Elongation of 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). 

FIGURE 25.12 Elongation of fatty acids in mitochondria is initiated by the thiolase reaction. The /3-ketoacyl intermediate thus formed undergoes the same three reactions (in reverse order) that are the basis of /3-oxidation of fatty acids. Reduction of the /3-keto group is followed by dehydration to form a double bond. Reduction of the double bond yields a fatty acyl-CoA that is elongated by two carbons. Note that the reducing coenzyme for the second step is NADH, whereas the reductant for the fourth step is NADPH. 

Chapter 19) Adrenal cortex Liver Fatty acid synthesis Elongation of fatty acids (Chapter 11) Desaturation of fatty acids Detoxification reactions... 

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 eukaryotes the elongation of fatty acids beyond Cl 6 palmitate is carried out by enzymes located on the cytosolic surface of the smooth endoplasmic reticulum (SER). Malonyl CoA is used as the two-carbon donor, and the fatty acid is elongated as its CoA derivative rather than its ACP derivative. 

Pantothenic acid has a central role in energy-yielding metabolism as the functional moiety of coenzyme A (CoA), in the biosynthesis of fatty acids as the prosthetic group of acyl carrier protein, and through its role in CoA in the mitochondrial elongation of fatty acids the biosynthesis of steroids, porphyrins, and acetylcholine and other acyl transfer reactions, including postsynthetic acylation of proteins. Perhaps 4% of all known enzymes utilize CoA derivatives. CoA is also bound by disulfide links to protein cysteine residues in sporulating bacteria, where it may be involved with heat resistance of the spores, and in mitochondrial proteins, where it seems to be involved in the assembly of active cytochrome c oxidase and ATP synthetase complexes. 

Cook HW. The influence of trans acids on desaturation and elongation of fatty acids. Lipids 1981 16 920-926. 

Fatty Acid Modification Elongation of Fatty Acids... 

The enzyme is present in two different forms. A membrane-bound 300 amino acid form is located mainly in the endoplasmic reticulum and outer mitochondrial membrane. The membrane form has a role in desaturation and elongation of fatty acids, cholesterol biosynthesis, and drug metabohsm. 

The elongation of fatty acids occurs in which of the diagrammatic structures shown below ... 

Acyl-CoAs are intermediates in oxidation of fatty acids, in fat synthesis, in elongation of fatty acids longer than palmitate (16 carbons), in fatty acid desaturation. 

See also Fatty Acids, Coenzyme A, Oxidation of Fatty Acids, Fat Synthesis, Elongation of Fatty Acids, Fatty Acid Desaturation, Thiolase... 

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... 

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. 

Vessby B, Gustafsson IB, Tengblad S, Boberg M, Andersson A. Desaturation and elongation of fatty acids and insulin action. Ann N Y Acad Sci. 2002 967 183-95. 

As mentioned in Section 11.1.1 the elongation of fatty acids is generally carried out by Type III fatty acid synthetases which use malonyl-CoA as the source of C2 units for addition. 

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). 

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. 

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 outer membrane contains the enzymes that are responsible for the desaturation and elongation of fatty acids synthesized in the cytosol (section 5.6.1.1), the enzymes for triacylglycerol synthesis from fatty acids (section 5.6.1.2) and phospholipases that catalyse the hydrolysis of phospholipids (section 4.3.1-2). 

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