Peroxisomal fatty acid elongation

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 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... 

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. 

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... 

Fig.1. Possible pathways for the intracellular movement of n-3 polyunsaturated fatty acid as it relates to the synthesis of 4,7,10,13,16,19-22 6. The pathway implies that when 24 6 (n-3) is produced in the endoplasmic reticulum, it preferentially moves to another cellular compartment rather than serving as a substrate for further chain elongation. It is not known whether fatty acids move between subcellular compartments as acyl-CoA or whether they are hydrolyzed followed by their reactivation at the subcellular site where they are to be metabolized. If 24 6 n-3 is to be metabolized by mitochondria, it must be transported across the outer (O.M.) and inner (I.M.) membranes into the mitochondrial matrix. This pathway has recently been shown to be of minor importance. The preferred, if not the exclusive pathway for 24 6 n-3 metabolism requires its movement to peroxisomes, where after one degradative cycle, the 22 6 n-3 preferentially moves back to the endoplasmic reticulum rather than serving as a substrate for continued (3-oxidation. Again it is not known in what form the 22 6 n-3 is transported, i.e., acyl-CoA or free fatty acid and how or whether these intracellular fatty acid movements require specific proteins.

The results presented here support the hypothesis that the 22 6n-3 synthetic pathway involves elongation and desaturation of 18 3n-3 to 24 6n-3, processes most likely carried out in microsomes then 24 6n-3 is transported to peroxisomes for one cycle of fatty acid P-oxidation to yield 22 6n-3. We showed that peroxisomal straight-chain acyl-Co A oxidase (AOxl), DBF, and 3-oxoacyl-CoA thiolase or sterol carrier protein X are involved in the P-oxidation of 24 6n-3 to 22 6n-3. 

The metabolism of CLA in peroxisomes shows interesting aspects in terms of a possible role in the formation and concentration of eicosanoids, especially as effected in different pathologic conditions. By either competing with linoleic acid for desaturation and elongation, or via peroxisomal P-oxidation, CLA may interfere with eicosanoid production and degradation. It is likely however that its action may depend on its incorporation and thereby its concentration in different tissues. The different rate of peroxisomal P-oxidation between t 0,c 2 and c9,tll, may also explain the different biological activities of the two isomers. Also, enhanced fatty acid oxidation... 

Figure 16.4 Long-chain and very long-chain fatty acid biosynthesis in mammals. The long-chain saturated fatty acids and unsaturated fatty acids of the n-10, n-7, and n-9 families (Top panel) can be synthesized from palmitic acid (Cl6 0) produced by the cellular fatty acid synthesis machinery. Long-chain fatty acids of the n-6 and n-3 famihes can only be synthesized from their respective precursors obtained from diets. The symbols of, , and stand for the involved activities of desaturation, elongation, and peroxisomal 3-oxidation, respectively, in the steps. Many isoforms of the genes corresponding to these activities were identified (see the review [34] for details).

---