Anabolism of Fatty Acids

The anabolism of fatty acids is not simply a reversal of the reactions of P-oxidation. Anabolism and catabolism are not, in general, the exact reverse of each other for instance, gluconeogenesis (Section 18.2) is not simply a reversal of the reactions of glycolysis. A hrst example of the differences between the degradation and the biosynthesis of fatty acids is that the anabolic reactions take place in the cytosol. We have just seen that the degradative reactions of P-oxidation take place in the mitochondrial matrix. The first step in fatty-acid biosynthesis is transport of acetyl-GoA to the cytosol. 

The conversion of three acetyl groups of acetyl-CoA to mevalonate takes place in several steps (Figure 21.26). We already saw the first of these steps, the production of acetoacetyl-CoA from two molecules of acetyl-CoA, when we discussed the formation of ketone bodies and the anabolism of fatty acids. A third molecule of acetyl-GoA condenses with acetoacetyl-GoA to produce -hydroxy- -methylglutaryl-CoA (also called HMG-GoAand 3-hydroxy-3-methylglutaryl-GoA). 

How do the first steps of fatty-acid synthesis take place The anabolism of fatty acids proceeds by a different pathway from P-oxidation. Acetyl-GoA is transported to the cytosol, where it is converted to malonyl-GoA. Some of the most important differences between the fatty-acid anabolism and catabolism are the requirement for biotin in anabolism, but not in catabolism, and the requirement for NADPH in anabolism, rather than the NAD required in catabolism. 

The one-carbon unit transferred in this reaction is bound to tetrahydrofolate, forming A ,A/ °-methylenetetrahydrofolate, in which the methylene (one-carbon) unit is bound to two of the nitrogens of the carrier (Figure 23.12). Tetrahydrofolate is not the only carrier of one-carbon units. We have already encountered biotin, a carrier of GOg, and we have discussed the role that biotin plays in gluconeogenesis (Section 18.2) and in the anabolism of fatty acids (Section 21.6). 

The molecular mechanism of fatty acid synthesis can best be understood if the anabolism of fatty acid is first examined in bacteria. The fatty acid synthetase complex of bacteria presents two major advantages it is readily solubilized, and it can be resolved into separate protein components. Three major stages of fatty acid synthesis can be described. First, acetyl-CoA reacts with an SH protein to yield bound acetyl derivatives and free CoA. This reaction is catalyzed by a fatty acid transacylase. Second, the acetyl 5 -protein... 

Whereas catabolism is fundamentally an oxidative process, anabolism is, by its contrasting nature, reductive. The biosynthesis of the complex constituents of the cell begins at the level of intermediates derived from the degradative pathways of catabolism or, less commonly, biosynthesis begins with oxidized substances available in the inanimate environment, such as carbon dioxide. When the hydrocarbon chains of fatty acids are assembled from acetyl-CoA units, activated hydrogens are needed to reduce the carbonyl (C=0) carbon of acetyl-CoA into a —CHg— at every other position along the chain. When glucose is... 

As a rule, the anabolic pathway by which a substance is made is not the reverse of the catabolic pathway by which the same substance is degraded. The two paths must differ in some respects for both to be energetically favorable. Thus, the y3-oxidation pathway for converting fatty acids into acetyl CoA and the biosynthesis of fatty acids from acetyl CoA are related but are not exact opposites. Differences include the identity of the acvl-group carrier, the stereochemistry of the / -hydroxyacyl reaction intermediate, and the identity of the redox coenzyme. FAD is used to introduce a double bond in jS-oxidalion, while NADPH is used to reduce the double bond in fatty-acid biosynthesis. 

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. 

Thioesters play a paramount biochemical role in the metabolism of fatty acids and lipids. Indeed, fatty acyl-coenzyme A thioesters are pivotal in fatty acid anabolism and catabolism, in protein acylation, and in the synthesis of triacylglycerols, phospholipids and cholesterol esters [145], It is in these reactions that the peculiar reactivity of thioesters is of such significance. Many hydrolases, and mainly mitochondrial thiolester hydrolases (EC 3.1.2), are able to cleave thioesters. In addition, cholinesterases and carboxylesterases show some activity, but this is not a constant property of these enzymes since, for example, carboxylesterases from human monocytes were found to be inactive toward some endogenous thioesters [35] [146], In contrast, allococaine benzoyl thioester was found to be a good substrate of pig liver esterase, human and mouse butyrylcholinesterase, and mouse acetylcholinesterase [147],... 

The pentose phosphate pathway (PPP, also known as the hexose monophosphate pathway) is an oxidative metabolic pathway located in the cytoplasm, which, like glycolysis, starts from glucose 6-phosphate. It supplies two important precursors for anabolic pathways NADPH+H+, which is required for the biosynthesis of fatty acids and isopren-oids, for example (see p. 168), and ribose 5-phosphate, a precursor in nucleotide biosynthesis (see p. 188). 

The / -keto esters are reduced to the respective chiral ft -hydroxy esters by at least two alternative enzymes one of which is D-directing the other one is L-directing (Fig. 3.4). A product mixture results that contains both enantiomeric forms, d and i.,b of the carbinol (/1-hydroxy ester) in varying degrees. In the case of ethyl acetoacetate (1) preferably the L-form of ethyl 3-hydroxybutyrate (l-4) is produced which is then secreted from the cell [55-58]. The L-directing enzyme is methyl butyralde-hyde reductase (MBAR EC 1.1.1.265), and the D-enantiomer is formed by the action of /J-ketoacyl reductase (KAR EC 1.1.1.100) which is a constituent of fatty acid anabolism (Fig. 3.4) [49, 59]. Alcohol dehydrogenase (ADH EC 1.1.1.1) L-directing activity is classically attributed to was shown to be inactive - moreover the enzyme is even inhibited by the substrate [2, 34, 37]. 

In some cases, acyl-CoA conjugates formed from xenobiotic acids can also enter the physiological pathways of fatty acids catabolism or anabolism. A few examples are known of xenobiotic alkanoic and arylalkanoic acids undergoing two-carbon chain elongation or two-, four- or even six-carbon chain shortening. In addition, intermediate metabolites of (3-oxidation may be seen, as illustrated in Figure 32.10 with valproic acid, whose acyl-CoA intermediate (22) is a substrate for some first steps of 3-oxidation. ... 

The citric acid cycle operates in both anabolic processes (e.g., the synthesis of fatty acids, cholesterol, heme, and glucose) and catabolic processes (e.g., amino acid degradation and energy production). 

Oxidation and 2-Carbon Chain Elongation. In some cases, acyl-CoA conjugates formed from xenobiotic acids can also enter the physiological pathways of fatty acids catabolism or anabolism. A few examples are known of xenobiotic alkanoic and arylalkanoic... 

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