The Oxidation of Fatty Acids

Several additional points should be made. First, although oxygen esters usually have lower group-transfer potentials than thiol esters, the O—acyl bonds in acylcarnitines have high group-transfer potentials, and the transesterification reactions mediated by the acyl transferases have equilibrium constants close to 1. Second, note that eukaryotic cells maintain separate pools of CoA in the mitochondria and in the cytosol. The cytosolic pool is utilized principally in fatty acid biosynthesis (Chapter 25), and the mitochondrial pool is important in the oxidation of fatty acids and pyruvate, as well as some amino acids. 

During catabolic and anabolic processes, a renovation of the molecular cellular components takes place. It should be emphasized that the catabolic and anabolic pathways are independent of each other. Be these pathways coincident and differing in the cycle direction only, the metabolism would have been side-tracked to the so-called useless, or futile, cycles. Such cycles arise in pathology, where a useless turnover of metabolites may occur. To avoid this undesirable contingency, the synthetic and degradative routes in the cell are most commonly separated in space. For example, the oxidation of fatty acids occurs in the mitochondria, while the synthesis thereof proceeds extramitochondrially, in the microsomes. 

The oxidation of fatty acids within the Knoop-Lynen cycle occurs in the matrix. The Knoop-Lynen cycle includes four enzymes that act successively on acetyl-CoA. These are acyl-CoA dehydrogenase (FAD-dependent enzyme), enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase (NAD-dependent enzyme), and acetyl-CoA acyltrans-ferase. Each turn, or revolution, of the fatty acid spiral produces... 

Another possible explanation for the low R. Q. s obtained after high-fat diets over short periods by Hawley, Johnson and Murlin186 is that in the oxidation of fatty acid chains the uptake of oxygen may outrun the production of carbon dioxide and thus lower the R. Q. Such a process of desaturation would remove the hydrogen but would not produce any carbon dioxide. 

The tricarboxylic acid cycle was therefore validated, having been tested not only in pigeon-breast muscle but also with brain, testis, liver, and kidney. The nature of the carbohydrate fragment entering the cycle was still uncertain. The possibility that pyruvate and oxaloacetate condensed to give a 7C derivative which would be decarboxy-lated to citrate, was dismissed partly because the postulated compound was oxidized at a very low rate. Further, work on the oxidation of fatty acids (see Chapter 7) had already established that a 2C fragment like acetate was produced by fatty acid oxidation, en route for carbon dioxide and water. It therefore seemed likely that a similar 2C compound might arise by decarboxylation of pyruvate, and thus condense with oxaloacetate. For some considerable time articles and textbooks referred to this unknown 2C compound as active acetate. ... 

Acetyl-CoA is derived from the oxidation of fatty acids and pyruvate carbons are diverted to OAA. Dotted lines indicate low activity heavy lines represent accelerated activity. 

If starvation lasts for more than 24 hours, the rate of degradation of body protein (process 2) exceeds the rate of protein synthesis (process 3). The resultant amino acids are converted to oxoacids, most of which are converted to glucose (process 6) which is released and used predominantly by the brain (see Chapter 6). In this condition, the ATP required for gluconeogenesis is obtained from the oxidation of fatty acids (Figure 8.14(b)). 

This sequence of reactions, namely oxidation of CH2-CH2 to CH=CH, then hydration to CH2-CHOH, followed by oxidation to CH2-CO, is a sequence we shall meet again in the -oxidation of fatty acids (see Section 15.4.1). The first oxidation utilizes FAD as coenzyme, the second NAD+. In both cases, participation of the oxidative phosphorylation system allows regeneration of the oxidized coenzyme and the subsequent generation of energy in the form of ATP. 

Toxicology. Propionic acid is an irritant to skin, eyes, and mucous membranes. Propionic acid is a normal intermediary metabolite during the oxidation of fatty acids. It occurs ubiquitously in the gastrointestinal tract as an end product of microbial digestion of carbohydrates. It represents up to 4% of the normal total plasma fatty acids. ... 

Vitamin Bjj (8.50, cobalamin) is an extremely complex molecule consisting of a corrin ring system similar to heme. The central metal atom is cobalt, coordinated with a ribofuranosyl-dimethylbenzimidazole. Vitamin Bjj occurs in liver, but is also produced by many bacteria and is therefore obtained commercially by fermentation. The vitamin is a catalyst for the rearrangement of methylmalonyl-CoA to the succinyl derivative in the degradation of some amino acids and the oxidation of fatty acids with an odd number of carbon atoms. It is also necessary for the methylation of homocysteine to methionine. 

The oxidation of fatty acids is catalyzed by the FAD-containing acyl coenzyme A dehydrogenases which transfer reducing equivalents to the mitochondrial respiratory chain via a flavin-containing electron transfer flavoprotein (ETF) and subsequently via an ETF dehydrogenase (an Fe/S flavoprotein In addition to the mammalian... 

Eugene Kennedy and Albert Lehninger showed in 1948 that, in eulcaiyotes, the entire set of reactions of the citric acid cycle takes place in mitochondria. Isolated mitochondria were found to contain not only all the enzymes and coenzymes required for the citric acid cycle, but also all the enzymes and proteins necessaiy for the last stage of respiration—electron transfer and ATP synthesis by oxidative phosphoiylation. As we shall see in later chapters, mitochondria also contain the enzymes for the oxidation of fatty acids and some amino acids to acetyl-CoA, and the oxidative degradation of other amino acids to a-ketoglutarate, succinyl-CoA, or oxaloacetate. Thus, in nonphotosynthetic eulcaiyotes, the mitochondrion is the site of most energy-yielding... 

