Elongation of acyl chains

Four enzymes participate in each iterative cycle of chain elongation (Fig. 3). The acetoacyl-ACP formed from the initiating FabH condensation is reduced by an NADPH-dependent P-ketoacyl-ACP reductase (fabG), and a water molecule is then removed by a P-hydroxyacyl-ACP dehydrase (fabA otfabZ). The last step is catalyzed by enoyl-ACP reductase (fabl or fabK) to form a saturated acyl-ACP, which serves as the substrate for another condensation reaction or when the chain length reaches 16-18 carbons is utilized for membrane phospholipid synthesis. p-Ketoacyl-ACP synthase I or II (fabB or fabF) initiates additional 

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The biosynthesis of hydrocarbons occurs by the microsomal elongation of straight chain, methyl-branched and unsaturated fatty acids to produce very long-chain fatty acyl-CoAs (Figure 11.1). The very long chain fatty acids are then reduced to aldehydes and converted to hydrocarbon by loss of the carboxyl carbon. The mechanism of hydrocarbon formation has been controversial. Kolattukudy and coworkers have reported that for a plant, an algae, a vertebrate and an insect, the aliphatic aldehyde is decarbonylated to the hydrocarbon and carbon monoxide, and that this process does not require cofactors (Cheesbrough and Kolattukudy, 1984 1988 Dennis and Kolattukudy, 1991,1992 Yoder et al., 1992). In contrast, the Blomquist laboratory has presented evidence that the aldehyde is converted to hydrocarbon and carbon dioxide in a process that... 

Figure 22.24. Reactions of Fatty Acid Synthase. Translocations of the elongating fatty acyl chain between the cysteine...

Three forms of 3-ketoacyl-ACP synthase have been discovered in plants. These forms may be distinguished by their substrate specificity they are homodimers with molecular weights of 43,000 to 45,000 per subunit. One, KAS III, appears to be responsible for the first condensation of acetyl-CoA and malonyl-ACP (Browse and Somerville, 1991 Ohlrogge et al., 1993). The activity of this enzyme in plants seems to bypass the need for acetyl-ACP, although that molecule is formed and accumulated in some plants (Ohlrogge et al., 1993). KAS I or 3-ketoacyl-ACP synthase elongates the acyl chain to palmitoyl-ACP, whereas KAS II converts palmitoyl-ACP to stearoyl-ACP (Ohlrogge et al., 1993). 

Chain elongation pathway is another route via which MCL-PHA precursors can be generated from non-related carbon sources by extending the acetyl CoA to acyl CoA. MCL-PHA precursors generated by the elongation of acyl CoA derived from fatty acids in this pathway is significant however, it only forms a minute fraction of the pathway used for the total PHA accumulation within the bacteria. The final step which involves the polymerisation of the (/J)-3-hydroxyacyl CoA into poly-(ff)-3-hydroxyacyl CoA is catalysed by the PHA synthase enzyme with the concomitant release of CoA (Zinn et al., 2001). 

Fatty acid desaturation, a second major source of variation in the phylogenetic distribution of fatty acids, has been reviewed in detail (294-302). Some bacteria have a unique anaerobic system for production of monounsaturated fatty acids. This mechanism is involved in elongation of medium-chain length c/.r-3-unsaturated fatty acyl intermediates, and functions via P,y-dehydration of P-OH intermediates. It should be noted that this process cannot generate methylene-interrupted polyunsaturated fatty acids. 

The acylation of enamines has been applied to the use of long-chain acid chlorides (388) and particularly to the elongation of fatty acids (389-391) and substituted aliphatic acids (392). The method has been used in the synthesis of the antineoplastic cycloheximide and related compounds (393-395) and in the acylation of steroids (396). Using an optically active chlorocarbonate, an asymmetric synthesis of lupinine could be achieved (397). 

There s a lot of shuffling of acyl groups between the pantetheine thiol and the thiol of a cysteine residue of the enzyme. They re shown in the correct position for all the reactions, so you have to do an acyl transfer at the end of each cycle to put the growing acyl chain back on the cysteine residues. The elongation step takes place with the growing acyl chain on cysteine and the malonyl-CoA on the pantetheine. At the end of the condensation reaction, the elongated chain is on the pantetheine. 

The elongation of the fatty acid by fatty acid synthase concludes at Cie, and the product, palmitate (16 0), is released. Unsaturated fatty acids and long-chain fatty acids can arise from palmitate in subsequent reactions. Fats are finally synthesized from activated fatty acids (acyl CoA) and glycerol 3-phosphate (see p. 170). To supply peripheral tissues, fats are packed by the hepatocytes into lipoprotein complexes of the VLDL type and released into the blood in this form (see p. 278). 

The conversion of oleoyl-CoA to linoleoyl-CoA is accomplished by some insects118 but does not take place in most animals. As a result of this biosynthetic deficiency, polyunsaturated fatty acids such as linoleic, linolenic, and the C20 arachidonic acid are necessary in the diet (Box 21-B). One essential function of linoleic acid is to serve as a precursor of prostaglandins and related prostanoids (Section D). Dietary linoleate is converted to its Co A derivative and then by sequential A6 desaturation,119 elongation, and then A5 desaturation, to the 20 4 (A5 8 11 14) arachidonoyl-CoA (Fig. 21-2, lower right). These acids are referred to as 0)6 because of the position of the last double bond. Linolenic acid can be converted in an analogous fashion to the CoA derivative of the 20 5 (A5 8 11 14 17 co6) eicosapentaenoic acid (EPA). The 22 6 docasahexaenoic acid (DHA Fig. 21-2) is apparently formed by elongation of the 22 5 acyl-CoA to 24 5, desaturation, transfer to a peroxisome or mitochondrion, and p oxidation to shorten the chain.953... 

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