited by NaBH4? Why?

9.Imagine a glycogen molecule with 8000 glucose residues. If branches occur every eight residues, how many reducing ends does the molecule have? If branches occur every 12 residues, how many reducing ends does it have? How many nonreducing ends does it have in each of these cases?

10.Explain the effects of each of the following on the rates of gluconeogenesis and glycogen metabolism:

a.Increasing the concentration of tissue fructose-1,6-bisphosphate

b.Increasing the concentration of blood glucose

c.Increasing the concentration of blood insulin

d.Increasing the amount of blood glucagon

e.Decreasing levels of tissue ATP

f.Increasing the concentration of tissue AMP

g.Decreasing the concentration of fructose-6-phosphate

FURTHER READING

Akermark, C., Jacobs, I., Rasmusson, M., and Karlsson, J., 1996. Diet and muscle glycogen concentration in relation to physical performance in Swedish elite ice hockey players. International Journal of Sport Nutrition

6:272–284.

Browner, M. F., and Fletterick, R. J., 1992. Phosphorylase: A biological transducer. Trends in Biochemical Sciences 17:66–71.

Fox, E. L., 1984. Sports Physiology, 2nd ed. Philadelphia: Saunders College Publishing.

Hanson, R. W., and Reshef, L., 1997. Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression. Annual Review of Biochemistry 66:581–611.

Hargreaves, M., 1997. Interactions between muscle glycogen and blood glucose during exercise. Exercise and Sport Sciences Reviews 25:21–39.

Hers, H.-G., and Hue, L., 1983. Gluconeogenesis and related aspects of glycolysis. Annual Review of Biochemistry 52:617–653.

Horton, E. S., and Terjung, R. L., eds. 1988. Exercise, Nutrition and Energy Metabolism. New York: Macmillan.

Huang, D., Wilson, W. A., and Roach, P. J., 1997. Glucose-6-P control of glycogen synthase phosphorylation in yeast. Journal of Biological Chemistry 272:22495–22501.

Johnson, L. N., 1992. Glycogen phosphorylase: Control by phosphorylation and allosteric effectors. FASEB Journal 6:2274–2282.

Larner, J., 1990. Insulin and the stimulation of glycogen synthesis: The road from glycogen structure to glycogen synthase to cyclic AMPdependent protein kinase to insulin mediators. Advances in Enzymology 63:173–231.

Newsholme, E. A., Chaliss, R. A. J., and Crabtree, B., 1984. Substrate cycles: Their role in improving sensitivity in metabolic control. Trends in Biochemical Sciences 9:277–280.

Newsholme, E. A., and Leech, A. R., 1983. Biochemistry for the Medical Sciences. New York: Wiley.

Pilkis, S. J., El-Maghrabi, M. R., and Claus, T. H., 1988. Hormonal regulation of hepatic gluconeogenesis and glycolysis. Annual Review of Biochemistry 57:755–783.

Rhoades, R., and Pflanzer, R., 1992. Human Physiology. Philadelphia: Saunders College Publishing.

Rolfe, D. F., and Brown, G. C., 1997. Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiological Reviews 77:731–758.

Rybicka, K. K., 1996. Glycosomes—The organelles of glycogen metabolism. Tissue and Cell 28:253–265.

Sies, H., ed., 1982. Metabolic Compartmentation. London: Academic Press.

Shulman, R. G., and Rothman, D. L., 1996. Nuclear magnetic resonance studies of muscle and applications to exercise and diabetes. Diabetes 45:S93–S98.

Stalmans, W., Cadefau, J., Wera, S., and Bollen, M., 1997. New insight into the regulation of liver glycogen metabolism by glucose. Biochemical Society Transactions 25:19–25.

Sukalski, K. A., and Nordlie, R. C., 1989. Glucose-6-phosphatase: Two concepts of membrane-function relationship. Advances in Enzymology 62:93– 117.

Taylor, S. S., et al., 1993. A template for the protein kinase family. Trends in Biochemical Sciences 18:84–89.

