Chain elongation of fatty acids

Nugteren, D.H. (1965) The Enzymatic Chain Elongation of Fatty Acids by Rat-Liver Microsomes, fiioc/u tn. Biophys. Acta 106,280-290. 

Fig. 2. Pathway for the microsomal chain elongation of fatty acids.

Rates of Component Reactions in the Microsomal Chain Elongation of Fatty Acids Using Livers from Rats Raised on a Normal Chow or Fat Free Diet ... 

In summary, it is now clear that unsaturated fatty acids serve as substrates for the synthesis of a variety of different prostaglandins, hydroxy fatty acids, and leukotrienes. The types and amounts of these compounds produced will in part depend on what type of dietary fat is included in the diet. In turn, the factors regulating the desaturation and chain elongation of fatty acids for subsequent incorporation into and release from phospholipids will contribute in defining what types and amounts of prostaglandins are produced to mediate and control physiological processes. 

Further desaturation and acyl chain elongation of fatty acids are generally accepted to involve cytosolic membranous systems associated with the endoplasmic reticulum (Stumpf, 1989). A critical importance, therefore, would appear to exist for a detailed understanding of the mechanics by which the fatty acids are exported from the plastid. At present, there is little available information on the precise transport system or its regulation. Although fatty acids are presumed to be released on hydrolysis of acyl-ACPs by specific thioesterases, it is not known whether an initial formation of acyl-CoA is required prior to transport across the plastidic membrane in association with carnitine or some other system. A direct transacylation between ACP and CoA or some carrier system would be less expensive energetically than a process involving hydrolysis and synthesis. 

Kolattukudy P E, Buckner J S 1972 Chain elongation of fatty acids by cell-free extracts of epidermis from pea leaves Pisum sativum). Biochem Biophys Res Commun 46 801-807... 

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). 

Knudsen, J., Clark, S. and Dils, R. 1976. Purification and some properties of a medium chain hydrolase from lactating-rabbit mammary gland which terminates chain elongation in fatty acid synthesis. Biochem. J. 160, 683-691. 

The pathway The first committed step in fatty acid biosynthesis is the carboxylation of acetyl CoA to form malonyl CoA which is catalyzed by the biotin-containing enzyme acetyl CoA carboxylase. Acetyl CoA and malonyl CoA are then converted into their ACP derivatives. The elongation cycle in fatty acid synthesis involves four reactions condensation of acetyl-ACP and malonyl-ACP to form acetoacetyl-ACP releasing free ACP and C02, then reduction by NADPH to form D-3-hydroxybutyryl-ACP, followed by dehydration to crotonyl-ACP, and finally reduction by NADPH to form butyryl-ACP. Further rounds of elongation add more two-carbon units from malonyl-ACP on to the growing hydrocarbon chain, until the C16 palmitate is formed. Further elongation of fatty acids takes place on the cytosolic surface of the smooth endoplasmic reticulum (SER). 

In the final installment of this story to date, Matsuoka et al. (2008) determined that female A. selenaria cretacea contained (llZ,14Z,17Z)-eicosa-ll,14,17-trienoic acid but not the longer-chain (13Z,16Z,19Z)-docosa-13,16,19-trienoic acid, in line with the fact that the pheromone of this species consists of 3Z,6Z,9Z-19 H and a corresponding monoepoxide (Matsuoka et al., 2008). That is, this geometrid only requires a C20 fatty acid precursor to decarboxylate to its C19 pheromone compounds. In contrast, as mentioned above, the arctiid species Syntomoides imaon, which produces C2i triene and tetraene pheromone components, was found to contain both (llZ,14Z,17Z)-eicosa-ll,14,17-trienoic acid and the longer-chain (13Z,16Z,19Z)-docosa-13,16,19-trienoic acid (Matsuoka et al., 2008). That is, the arctiid species requires the C22 precursor in order to produce its C21 pheromone components by decarboxylation, whereas the geometrid species only requires the C20 precursor, because its pheromone is composed of the shorter-chain C19 compounds. These data suggest that the chain elongation of linolenic acid and related precursors is under precise control. 

First, the use of two specific reactions — All desaturation and controlled 2 carbon chain shortening of fatty acid precursors to account for the biosynthesis of a large number of pheromones — has been an extremely fruitful approach. Even in a case where it seemed uncertain if this approach was appropriate (22)r it turned out that it was (23.). Other reactions should now be added to increase the range of products accounted for. Examples already mentioned include the A10 desaturase and the chain elongation of branched-chain starting materials. Other functional groups that appear in sex pheromones should also be accounted for, such as epoxides. 

Several additional reactions are required for the elongation of fatty-acid chains and the introduction of double bonds. When mammals produce fatty acids with longer chains than that of pahnitate, the reaction does not involve cytosolic fatty-acid synthase. There are two sites for the chain-lengthening reactions the endoplasmic reticulum (ER) and the mitochondrion. In the chain-lengthening reactions in the mitochondrion, the intermediates are of the acyl-GoA type rather than the acyl-AGP type. In other words, the chainlengthening reactions in the mitochondrion are the reverse of the catabolic reactions of fatty acids, with acetyl-GoA as the source of added carbon atoms this is a difference between the main pathway of fatty-acid biosynthesis and these modification reactions. In the ER, the source of additional carbon atoms... 

Elongation of fatty acids is important in two commercial oil seeds, rape and jojoba. Most varieties of rape accumulate large quantities of d5-13-docosenoic (erucic) acid in their seed triacylglycerols. This is formed by elongation of oleic acid and the reactions have been studied in rape and the closely related Crambe abyssinica (Appleby etaL, 1974). Elongation in jojoba (which accumulates lipid as wax esters) uses a system with oleoyl-CoA and malonyl-CoA as substrates. The enzymes involved have been studied in jojoba and other plants where very-long-chain fatty acids are synthesized (Pollard and Stumpf, 1980). 

One cycle of chain elongation by fatty acid synthase... 

It is generally considered that there are three systems of fatty acid synthesis. The first, which is highly active, is centred in the cell cytoplasm and results mainly in the production of palmitate from acetyl-coenzyme A or butyryl-coenzyme A. Nearly all other fatty acids are produced by modification of this acid. The second system occurs chiefly in the endoplasmic reticulum and to a minor extent in the mitochondria. It involves elongation of fatty acid chains by two-carbon addition, with malonyl-CoA as donor. The third system, confined to the endoplasmic reticulum, brings about desaturation of preformed fatty acids. 

A mitochondrial system for elongation of fatty acid chains, using acetyl-CoA as the two-carbon donor does exist but has limited activity with acyl-CoA substrates with 16 or more carbon atoms and is probably concerned with the lengthening of shorter chains. 

The primary product synthesized by the de novo pathway is 16 0. While 16 0 is an important fatty acid, there is a need to synthesize longer-chain acids. Enzymes for elongation of fatty-acids have been found in membranes of the endoplasmic reticulum... 

Historically, many attempts have been made to systematize the arrangement of fatty acids in the glyceride molecule. The even (34), random (35), restricted random (36), and 1,3-random (37) hypotheses were developed to explain the methods nature utilized to arrange fatty acids in fats. Invariably, exceptions to these theories were encountered. Plants and animals were found to biosynthesize fats and oils very differently. This realization has led to closer examination of biosynthetic pathways, such as chain elongation and desaturation, in individual genera and species. 

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