Fatty acid /?-oxidation

The processes of electron transport and oxidative phosphorylation are membrane-associated. Bacteria are the simplest life form, and bacterial cells typically consist of a single cellular compartment surrounded by a plasma membrane and a more rigid cell wall. In such a system, the conversion of energy from NADH and [FADHg] to the energy of ATP via electron transport and oxidative phosphorylation is carried out at (and across) the plasma membrane. In eukaryotic cells, electron transport and oxidative phosphorylation are localized in mitochondria, which are also the sites of TCA cycle activity and (as we shall see in Chapter 24) fatty acid oxidation. Mammalian cells contain from 800 to 2500 mitochondria other types of cells may have as few as one or two or as many as half a million mitochondria. Human erythrocytes, whose purpose is simply to transport oxygen to tissues, contain no mitochondria at all. The typical mitochondrion is about 0.5 0.3 microns in diameter and from 0.5 micron to several microns long its overall shape is sensitive to metabolic conditions in the cell. 

The space inside the inner mitochondrial membrane is called the matrix, and it contains most of the enzymes of the TCA cycle and fatty acid oxidation. (An important exception, succinate dehydrogenase of the TCA cycle, is located in the inner membrane itself.) In addition, mitochondria contain circular DNA molecules, along with ribosomes and the enzymes required to synthesize proteins coded within the mitochondrial genome. Although some of the mitochondrial proteins are made this way, most are encoded by nuclear DNA and synthesized by cytosolic ribosomes. 

This is a crucial point because (as we will see) proton transport is coupled with ATP synthesis. Oxidation of one FADHg in the electron transport chain results in synthesis of approximately two molecules of ATP, compared with the approximately three ATPs produced by the oxidation of one NADH. Other enzymes can also supply electrons to UQ, including mitochondrial 5w-glyc-erophosphate dehydrogenase, an inner membrane-bound shuttle enzyme, and the fatty acyl-CoA dehydrogenases, three soluble matrix enzymes involved in fatty acid oxidation (Figure 21.7 also see Chapter 24). The path of electrons from succinate to UQ is shown in Figure 21.8. 

Mobilization of Fats from Dietary Intake and Adipo.se Ti.ssne /3-Oxidation of Fatty Acids /3-Oxidation of Odd-Carbon Fatty Acids /3-Oxidation of Unsatnrated Fatty Acids Other Aspects of Fatty Acid 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... 

Migratory Birds Travel Long Distances on Energy from Fatty Acid Oxidation... 

Fatty Acid Oxidation Is an Important Source of Metabolic Water for Some Animals... 

Succinyl-CoA derived from propionyl-CoA can enter the TCA cycle. Oxidation of succinate to oxaloacetate provides a substrate for glucose synthesis. Thus, although the acetate units produced in /3-oxidation cannot be utilized in glu-coneogenesis by animals, the occasional propionate produced from oxidation of odd-carbon fatty acids can be used for sugar synthesis. Alternatively, succinate introduced to the TCA cycle from odd-carbon fatty acid oxidation may be oxidized to COg. However, all of the 4-carbon intermediates in the TCA cycle are regenerated in the cycle and thus should be viewed as catalytic species. Net consumption of succinyl-CoA thus does not occur directly in the TCA cycle. Rather, the succinyl-CoA generated from /3-oxidation of odd-carbon fatty acids must be converted to pyruvate and then to acetyl-CoA (which is completely oxidized in the TCA cycle). To follow this latter route, succinyl-CoA entering the TCA cycle must be first converted to malate in the usual way, and then transported from the mitochondrial matrix to the cytosol, where it is oxida-... 

Calculate the volume of metabolic water available to a camel through fatty acid oxidation if it carries 30 lb of triacylglycerol in its hump. 

Even though acetate units, such as those obtained from fatty acid oxidation, cannot be used for net synthesis of carbohydrate in animals, labeled carbon from " C-labeled acetate can be found in newly synthesized glucose (for example, in liver glycogen) in animal tracer studies. Explain how this can be. Which carbons of glucose would you expect to be the first to be labeled by "Relabeled acetate ... 

What would be the consequences of a deficiency in vitamin Bi2 for fatty acid oxidation What metabolic intermediates might accumulate ... 

Bennett, M. J., 1994. The enzyme.s of mitochondrial fatty acid oxidation. 

