Biosynthesis of saturated fatty acids

The synthesis of saturated fatty acids is very similar in all organisms. The overall reaction for the formation of palmitic acid is 

Reactions catalyzed by acetyl-CoA carboxylase. In E. coli, BCCP and the two enzymatic activities (biotin carboxylase and carboxyltransferase) can be separated from each other. In contrast, in the liver all three components exist on a single multifunctional polypeptide. 

Structure of A -carboxybiotin linked to biotin carboxyl carrier protein (BCCP). BCCP is one of the components of acetyl-CoA carboxylase isolated from E. coli. 

Comparing this equation with the equation for the complete oxidation of palmitoyl-CoA (see table 18.1, equation 1), we find major differences in carriers and intermediates. The principal electron carrier in the anabolic pathway is the NADPH-NADP+ system in the catabolic pathway, /3 oxidation, the principal electron carriers are FAD-FADH2 and NAD+-NADH. The second striking difference between the two pathways is that malonyl-CoA is the principal substrate in the anabolic pathway but plays no role in the catabolic pathway. These differences reflect the fact that the two pathways do not share common enzymes. Indeed, in animal cells the reactions occur in separate cell compartments biosynthesis takes place in the cytosol, whereas catabolism occurs in the mitochondria. 

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Once an enzyme-catalysed reaction has occurred the product is released and its engagement with the next enzyme in the sequence is a somewhat random event. Only rarely is the product from one reaction passed directly onto the next enzyme in the sequence. In such cases, enzymes which catalyse consecutive reactions, are physically associated or aggregated with each other to form what is called a multi enzyme complex (MEC). An example of this arrangement is evident in the biosynthesis of saturated fatty acids (described in Section 6.30). Another example of an organized arrangement is one in which the individual enzyme proteins are bound to membrane, as for example with the ATP-generating mitochondrial electron transfer chain (ETC) mechanism. Intermediate substrates (or electrons in the case of the ETC) are passed directly from one immobilized protein to the next in sequence. 

Figure 17-12 The reactions of cytoplasmic biosynthesis of saturated fatty acids. Compare with pathway of (3 oxidation (Fig. 17-1).

Fatty Acid Oxidation Yields Large Amounts of ATP Additional Enzymes Are Required for Oxidation of Unsaturated Fatty Acids in Mitochondria Ketone Bodies Formed in the Liver Are Used for Energy in Other Tissues Summary of Fatty Acid Degradation Biosynthesis of Saturated Fatty Acids... 

Fig. 2.13 Biosynthesis of saturated fatty acids in plants and animals. Palmitate is formed by successive additions of malonyl coenzyme A to the enzyme-bound chain, with C02 being lost at each addition.This results in chain elongation by a (CH2)2 unit at each step. Details of the formation of butyryl (C4) from acetyl (C2) are shown, while the subsequent six further additions, terminating in palmitate, proceed similarly.

Lynen, F. Biosynthesis of saturated fatty acids. Fed. Proc. 1961,20, 941-951. 

This section will define the reactions involved in the formation of palmitic and stearic acids. A review by Stumpf (1977) examines the biosynthesis of saturated fatty acids in plants. More specialized reviews are those of Givan and Harwood (1976) and those found in Recent Advances in the Chemistry and Biochemistry of Plant Lipids, edited by Galliard and Mercer (1975). An excellent although somewhat out-of-date monograph on plant lipids by Hitchcock and Nichols (1971) is a source of much information. 

After the enzymatic mechanism of /S-oxidation was elucidated, it has been assumed, that the biosynthesis of saturated fatty acids may proceed by a reversal of the jS-oxidation starting from acetate. 

Stumpf PK. The biosynthesis of saturated fatty acids. In Stumpf PK, Conn EE, editors. The Biochemistry of Plants A comprehensive treatise, vol 9. New York Academic Press, 1987 121-157. Harwood JL. Fatty acid metabolism. Annu Rev Plant Physiol Mol Biol 1988 39 101-138. 

The biosynthesis of saturated fatty acids has been extensively studied over the years. Already in 1907, Raper reported that fatty acids most likely were derived from a precursor [3]. In 1944, isotopically labeled compounds became available, and Rittenberg and Bloch fed rats with labeled acetate and concluded that fatty acids were indeed synthesized by successive condensation of units. They suspected that the actual metabolic intermediate was an activated form of acetate [4]. Finally, in 1948, Lipmann and... 

The Fatty Acid Synthase Enzyme Systems The FAS enzyme systems are central for the biosynthesis of saturated fatty acids [1] and share many similarities with the polyketide synthases (PKSs) involved in the biosynthesis of many polyketides [6] see Section 2.1 for details. Common precursors, functional gronps, and reactions are involved in each biosynthetic step. Saturated fatty acids, such as palmitic acid (1, Scheme 3.2), represent a rather small and structurally simple class of natural products produced by the FAS enzyme systems. The FAS enzyme system in animals is a large multifunctional protein with seven individnal... 

To summarize, all catalytic domains necessary for the biosynthesis of saturated fatty acid, such as palmitic acid (1), are distributed on two multidomain polypeptides in fungi, while in animals the domains are on a single polypeptide. These features ensure the efficient shuttle of substrates by ACP during the biosynthesis of fatty acids. Amazingly, the iterative animal FAS complex, involved in seven condensation reactions and 21 p-carbon processing steps, produces the C16 fatty acid 1 in less than a second. 

Biosynthesis of saturated fatty acids de novo synthesis by acetyl-CoA carboxylase and fatty acid synthetase and elongation reactions for pre-formed acids... 

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