Van Schaftingen, E., and Hers, H.-G., 1981. Inhibition of fructose-1,6-bis- phosphatase by fructose-2,6-bisphosphate. Proceedings of the National Academy of Sciences, USA 78:2861–2863.

Williamson, D. H., Lund, P., and Krebs, H. A., 1967. The redox state of free nicotinamide–adenine dinucleotide in the cytoplasm and mitochondria of rat liver. Biochemical Journal 103:514–527.

Woodget, J. R., 1991. A common denominator linking glycogen metabolism, nuclear oncogenes, and development. Trends in Biochemical Sciences 16:177–181.

Chapter 24

Fatty Acid Catabolism

The hummingbird’s tremendous capacity to store and use fatty acids enables it to make migratory journeys of remarkable distances. (Two Hummingbirds Lithograph; The Academy of Natural

Sciences of Philadelphia/Corbis Images)

Fatty acids represent the principal form of stored energy for many organisms. There are two important advantages to storing energy in the form of fatty acids. (1) The carbon in fatty acids (mostly OCH2O groups) is almost completely reduced compared to the carbon in other simple biomolecules (sugars, amino acids). Therefore, oxidation of fatty acids will yield more energy (in the form of ATP) than any other form of carbon. (2) Fatty acids are not generally hydrated as monoand polysaccharides are, and thus can pack more closely in storage tissues. This chapter will be devoted to several important aspects of fatty acid catabolism. Lipid biosynthetic processes will be considered in Chapter 25.

The fat is in the fire.

Proverbs, JOHN HEYWOOD (1497–1580)

OUTLINE

24.1 ● Mobilization of Fats from Dietary Intake and Adipose Tissue

24.2 ● -Oxidation of Fatty Acids

24.3 ● -Oxidation of Odd-Carbon Fatty Acids 24.4 ● -Oxidation of Unsaturated Fatty Acids 24.5 ● Other Aspects of Fatty Acid Oxidation 24.6 ● Ketone Bodies

775

776 Chapter 24 ● Fatty Acid Catabolism

Fatty Acid Catabolism

● Scanning electron micrograph of an adipose cell (fat cell). Globules of triacylglycerols occupy most of the volume of such cells.

“La Sapienza,” Rome/Science Photo Library/Photo Researchers, Inc.)

24.1 ● Mobilization of Fats from Dietary

Intake and Adipose Tissue

Modern Diets Are Often High in Fat

Fatty acids are acquired readily in the diet and can also be made from carbohydrates and the carbon skeletons of amino acids. Fatty acids provide 30% to 60% of the calories in the diets of most Americans. For our caveman and cavewoman ancestors, the figure was probably closer to 20%. Dairy products were apparently not part of their diet, and the meat they consumed (from fast-mov- ing animals) was low in fat. In contrast, modern domesticated cows and pigs are actually bred for high fat content (and better taste). However, woolly mammoth burgers and saber-toothed tiger steaks are hard to find these days—even in the gourmet sections of grocery stores—and so, by default, we consume (and metabolize) large quantities of fatty acids.

Triacylglycerols Are a Major Form of Stored Energy in Animals

Although some of the fat in our diets is in the form of phospholipids, triacylglycerols are a major source of fatty acids. Triacylglycerols are also our principal stored energy reserve. As shown in Table 24.1, the energy available in stores of fat in the average person far exceeds the energy available from protein, glycogen, and glucose. Overall, fat accounts for approximately 83% of available energy, partly because more fat is stored than protein and carbohydrate, and partly because of the substantially higher energy yield per gram for fat compared with protein and carbohydrate. Complete combustion of fat yields about 37 kJ/g, compared with about 16 to 17 kJ/g for sugars, glycogen, and amino acids. In animals, fat is stored mainly as triacylglycerols in specialized cells called adipocytes or adipose cells. As shown in Figure 24.1, triacylglycerols, aggregated to form large globules, occupy most of the volume of adipose cells. Much smaller amounts of triacylglycerols are stored as small, aggregated globules in muscle tissue.