Grynberg, A., and Demai.son, L., 1996. Fatty acid oxidation in the heart. 

McGarry, J. D., and Foster, D. W., 1980. Regulation of hepatic fatty acid oxidation and ketone body production. Annual Review of Biochemistry 49 395-420. 

Pollitt, R. J., 1995. Disorders of mitochondrial long-chain fatty acid oxidation. Journal of Inherited Metabolic Disease 18 473—490. 

Romijn, J. A., Coyle, E. R, Sidossis, L. S., et al., 1996. Relationship between fatty acid delivery and fatty acid oxidation during strenuous exercise. Journal of Applied Physiology 79 1939—1945. 

Schulz, H., 1987. Inhibitors of fatty acid oxidation. Life Sciences 40 1443-1449. 

Sherratt, H. S., 1994. Introduction The regulation of fatty acid oxidation in cells. Biochemical Society Transactions 22 421—422. 

Srere, P. A., and Snmegi, B., 1994. Processivity and fatty acid oxidation. 

Yagoob, R, Newsholme, E. A., and Calder, P. C., 1994. Fatty acid oxidation by lymphocytes. Biochemical Society Transactions 22 116S. 

Fatty acid oxidation produces mitochondrial acetyl-CoA. 

The acetyl-CoA derived from amino acid degradation is normally insufficient for fatty acid biosynthesis, and the acetyl-CoA produced by pyruvate dehydrogenase and by fatty acid oxidation cannot cross the mitochondrial membrane to participate directly in fatty acid synthesis. Instead, acetyl-CoA is linked with oxaloacetate to form citrate, which is transported from the mitochondrial matrix to the cytosol (Figure 25.1). Here it can be converted back into acetyl-CoA and oxaloacetate by ATP-citrate lyase. In this manner, mitochondrial acetyl-CoA becomes the substrate for cytosolic fatty acid synthesis. (Oxaloacetate returns to the mitochondria in the form of either pyruvate or malate, which is then reconverted to acetyl-CoA and oxaloacetate, respectively.)... 

FIGURE 25.1 The citrate-malate-pyruvate shuttle provides cytosolic acetate units and reducing equivalents (electrons) for fatty acid synthesis. The shuttle collects carbon substrates, primarily from glycolysis but also from fatty acid oxidation and amino acid catabolism. Most of the reducing equivalents are glycolytic in origin. Pathways that provide carbon for fatty acid synthesis are shown in blue pathways that supply electrons for fatty acid synthesis are shown in red. 

The next three steps—reduction of the /3-carbonyl group to form a /3-alcohol, followed by dehydration and reduction to saturate the chain (Figure 25.7) — look very similar to the fatty acid degradation pathway in reverse. However, there are two crucial differences between fatty acid biosynthesis and fatty acid oxidation (besides the fact that different enzymes are involved) First, the alcohol formed in the first step has the D configuration rather than the L form seen in catabolism, and, second, the reducing coenzyme is NADPH, although NAD and FAD are the oxidants in the catabolic pathway. 

FIGURE 25.16 Regulation of fatty acid synthesis and fatty acid oxidation are conpled as shown. Malonyl-CoA, produced during fatty acid synthesis, inhibits the uptake of fatty acylcarnitine (and thus fatty acid oxidation) by mitochondria. When fatty acyl CoA levels rise, fatty acid synthesis is inhibited and fatty acid oxidation activity increases. Rising citrate levels (which reflect an abundance of acetyl-CoA) similarly signal the initiation of fatty acid synthesis. 

Lopa.schnk, G. D., and Gamble, J., 1994. The 1993 Merck Fro.s.st Award. Acetyl-CoA carboxylase an important regulator of fatty acid oxidation in die heart. Canadian Journal of Physiology and Pharmacology 72 1101 — 1109. 

Antidiabetic Drugs other than Insulin. Figure 3 The antihyperglycaemic effect of metformin involves enhanced insulin-mediated suppression of hepatic glucose production and muscle glucose uptake. Metformin also exerts non-insulin-dependent effects on these tissues, including reduced fatty acid oxidation and increased anaerobic glucose metabolism by the intestine. FA, fatty acid f, increase i decrease. 

Pancreas t Fatty acid oxidation Protection of pancreatic (3-cells from lipotoxicity... 

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