Fatty acids, oxidation separation

Although fatty acids are both oxidized to acetyl-CoA and synthesized from acetyl-CoA, fatty acid oxidation is not the simple reverse of fatty acid biosynthesis but an entirely different process taking place in a separate compartment of the cell. The separation of fatty acid oxidation in mitochondria from biosynthesis in the cytosol allows each process to be individually controlled and integrated with tissue requirements. Each step in fatty acid oxidation involves acyl-CoA derivatives catalyzed by separate enzymes, utihzes NAD and FAD as coenzymes, and generates ATP. It is an aerobic process, requiring the presence of oxygen. 

Figure 16.5 Effect of malonyl-CoA on the glucose/fatty acid cycle. Malonyl-CoA is an inhibitor of fatty acid oxidation, so that it decreases fatty acid oxidation in muscle and thus facilitates glucose utilisation (See Figure 7.14). Malonyl-CoA is formed from acetyl-CoA via the enzyme acetyl-CoA carboxylase, which is activated by insulin. Insulin therefore has three separate effects to stimulate glucose utilisation in muscle.

These organelles are the sites of energy production of aerobic cells and contain the enzymes of the tricarboxylic acid cycle, the respiratory chain, and the fatty acid oxidation system. The mitochondrion is bounded by a pair of specialized membranes that define the separate mitochondrial compartments, the internal matrix space and an intermembrane space. Molecules of 10,000 daltons or less can penetrate the outer membrane, but most of these molecules cannot pass the selectively permeable inner membrane. By a series of infoldings, the internal membrane forms cristae in the matrix space. The components of the respiratory chain and the enzyme complex that makes ATP are embedded in the inner membrane as well as a number of transport proteins that make it selectively permeable to small molecules that are metabolized by the enzymes in the matrix space. Matrix enzymes include those of the tricarboxylic acid cycle, the fatty acid oxidation system, and others. 

This separation is necessary for energetic reasons, as will be evident in subsequent chapters. It also facilitates the control of metabolism. In eukaryotes, metabolic regulation and flexibility also are enhanced by compartmentalization. For example, fatty acid oxidation takes place in mitochondria, whereas fatty acid synthesis takes place in the cytosol. 

Majority of fatty acids exist in the form of glycerol ester and these constitute a major esterified to glycerol fraction of fats of oils. As an example, in palm oil, the natural mixture of fatty acids is separated into two fractions, namely olein, which contains the lowest possible amount of saturated fatty acids, and stearin, which contains the lowest possible amount of unsaturated fatty acids. Independent of the process of separation employed, the starting mixture of fatty acids or feed stock should meet certain specifications. A high-quality product with undamaged fatty acids (e.g., less oxidation, minimum isomerization) and fatty acids in the form of mono-, di-, or triacylglycerols, or salts of fatty acids with minimum amount of impurities is necessary for the feed stock (1). 

Figure 5. The data show how patients with confirmed or suspected defects of the mitochondrial respiratory chain can be separated from patients with confirmed long chain fatty acid oxidation defects (data from Figure 4 plus 8 cases of LCHAD). In each case the release of H O from [9,10- H)myristate, [9,10- H]palmitate and [9,10- H]oleate was determined in parallel with at least 3 unaffected cell lines (not all control data plotted). All determinations were in duplicate and the activities for the individual cell lines are expressed as a proportion of the assay mean.

In another respect the physical separation of the initial activation step from the subsequent oxidative steps in fatty acid oxidation enables the partitioning of acyl Co As between the esterification pathway (cyto-... 

Secondary alcohols (C q—for surfactant iatermediates are produced by hydrolysis of secondary alkyl borate or boroxiae esters formed when paraffin hydrocarbons are air-oxidized ia the presence of boric acid [10043-35-3] (19,20). Union Carbide Corporation operated a plant ia the United States from 1964 until 1977. A plant built by Nippon Shokubai (Japan Catalytic Chemical) ia 1972 ia Kawasaki, Japan was expanded to 30,000 t/yr capacity ia 1980 (20). The process has been operated iadustriaHy ia the USSR siace 1959 (21). Also, predominantiy primary alcohols are produced ia large volumes ia the USSR by reduction of fatty acids, or their methyl esters, from permanganate-catalyzed air oxidation of paraffin hydrocarbons (22). The paraffin oxidation is carried out ia the temperature range 150—180°C at a paraffin conversion generally below 20% to a mixture of trialkyl borate, (RO)2B, and trialkyl boroxiae, (ROBO). Unconverted paraffin is separated from the product mixture by flash distillation. After hydrolysis of residual borate esters, the boric acid is recovered for recycle and the alcohols are purified by washing and distillation (19,20). 

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. 

Examples of such intra cellular membrane transport mechanisms include the transfer of pyruvate, the symport (exchange) mechanism of ADP and ATP and the malate-oxaloacetate shuttle, all of which operate across the mitochondrial membranes. Compartmentalization also allows the physical separation of metabolically opposed pathways. For example, in eukaryotes, the synthesis of fatty acids (anabolic) occurs in the cytosol whilst [3 oxidation (catabolic) occurs within the mitochondria. 

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