Hormones Signal the Release of Fatty Acids from Adipose Tissue

The pathways for liberation of fatty acids from triacylglycerols, either from adipose cells or from the diet, are shown in Figures 24.2 and 24.3. Fatty acids are mobilized from adipocytes in response to hormone messengers such as adren-

Table 24.1

Stored Metabolic Fuel in a 70-kg Person

Sources: Owen, O. E., and Reichard, G. A., Jr., 1971. Progress in Biochemistry and Pharmacology

6:177; Newsholme, E. A., and Leech, A. R., 1983. Biochemistry for the Medical Sciences. New York: Wiley.

aline, glucagon, and ACTH (adrenocorticotropic hormone). These signal molecules bind to receptors on the plasma membrane of adipose cells and lead to the activation of adenylyl cyclase, which forms cyclic AMP from ATP. (Second messengers and hormonal signaling are discussed in Chapter 34.) In adipose cells, cAMP activates protein kinase A, which phosphorylates and activates a triacylglycerol lipase (also termed hormone-sensitive lipase) that hydrolyzes a fatty acid from C-1 or C-3 of triacylglycerols. Subsequent actions of diacylglycerol lipase and monoacylglycerol lipase yield fatty acids and glycerol. The cell then releases the fatty acids into the blood, where they are carried (in complexes with serum albumin) to sites of utilization.

Degradation of Dietary Fatty Acids Occurs

Primarily in the Duodenum

Dietary triacylglycerols are degraded to a small extent (via fatty acid release) by lipases in the low-pH environment of the stomach, but mostly pass untouched into the duodenum. Alkaline pancreatic juice secreted into the

Hormone

● Liberation of fatty acids from triacylglycerols in adipose tissue is hormonedependent.

Entry of pancreatic juice into duodenum

of intestinal wall

2 fatty acyl CoA

duodenum (Figure 24.3a) raises the pH of the digestive mixture, allowing hydrolysis of the triacylglycerols by pancreatic lipase and by nonspecific esterases, which hydrolyze the fatty acid ester linkages. Pancreatic lipase cleaves fatty acids from the C-1 and C-3 positions of triacylglycerols, and other lipases and esterases attack the C-2 position (Figure 24.3b). These processes depend upon the presence of bile salts, a family of carboxylic acid salts with steroid backbones (see also Chapter 25). These agents act as detergents to emulsify the triacylglycerols and facilitate the hydrolytic activity of the lipases and esterases. Short-chain fatty acids (10 carbons or less) released in this way are absorbed directly into the villi of the intestinal mucosa, whereas long-chain fatty acids, which are less soluble, form mixed micelles with bile salts, and are carried in this fashion to the surfaces of the epithelial cells that cover the villi (Figure 24.4). The fatty acids pass into the epithelial cells, where they are condensed with glycerol to form new triacylglycerols. These triacylglycerols aggregate with lipoproteins to form particles called chylomicrons, which are then transported into the lymphatic system and on to the bloodstream, where they circulate to the liver, lungs, heart, muscles, and other organs (Chapter 25). At these sites, the triacylglycerols are hydrolyzed to release fatty acids, which can then be oxidized in a highly exergonic metabolic pathway known as

-oxidation.

24.2 ● -Oxidation of Fatty Acids

Franz Knoop and the Discovery of -Oxidation

The earliest clue to the secret of fatty acid oxidation and breakdown came in the early 1900s, when Franz Knoop carried out experiments in which he fed dogs fatty acids in which the terminal methyl group had been replaced with a

FIGURE 24.4 ● In the small intestine, fatty acids combine with bile salts in mixed micelles, which deliver fatty acids to epithelial cells that cover the intestinal villi. Triacylglycerols are formed within the epithelial cells.

● The oxidative breakdown of phenyl fatty acids observed by Franz Knoop. He observed that fatty acid analogs with even numbers of carbon atoms yielded phenyl acetate, whereas compounds with odd numbers of carbon atoms produced only benzoate.