Enzyme of fatty acid synthesis

In animals, the enzymes of fatty acid synthesis are components of one long polypeptide chain, the fatty acid synthase, whereas no similar association exists for the degradative enzymes. (Plants and bacteria employ separate enzymes to carry out the biosynthetic reactions.)... 

Rittenberg and Bloch showed in the late 1940s that acetate units are the building blocks of fatty acids. Their work, together with the discovery by Salih Wakil that bicarbonate is required for fatty acid biosynthesis, eventually made clear that this pathway involves synthesis of malonyl-CoA. The carboxylation of acetyl-CoA to form malonyl-CoA is essentially irreversible and is the committed step in the synthesis of fatty acids (Figure 25.2). The reaction is catalyzed by acetyl-CoA carboxylase, which contains a biotin prosthetic group. This carboxylase is the only enzyme of fatty acid synthesis in animals that is not part of the multienzyme complex called fatty acid synthase. 

Both of the major enzymes of fatty acid synthesis are also affected by insulin ... 

As the name anaerobic implies, the double bond of the fatty acid is inserted in the absence of oxygen. Biosynthesis of monounsaturated fatty acids follows the pathway described previously for saturated fatty acids until the intermediate /3-hydroxydecanoyl-ACP is reached (fig. 18.15). At this point, a new enzyme, /3-hydroxydecanoyl-ACP dehydrase, becomes involved. This dehydrase can form the a-j8 trans double bond, and saturated fatty acid synthesis can occur as previously discussed. In addition, this dehydrase is capable of isomerization of the double bond to a cis /3-y double bond as shown in figure 18.15. The /3-y unsaturated fatty acyl-ACP is subsequently elongated by the normal enzymes of fatty acid synthesis to yield pal-mitoleoyl-ACP (16 1A9). The conversion of this compound to the major unsaturated fatty acid of E. coli, cA-vacccnic acid (18 1A11), requires a condensing enzyme that we have not previously discussed, /3-ketoacyl-ACP synthase II, which shows a preference for palmitoleoyl-ACP as a substrate. The subsequent conversion to vaccenyl-ACP is cata-... 

In this cycle, one molecule of acetyl-CoA is formed from two molecules of bicarbonate (Figure 3.5). The key carboxylating enzyme is the bifunctional biotin-dependent acetyl-CoA/propionyl-CoA carboxylase. In Bacteria and Eukarya, acetyl-CoA carboxylase catalyzes the first step of fatty acid biosynthesis. However, Archaea do not contain fatty acids in their lipids, and acetyl-CoA carboxylase cannot serve as the key enzyme of fatty acid synthesis rather, it is responsible for autotrophy. 

The enzymes of fatty acid synthesis in higher organisms are joined in a single polypeptide chain called fatty acid synthase. In contrast, the degradative enzymes do not seem to be associated. 

This last point is important because many of the enzymes of fatty acid synthesis require NADPH. The pentose phosphate pathway (Section 18.4) is the principal source of NADPH in most organisms, but here we have another source (Figure 19.14). 

The studies of the individual enzymes of fatty acid synthesis in higher plants has shown that the two reductive steps, p-ketoacyl ACP reductase and enoyl ACP reductase have different cofactor requirements. As a result the synthesis of fatty acids depends on the availability of both NADH and NADPH. While the provision of NADPH can be attributed to the photosynthetic reactions, the source of NADH in the chloroplast is less certain. Takahama etal (8) have demonstrated that the content of NADPH in the chloroplast is influenced by illumination as expected, but there is no such fluctuation of the oxidation state of NAD/NADH. The production of NADH to be utilized in fatty acid synthesis would therefore appear to depend on dark reactions. One possibility would be by the action of pyruvate dehydrogenase, which would generate not only the NADH required for reduction in fatty acid synthesis but also the precursor acetyl CoA. 

Murata M., Ide, T., and Hara, K. (1997) Reciprocal Responses to Dietary Diacylglycerol of Hepatic Enzymes of Fatty Acid Synthesis and Oxidation in the Rat, Br. J. Nutr. 77,107-121. 

Regulation of enzyme level serves as a coarse control over fatty acid synthesis. In response to changes in physiological state, the levels of the enzymes of fatty acid synthesis fluctuate coordinately. Fatty acid synthesis is also regulated by the direct action of metabolite effectors on key enzymes in the pathway. This means of control is more responsive to sudden alterations in cellular fatty acid requirements. In the case of the committed acetyl-CoA carboxylation step, citrate has been shown to be a positive feed-forward allosteric effector. Since this is the rate-determining step, activation by citrate can effectively adjust the rate of fatty acid synthesis to momentary fluctuations in cellular needs. 

Evidence for the pathways involved in the generation of acetyl-CoA and reducing equivalents for fatty acid synthesis has been obtained by studying the fluctuations in enzyme levels induced by changes in nutritional and hormonal state. The levels of these enzymes change coordinately along with the levels of the other enzymes of fatty acid synthesis, acetyl-CoA carboxylase and fatty acid synthetase, which is consistent with their role in the biosynthetic process. 

Acetoacetate Metabolism. An active deacylase in liver is responsible for the formation of free acetoacetate from its CoA derivative. The j8-hydroxybutyric dehydrogenase mentioned above and a decarboxylase are capable of converting acetoacetate into the other ketone bodies, /3-hydroxybutyrate, and acetone. liver does not contain a mechanism for activating acetoacetate. Heart muscle has been found to contain a specific thiophorase that forms acetoacetyl CoA at the expense of suc-cinyl CoA. Acetoacetate is thus used by peripheral tissues by activation through transfer, then reaction with either the enzymes of fatty acid synthesis or jS-ketothiolase and the enzymes that use acetyl CoA. 

Diets that are relatively rich in polyunsaturated fatty acids result in decreased synthesis of fatty acids in the liver (section 5.6.1) this means that there is less export of lipids from the liver in VLDL (section 5.6.2.2), which are the precursors of LDL in the circulation. Polyunsaturated fatty acids (or their derivatives) act via nuclear receptors (section 10.4) to reduce the transcription of the genes coding for acetyl CoA carboxylase and other key enzymes of fatty acid synthesis (section 5.6.1). 

The de novo synthesized fatty acids in Cuphea wrightii were predominantly of medium chain length and were mainly deposited in triglycerides of the embryo (up to 60 %). In Cuphea racemosa, in contrast,longer chain fatty acids were the major component and were found (up to 50 %) in polar lipids within both embryo and seed coat (Table 1).In order to get an idea for the different lipid synthesizing capacities in the seeds of both Cuphea species important substrate- (acetate and pyruvate) and cofactor concentrations (ATP and ADP) for key enzymes of fatty acid synthesis have been measured in seed extracts and... 

Buettner et al. (2006) demonstrated the ability of n-3 PUFAs from fish oil to suppress hepatic FAS. In this study, rats that were fed high-fat (42% energy) lard, olive oil or coconut oil diets for 12 weeks had increased hepatic FAS and stearoyl-CoA desaturase, which are major enzymes of fatty acid synthesis, however, in high-fat fish oil-fed rats, there was no upregulation of these genes compared to standard chow fed rats. 

Hiilsman et al. (1966) and Christ and Hiilsman (1962) even postulated that mitochondria would be a better site for fatty acid synthesis than the cytoplasm, and that the synthesizing activity of the cytoplasm is artificial because of the release of mitochondrial enzymes into the cytoplasm during centrifugation. These authors support the hypothesis that the enzymes of fatty acid synthesis could be located on the mitochondrial surface, lliffe and Myant (1964) agree with this concept. 

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