Reductive processing, fatty acid synthase

This four-step cycle includes condensation of acetate and malonate to give ketobu-tanoate with subsequent reduction to butanoate in three further steps. These are reduction to the 3R hydroxy acid, dehydration to the 2t acid, and reduction again. Reduction is affected by NADPH and a proton. The process is then repeated to add further two-carbon units until a thioesterase liberates the free acid. This sequence requires a fatty acid synthase, which contains the enzymes needed for each of the four steps viz. p-ketoacyl-ACP synthase, p-ketoacyl-ACP reductase, p-ketoacyl-ACP dehydrase, and enoyl-ACP reductase, respectively. 

The subsequent series of reactions that lead eventually to the formation of palmitate in mammals are carried out by a multienzyme complex known as fatty acid synthase. The initial two carbons, which eventually form C-15 and C-16 of palmitate, are supplied in the form of acetyl-CoA which acts as a primer for the subsequent condensation of malonyl-CoA units which lose CO2 in the process. The hydrogens required for the reductive reactions are all supplied by NADPH and the overall process may be represented as follows ... 

The basic principle of polyketide assembly is highly related to that of fatty acid biosynthesis [14, 16]. In both biosynthetic systems, an acyl-primed ketosynthase (KS) catalyzes chain extension by decarboxylative Claisen condensation with malonate activated by its attachment to coenzyme A or an acyl carrier protein (ACP) via a thioester bond (Scheme 2.2). hi fatty acid synthases (FASs), the resulting ketone is rednced to the corresponding alcohol by a ketore-ductase (KR), dehydrated by action of a dehydratase (DH) to give the alkene with snbseqnent donble-bond reduction by an enoyl rednctase (ER) yielding the saturated system (cf. Section 3.2). The latter can then be transferred onto the KS domain and enter the next cycle of chain extension and complete rednction. This homologation process facilitates the assembly of long-chain satnrated fatty acids, for example, palmitic acid, after seven cycles, which will ultimately be released from the catalytic system by saponification of the... 

Figure 6 Fatty-acid biosynthesis. Cytoplasmic acetyl-CoA (AcCoA) is the primary substrate for de novo fatty-acid synthesis. This two-carbon compound most commonly derives from the glycolytic degradation of glucose, and its formation is dependent upon several reactions in the mitochondria. The mitochondrial enzyme pyruvate carboxylase is found primarily in tissues that can synthesize fatty acids. AcCoA is converted to maionyl-CoA (MalCoA) by acetyl-CoA carboxylase. Using AcCoA as a primer, the fatty-acid synthase multienzyme complex carries out a series of reactions that elongate the growing fatty acid by two carbon atoms. In this process MalCoA condenses with AcCoA, yielding an enzyme-bound four-carbon /3-ketoacid that is reduced, dehydrated, and reduced again. The product is enzyme-bound 4 0. This process is repeated six more times, after which 16 0 is released from the complex. The reductive steps require NADPH, which is derived from enzyme reactions and pathways shown in grey. Enz refers to the fatty acid synthase multienzyme complex.

In genetically normal people, fasting results in a reduction of fatty acid synthase activity with loss of the coenzyme of ACP, which thus achieves the desired objective of a shift away from fatty acid synthesis, towards breakdown. This interconversion of apo-ACP and holo-ACP is thus a very important process for the short-term regulation of fatty acid synthesis. 

In fatty acid synthesis or degradation (Fig. 4), once the substrate is in the form of alkanoyl-CoA, a two-step process involving a 3-ketoacyl-CoA reductase and a PHA synthase occurs. The reduction step requires NADPH. A suitable supply of intracellular substrate appears to be the key factor controlling the rate of biosynthesis. If P. oleovorans is fed octanoate, it accumulates much more PHA than if hexanoate or dodecanoate are added. Nevertheless, the S5mthase is relatively nonspecific. P. oelovorans can accumulate polymers in which the side chain of the monomers contain double bonds, branches, cyclic structures, or even halogen atoms if the appropriate substrate is supplied. 

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