FIGURE 16-22 Relationship between the glyoxylate and citric acid cycles. The reactions of the glyoxylate cycle (in glyoxysomes) proceed simultaneously with, and mesh with, those of the citric acid cycle (in mitochondria), as intermediates pass between these compartments. The conversion of succinate to oxaloacetate is catalyzed by citric acid cycle enzymes. The oxidation of fatty acids to acetyl-CoA is described in Chapter 17 the synthesis of hexoses from oxaloacetate is described in Chapter 20. 

The acetyl-CoA produced from the oxidation of fatty acids can be oxidized to C02 and H20 by the citric acid cycle. The following equation represents the balance sheet for the second stage in the oxidation of palmitoyl-CoA, together with the coupled phosphorylations of the third stage ... 

Portions of the carbon skeletons of seven amino acids— tryptophan, lysine, phenylalanine, tyrosine, leucine, isoleucine, and threonine—yield acetyl-CoA and/or acetoacetyl-CoA, the latter being converted to acetyl-CoA (Fig. 18-21). Some of the final steps in the degrada-tive pathways for leucine, lysine, and tryptophan resemble steps in the oxidation of fatty acids. Threonine (not shown in Fig. 18-21) yields some acetyl-CoA via the minor pathway illustrated in Figure 18-19. 

Some electrons enter this chain of carriers through alternative paths. Succinate is oxidized by succinate dehydrogenase (Complex II), which contains a flavoprotein that passes electrons through several Fe-S centers to ubiquinone. Electrons derived from the oxidation of fatty acids pass to ubiquinone via the electron-transferring flavoprotein. 

The brain has no significant stores of triacylglycerol, and the oxidation of fatty acids obtained from blood makes little contribution to energy production because fatty acids do not efficiently cross the blood-brain barrier. The intertissue exchanges characteristic of the absorptive period are summarized in Figure 24.8. 

Increased fatty acid oxidation The oxidation of fatty acids derived from adipose tissue is the major source of energy in hepatic tis sue in the postabsorptive state (see Figure 24.11, ). 

A major factor controlling the oxidation of fatty acids is the rate of entry into the mitochondria. While some long-chain fatty acids (perhaps 30% of the total) enter mitochondria as such and are converted to CoA derivatives in the matrix, the majority are "activated" to acyl-CoA derivatives on the inner surface of the outer membranes of the mitochondria. Penetration of these acyl-CoA derivatives through the mitochondrial inner membrane is facilitated by L-camitine 41 44... 

To complete the oxidation of fatty acids the acetyl units of acetyl-CoA generated in the P oxidation sequence must be oxidized to carbon dioxide and water.77 The citric acid (or tricarboxylic acid) cycle by which this oxidation is accomplished is a vital part of the metabolism of almost all aerobic creatures. It occupies a central position in metabolism because of the fact that acetyl-CoA is also an intermediate in the catabolism of carbohydrates and of many amino acids and other compounds. The cycle is depicted in detail in Fig. 10-6 and in an abbreviated form, but with more context, in Fig. 17-4. 

The mitochondrial inner membrane has no transport system for NAD+ or NADH. In animal cells, most of the NADH that must be oxidized by the respiratory chain is generated in the mitochondrial matrix by the TCA cycle or the oxidation of fatty acids. However, NADH also is generated by glycolysis in the cytosol. If 02 is available, it clearly is advantageous to reoxidize this NADH by the respiratory chain, rather than by the formation of lactate or ethanol as described in chapter 12. This is evident from the findings that approximately 2.5 molecules of ATP can be formed for each NADH oxidized in the mitochondria, whereas no ATP is made when NADH is oxidized by the cytosolic lactate dehydrogenase or alcohol dehydrogenase. 

Oxidation, in combination with the tricarboxylic acid cycle and respiratory chain, provides more energy per carbon atom than any other energy source, such as glucose and amino acids. The equations for the complete oxidation of palmitoyl-CoA are shown in table 18.1. Equation (1) in the table shows the oxidation of palmitoyl-CoA by the enzymes of j8 oxidation. Each of the products of equation (1) is further oxidized by the respiratory chain, equations (2) and (3), or by the tricarboxylic acid cycle and the respiratory chain, equation (4). When the reactions of equations (l)-(4) are summed, the result is equation (5). Hence, complete oxidation of one molecule of palmitoyl-CoA yields 108 ATP + 16C02 + 123 H20 and CoA. The water generated by /3 oxidation seems almost incidental to this process, but is crucial in several animal species. For example, the oxidation of fatty acids is used as a major source of H20 by the killer... 

The degradation of fatty acids occurs by an oxidation process in the mitochondria. The breakdown of the 16-carbon saturated fatty acid, palmitate, occurs in blocks of two carbon atoms by a cyclical process. The active substrate is the acyl-CoA derivative of the fatty acid. Each cycle involves four discrete enzymatic steps. In the process of oxidation the energy is sequestered in the form of reduced coenzymes of FAD and NAD+. These reduced coenzymes lead to ATP production through the respiratory chain. The oxidation of fatty acids yields more energy per carbon than the oxidation of glucose because saturated fatty acids are in the fully reduced state. 

Oxidation of phenols is one of the most important aspects of these compounds to the biologist. Oxidation of phenolic compounds can result in the browning of tissues. Well-known examples are the browning of lfuits after they have been cut. Oxidation can also result in the formation of metabolites that are toxic to animals and plants, and that can account for spoilage of foods in processing. On the other hand, toxic compounds formed from the oxidation of phenolics can inhibit pathogenic microorganisms. Certain phenols are used as retardants or antioxidants to prevent the oxidation of fatty acids. 

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