Fatty acids, long-chain elongation

Kihara, A. (2012) Very long-chain fatty acids elongation, physiology and related disorders. J. Biochem. 152 387-395. 

Figure 7. Enzymatic steps in long-chain fatty acid elongation. Enzymatic steps of microsomal fatty acyl chain elongation. ELOVL, elongation of very-long-chain fatty acids KAR, 3-ketoacyl-CoA reductase HADC, 3-hydroxyacyl-CoA dehydratase TER, /rowi-2,3-enoyl-CoA reductase [108].

After the extraction of lipid and nonlipid components from the leaves of mandarin orange Citrus reticulata, the lipid fraction was further separated by PTLC to determine different lipid classes that affect the chemical deterrence of C. reticulata to the leaf cutting ecat Acromyrmex octopinosus. These lipids seem to be less attractive to the ants [81a]. The metabolism of palmitate in the peripheral nerves of normal and Trembler mice was studied, and the polar lipid fraction purified by PTLC was used to determine the fatty acid composition. It was found that the fatty acid composition of the polar fraction was abnormal, correlating with the decreased overall palmitate elongation and severely decreased synthesis of saturated long-chain fatty acids (in mutant nerves) [81b]. 

FIGURE 3-7 Pathways for the interconversion of brain fatty acids. Palmitic acid (16 0) is the main end product of brain fatty acid synthesis. It may then be elongated, desaturated, and/or P-oxidized to form different long chain fatty acids. The monoenes (18 1 A7, 18 1 A9, 24 1 A15) are the main unsaturated fatty acids formed de novo by A9 desaturation and chain elongation. As shown, the very long chain fatty acids are a-oxidized to form a-hydroxy and odd numbered fatty acids. The polyunsaturated fatty acids are formed mainly from exogenous dietary fatty acids, such as linoleic (18 2, n-6) and a-linoleic (18 2, n-3) acids by chain elongation and desaturation at A5 and A6, as shown. A A4 desaturase has also been proposed, but its existence has been questioned. Instead, it has been shown that unsaturation at the A4 position is effected by retroconversion i.e. A6 unsaturation in the endoplasmic reticulum, followed by one cycle of P-oxidation (-C2) in peroxisomes [11], This is illustrated in the biosynthesis of DHA (22 6, n-3) above. In severe essential fatty acid deficiency, the abnormal polyenes, such as 20 3, n-9 are also synthesized de novo to substitute for the normal polyunsaturated acids. 

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). 

Kemp S, Valianpour F, Denis S, Ofman R, Sanders RJ, Mooyer P, Barth PG, Wanders RJ (2005) Elongation of very long-chain fatty acids is enhanced in X-linked adrenoleukodystrophy. Mol Genet Metab 84 144-151... 

Although palmitate, a 16-carbon, fully saturated LCFA (16 0), is to primary end-product of fatty acid synthase activity, it can be further I elongated by the addition of two-carbon units in the endoplasmic] reticulum (ER) and the mitochondria. These organelles use separate enzymic processes. The brain has additional elongation capabilities, allowing it to produce the very-long-chain fatty acids (up to 24 car bons) that are required for synthesis of brain lipids. 

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... 

The biosynthesis of polyketides is analogous to the formation of long-chain fatty acids catalyzed by the enzyme fatty acid synthase (FAS). These FASs are multi-enzyme complexes that contain numerous enzyme activities. The complexes condense coenzyme A (CoA) thioesters (usually acetyl, propionyl, or malonyl) followed by a ketoreduction, dehydration, and enoylreduction of the [3-keto moiety of the elongated carbon chain to form specific fatty acid products. These subsequent enzyme activities may or may not be present in the biosynthesis of polyketides. 

All of the following are true about long-chain fatty acid chain elongation except... 

As a result of impaired activity of acetyl CoA and propionyl CoA carboxylases, there are changes in the fatty acid composition of lipids in the lymphocytes of biotin-deficient rats. There is an increase in the proportion of long-chain fatty acids (C22 0 to C30 0) and odd-carbon fatty acids (Cl 5 0 to C29 0), with a decrease in the proportion of unsaturated fatty acids and the ratio of ds-vaccenic acid (C18 l )9) palmitoleic acid (C16 lft)6), which is indicative of impaired elongation and desaturation of fatty acids (Liu et al., 1994). 

The essential fatty acids are also converted in the btxly to the 22-carbon fatty addsdocosapenta erioic aci d (DPA) and d oco sahexaenoic acid (DH A), DFA is made from linoleic acid DHA is made from linoienic acid. The functions of these 22-carbon fatty acids are not clear, but they may be important for vision and for other functions of the nervous system. DPA and DHA can be further elongated, in the body, to the very-long-chain fatty acids." The very-long-chain fatty acids contain 24 to 34 carbons, and occur in the brain, rods of the retina, and in the testes (Suh et ai, 1996). Their functions arc not dear. 

Elongation of long-chain fatty acids occurs in the endoplasmic reticulum. 

Abbreviations NBD, nucleotide binding domain TMS, transmembrane-spanning segment NTE, N-terminal extension PDR, pleiotropic drug resistance PM, plasma membrane V, vacuole M, mitochondrion P, peroxisome C, cytoplasm LCFA, long chain fatty acid EF, elongation factor. 

Fig. 1. Metabolic pathway of essential fatty acids. Recent evidence indicated that 22 6n-3 are produced by [l-oxidation of 24 6n-3, which is desaturated from 24 5n-3, after elongation from 22 5n-3. Very long-chain fatty acids in the box are found in the retina however, the metabolism and function is not known.

Leonard, A. E., Pereira, S. L., Sprecher, H., and Huang, Y. S. Elongation of long-chain fatty acids. Prog Lipid Res 43 (2004) 36-54. 

Abbreviations FASN, fatty acid synthase ACC, acetyl-CoA-carboxylase ACL, ATP-citrate lyase NADPH, nicotinamide adenine dinucleotide phosphate MAT, malonyl acetyl transferases KS, ketoacyl synthase KR, p-ketoacyl reductase DH, p-hydroxyacyl dehydratase ER, enoyl reductase TE, thioesterase ACP, acyl carrier protein VLCFA, very long chain fatty acids ELOVL, elongation of very long chain fatty acids SCDl, stearoyl-CoA desaturase-1 AMPK, AMP-activated kinase ME, malic enzyme FASKOL, liver-specific deletion of FAS PPARa, Peroxisome Proliferator-Activating Receptor alpha HMG-CoA, 3-hydroxy-3-methyl-glutaryl-CoA SREBP, sterol response element binding protein SIP, site-one protease S2P, site-two... 

After fatty acid synthesis, downstream enzymes can further modify palmi-tate for various cellular functions. In the endoplasmic reticulum, the 16 carbon fatty acid can be modified to fatty acids with eighteen or more carbons known as very long chain fatty acids (VLCFA), such as stearate (18 0) by a family of elongase enzymes called elongation of very long chain fatty acids (ELOVLl-6) (Jakobsson et ah, 2006). Palmitate and stearate can also be desaturated by stearoyl-CoA desaturase-1 (SCDl) at the cis-9 carbon to palmitoleate (16 1) and oleate (18 1), respectively (Sampath and Ntambi,... 

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