Fatty acid degradation

Intermediates in fatty acid synthesis are linked covalently to the suifhydryl groups of special proteins, the acyl carrier proteins. In contrast, fatty acid breakdown intermediates are bound to the —SH group of coenzyme A. Fatty acid synthesis occurs in the cytosol, whereas fatty acid degradation takes place in mitochondria. 

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. 

There is evidence from a number of in vitro studies that the vitamin E peroxyl radical formed during fatty-acid degradation may be converted to vitamin E plus nonradical through the actions of vitamin C (Burton et al., 1985). RA patients have reduced serum ascorbate levels (Situnayake et al., 1991) and potentially a reduced capacity for the regeneration of vitamin E. In vitro studies suggest that vitamin E becomes a pro-oxidant when ascorbate levels are low (Bowry and Stocker, 1993). 

Fatty acid degradation Source of energy and metabolites for other pathways CoA, NADH... 

Fatty acid degradation involves a reverse Claisen... 

By contrast, acetyl CoA does not have anaplerotic effects in animal metabolism. Its carbon skeleton is completely oxidized to CO2 and is therefore no longer available for biosynthesis. Since fatty acid degradation only supplies acetyl CoA, animals are unable to convert fatty acids into glucose. During periods of hunger, it is therefore not the fat reserves that are initially drawn on, but proteins. In contrast to fatty acids, the amino acids released are able to maintain the blood glucose level (see p. 308). 

The tricarboxylic acid cycle not only takes up acetyl CoA from fatty acid degradation, but also supplies the material for the biosynthesis of fatty acids and isoprenoids. Acetyl CoA, which is formed in the matrix space of mitochondria by pyruvate dehydrogenase (see p. 134), is not capable of passing through the inner mitochondrial membrane. The acetyl residue is therefore condensed with oxaloacetate by mitochondrial citrate synthase to form citrate. This then leaves the mitochondria by antiport with malate (right see p. 212). In the cytoplasm, it is cleaved again by ATP-dependent citrate lyase [4] into acetyl-CoA and oxaloacetate. The oxaloacetate formed is reduced by a cytoplasmic malate dehydrogenase to malate [2], which then returns to the mitochondrion via the antiport already mentioned. Alternatively, the malate can be oxidized by malic enzyme" [5], with decarboxylation, to pyruvate. The NADPH+H formed in this process is also used for fatty acid biosynthesis. 

Fat synthesis in the liver (right). Fatty acids and fats are mainly synthesized in the liver and in adipose tissue, as well as in the kidneys, lungs, and mammary glands. Fatty acid biosynthesis occurs in the cytoplasm—in contrast to fatty acid degradation. The most important precursor is glucose, but certain amino acids can also be used. 

The next step in fatty acid degradation is the addition of a water molecule to the double bond of the enoyl CoA hydration), with formation of p-hydroxyacyl CoA. 

The carnitine shuttle is the rate-determining step in mitochondrial fatty acid degradation. Malonyl CoA, a precursor of fatty acid biosynthesis, inhibits carnitine acyltransferase (see p. 162), and therefore also inhibits uptake of fatty acids into the mitochondrial matrix. 

Unsaturated fatty acids usually contain a cis double bond at position 9 or 12—e.g., linoleic acid (18 2 9,12). As with saturated fatty acids, degradation in this case occurs via p-oxida-tion until the C-9-ds double bond is reached. Since enoyl-CoA hydratase only accepts substrates with trans double bonds, the corresponding enoyl-CoA is converted by an iso-merase from the ds-A, cis- A isomer into the trans-A, cis-A isomer [1]. Degradation by p-oxidation can now continue until a shortened trans-A, ds-A derivative occurs in the next cycle. This cannot be isomerized in the same way as before, and instead is reduced in an NADPH-dependent way to the trans-A compound [2]. After rearrangement by enoyl-CoA isomerase [1 ], degradation can finally be completed via normal p-oxidation. 

Enzyme defects are also known to exist in the minor pathways of fatty acid degradation. In Refsum disease, the methyl-branched phytanic acid (obtained from vegetable foods) cannot be degraded by a-oxidation. In Zellweger syndrome, a peroxisomal defect means that long-chain fatty acids cannot be degraded. 

In eukaryotes, the cytoplasm, representing slightly more than 50% of the cell volume, is the most important cellular compartment. It is the central reaction space of the cell. This is where many important pathways of the intermediary metabolism take place—e.g., glycolysis, the pentose phosphate pathway, the majority of gluconeogenesis, and fatty acid synthesis. Protein biosynthesis (translation see p. 250) also takes place in the cytoplasm. By contrast, fatty acid degradation, the tricarboxylic acid cycle, and oxidative phosphorylation are located in the mitochondria (see p. 210). 

Parallel Pathways for Amino Acid and Fatty Acid Degradation The carbon skeleton of leucine is degraded by a series of reactions closely analogous to those of the citric acid cycle and j8 oxidation. For each reaction, (a) through (f), indicate its type, provide an analogous example from the citric acid cycle or /3-oxidation pathway (where possible), and note any necessary cofactors. 

During a fast, the liver is flooded with fatty acids mobilized from adipose tissue. The resulting elevated hepatic acetyl CoA produced primarily by fatty acid degradation inhibits pyruvate dehydrogenase (see p. 108), and activates pyruvate carboxylase (see p. 117). The oxaloacetate thus produced is used by the liver for gluconeogenesis rather than for the TCA cycle. Therefore, acetyl Co A is channeled into ketone body synthesis. 

When the rate of formation of ketone bodies is greater than the rate of their use, their levels begin to rise in the blood (ketonemia) and eventually in the urine (ketonuria). These two conditions are seen most often in cases of uncontrolled, type 1 (insulin-dependent) diabetes mellitus. In such individuals, high fatty acid degradation produces excessive amounts of acetyl CoA. It also depletes the NAD+ pool and increases the NADH pool, which slows the TCA cycle (see p. 112). This forces the excess acetyl CoA into the ketone body pathway. In diabetic individuals with severe ketosis, urinary excre-... 

Dehydrogenation Oxidation of the products formed in the above reaction yields a-p-unsaturated acyl CoA derivatives. This reac tion is analagous to the dehydrogenation described in the p-oxidation scheme of fatty acid degradation (see p. 190). 

Fatty acid degradation ((3-oxidation) occurs in mitochondria. The carnitine shuttle is... 

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