Fatty Branched oxidation

Know pathways of triglyceride biosynthesis and catabolism, the /3-oxidative pathway, and pathways for the degradation of pro-pionyl-CoA, branched fatty acids, and unsaturated fatty acids identify cofactors required calculate ATP yields for fatty acid oxidation know the identity of key enzymes in each pathway. 

The degradation of the hranched-chain amino acids employs reactions that we have encountered previously in the citric acid cycle and fatty acid oxidation. Leucine is transaminated to the corresponding a-ketoacid, a-ketoisocaproate. This a-ketoacid is oxidatively decarboxylated to isovaleryl CoA by the branched-chain a-ketoacid dehydrogenase complex. 

Isoleucine is a good example of branched-chain amino acids for a semi-in-depth examination. Unique aspects of the metabolism of valine and leucine are highlighted. After transamination and oxidative decarboxylation to form the branched-chain fatty-acyl CoA, a double bond is formed between a and b carbons utilizing FAD then water is added to form a b hydroxy derivative (Fig. 18.4). Then a NAD+-dependent dehydrogenase produces a keto derivative of the branched-chain fatty-acyl CoA. The similarity to straight-chain fatty-acid oxidation should be noted. This keto fragment is cleaved with participation of coenzyme A to form acetyl CoA, which ei-... 

In addition to the four acyl-CoA dehydrogenases involved in fatty acid oxidation, three acyl-CoA dehydrogenases specific for metabolites of branched-chain amino acids have been characterized, niey are isovaleryl-CoA dehydrogenase, 2-methyl-branched-chain acyl-CoA dehydrogenase, and isobutyryl-CoA dehydrogenase, which may also function in the P-oxidation of branched-chain carboxylic acids. 

Interestingly, fatty add oxidation studies in fibroblasts from our patient revealed deficient oxidation of both straight-chain as well as 2-methyl-branched fatty acids (C26 0 and pristanic acid, respectively). These data suggest that the D-bifimctional protein may also be the primary hydratase/dehydrogenase involved in C26 0 p-oxidation. This is now under active study. 

In conclusion, ESI/MS/MS of plasma or serum samples is a suitable and rapid technique for detecting defects in the catabolism of branched-chain amino acids and defects in mitochondrial fatty-acid oxidation with a high sensitivity and accuracy. 

Intracellular Distribution of Fatty Acid Oxidation Branched Fatty Acid Oxidation a- and cu-Oxidations... 

Recently, Whitehouse et al. [357] reported on some effects of SK F-525 and metyrapone (CLV) on hpid oxidation in vitro with mouse hver mitochondria. SK Sc F-525 was found to stimulate fatty acid oxidation and to have no effect on branched chain fatty acid oxidation, while metyrapone did not affect fatty acid oxidation but enhanced branched chain fatty acid oxidation. Both compounds were found to inhibit the oxidation of 26-hydroxy- and 7a-hydroxy-cholesterol to COg with comparable effectiveness [357]. Netter and his associates [358] have shown that metyrapone decreased the rate of hepatic drug hydroxyla-tions in vitro and in vivo. 

The free radical reaction may be accelerated and propagated via chain branching or homolytical fission of hydroperoxides formed to generate more free radicals (equations (11.4), (11.5)). Free radicals formed can initiate or promote fatty acid oxidation at a faster rate. Thus, once initiated, the free radical reaction is self-sustaining and capable of oxidizing large amounts of lipids. On the other hand, the free radical chain reaction may be terminated by antioxidants (AH) such as vitamin E (tocopherols) that competitively react with a peroxy radical and remove a free radical from the system (equation (11.6)). Also, the chain reaction may be terminated by self-quenching or pol)rmerization of free radicals to form non-radical dimers, trimers and polymers (equation (11.7)). 

An example of sensitive regulation at a branch point may be provided by the pathways of fatty acid utilization and oxidation in tissues. An increase in the extracellular long-chain fatty acid concentration results in many mammalian tissues in an increase in the rate of fatty acid oxidation. This is considered to be important in providing an alternative fuel for the tissue when the carbohydrate stores of the body are being depleted. Nonetheless the rate of fatty acid oxidation should also be controlled by the tissue in response to the demand for ATP this could be produced by... 

If the direct feedback link is strong, so that the flux is very sensitive to regulators of the tricarboxylic acid cycle, the flux will not be sensitive to changes in extracellular fatty acid concentration, resulting from increased mobilization from the adipose tissue reserves. This would be unfortunate since the extracellular fatty acid concentration is an important signal for tissues to increase their rate of fatty acid oxidation when carbohydrate stores are being depleted (carbohydrate stress). However, if a branch point exists at the level of acetyl-CoA, the resulting branched system provides feedback indirectly, as discussed in Section II. [Such a branch could be the pathway that produces ketone bodies (in the liver) or deacylation to acetate which may occur in some tissues—see Knowles et al. (28) and Buckley and Williamson (6). ... 

The basic flow sheet for the flotation-concentration of nonsulfide minerals is essentially the same as that for treating sulfides but the family of reagents used is different. The reagents utilized for nonsulfide mineral concentrations by flotation are usually fatty acids or their salts (RCOOH, RCOOM), sulfonates (RSO M), sulfates (RSO M), where M is usually Na or K, and R represents a linear, branched, or cycHc hydrocarbon chain and amines [R2N(R)3]A where R and R are hydrocarbon chains and A is an anion such as Cl or Br . Collectors for most nonsulfides can be selected on the basis of their isoelectric points. Thus at pH > pH p cationic surfactants are suitable collectors whereas at lower pH values anion-type collectors are selected as illustrated in Figure 10 (28). Figure 13 shows an iron ore flotation flow sheet as a representative of high volume oxide flotation practice. 

Although /3-oxidation is universally important, there are some instances in which it cannot operate effectively. For example, branched-chain fatty acids with alkyl branches at odd-numbered carbons are not effective substrates for /3-oxidation. For such species, a-oxidation is a useful alternative. Consider phy-tol, a breakdown product of chlorophyll that occurs in the fat of ruminant animals such as sheep and cows and also in dairy products. Ruminants oxidize phytol to phytanic acid, and digestion of phytanic acid in dairy products is thus an important dietary consideration for humans. The methyl group at C-3 will block /3-oxidation, but, as shown in Figure 24.26, phytanic acid a-hydroxylase places an —OFI group at the a-carbon, and phytanic acid a-oxidase decar-boxylates it to yield pristanie add. The CoA ester of this metabolite can undergo /3-oxidation in the normal manner. The terminal product, isobutyryl-CoA, can be sent into the TCA cycle by conversion to succinyl-CoA. 

FIGURE 24.26 Branched-chain fatty acids are oxidized by o -oxidation, as shown for phytanic acid. The product of the phytanic acid oxidase, pristanic acid, is a suitable substrate for normal /3-oxidation. Isobutyryl-CoA and propionyl-CoA can both be converted to suc-cinyl-CoA, which can enter the TCA cycle. 

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