Fatty acid metabolism chain elongation

Fig. 2. Summary of the mammalian metabolism of two essential fatty acids, linoleic acid and a-linolenic acid, to other fatty acids of the w6 and w3 series. These fatty acids are chain-elongated and desaturated to yield the three derived essential eicosenoic acids, which are precursors of the prostaglandins of the 1-, 2-and 3-series (PG, PG2 and PG3 in this figure). Reproduced with permission from AnggM, E. and Oliw, E. (1981) Kidney Int, 19, 771-780.

Certain long-chain unsaturated fatty acids of metabolic significance in mammals are shown in Figure 23-1. Other C20, C22, and C24 polyenoic fatty acids may be derived from oleic, linoleic, and a-flnolenic acids by chain elongation. Palmitoleic and oleic acids are not essential in the diet because the tissues can introduce a double bond at the position of a saturated fatty acid. 

Fig. 1. Schematic representation of the relation between fatty acid metabolism and PHA synthesis in P. putida (Eggink et al. 1992). The possibility to generate PHA precursors by elongation of medium chain length fatty acids (see text) is not included in this figure.

The discovery of a novel pathway for biosynthesis of medium and short chain fatty acids in plants (a-keto acid elongation pathway, 1) raises the possibility (however unlikely) that medium-chain fatty acids (mcFAs) of certain oil seeds producing them may be derived by this pathway. Alternatively, these may be formed after release of elongating fatty acid chains from fatty acid synthase mediated biosynthesis (FAS) by specific medium chain thioesterases [2, 3,4]. Thus far the aKAE pathway is only known to occur in trichome glands of plants in the family Solanaceae. In the aKAE pathway, iso-, anteiso- or straight-chain keto acid products of branched-chain amino acid metabolism are elongated by one carbon (via acetate) per cycle. The final step is predicted to be oxidative decarboxylation to yield CoA activated acids. The mechanism that determines the chain length of aKAE products is not understood [1]. 

Figure 3.7 Model of intermolecular fatty acid synthetase mechanism in the a2 2 protomer of yeast. A, acetyl transferase E, enoyl reductase D, dehydratase P, palmitoyl transferase M, malonyl transferase C, 5-ketoacyl synthase R. )5-ketoacyl reductase ACP, acyl carrier protein. Dotted lines and arrows delineate the route taken by intermediates when sequentially processed on different FAS domains. Numbers indicate the reaction sequence. Catalytically active dohnains, at a specific moment, are marked by bold lines. Shaded areas on E and P domains potentially interact by hydrophobic attraction in the presence of palmitate (b). On the protomer depicted in (a) fatty acyl chain elongation occurs in one half of the a2 2 protomer. In (b) chain termination is induced by hydrophobic interaction between E> bound palmitate and P. Subsequently, palmitate Is transferred to Its O-ester binding site on P. Inactivation of the left half of simultaneously activates its right half (b). Redrawn from Schweizer (1984) with permission of the author and Elsevier Science Publishers, BV. From Fatty Acid Metabolism and its Regulation (1984) (ed. S. Numa), p. 73, Figure 7.

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]. 

Palmitic acid may be converted to stearic acid (C1K 0) by elongation of the carbon chain. Desaturation of stearic acid produces oleic acid (C18 1 A9). Linoleic acid (Ci8 2A9,12), however, cannot be synthesized in mammalian tissues. Therefore, it is an essential fatty acid for animals and must be obtained from the diet it has two important metabolic roles. One is to maintain the fluid state of membrane lipids, lipoproteins, and storage lipids. The other role is as a precursor of arachidonic acid, which has a specialized role in the formation of prostaglandins (Sec. 13.9). 

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.

Once ingested, these essential fatty acids can be metabolized into longer, more unsaturated products (Holman, 1968). This process involves sequential desaturation (adding double bonds) and chain elongation (adding carbon atoms), as shown in Fig. 1. The important aspect of Fig. 1 is that the n-6 and n-3 families compete for the enzymes responsible for desaturation (Sinclair, 1993). The main metabolite of the n-6 series is arachidonic acid (20 4n-6, AA), whereas eicosapentaenoic acid (20 5n-3, EPA) and docosahexaenoic acid (22 6n-3, DHA) are the main metabolites ofthe n-3 series (Holman, 1968). The metabolic pathways leading to DHA are complicated by involving retroconversion from 24 6n-3 to 22 6n-3 (DHA) (Voss et al., 1991). 

Linoleic acid (LA or 18 2n-6) An 18-carbon, two double-bond fatty acid. It is the most predominant PUFA in the Western diet. It is found in mayoimaise, salad dressings, and in the seeds and oils of most plants, with the exception of coconut, cocoa, and palm. Linoleic acid is metabolized into longer-chain fatty acids, such as arachidonic acid and gamma-linolenic acid, in animals through a process of chain elongation and desaturations. 

Fig. 10. Coordinate regulation of fatty acid and phospholipid metabolism. The pleiotropic regulator ppGpp regulates transfer of fatty acids to the membrane via inhibition of the PlsB acyltransferase step, coordinating phospholipid synthesis with macromolecular synttesis. PlsB inhibition leads to the accumulation of long-chain acyl-ACPs that feedback inhibit their own synthesis at the point of initiation (inhibition of acetyl-CoA carboxylase and FabH) and elongation, by inhibition of Fabl. LPA, lysophosphatidic acid G3P, glycerol-3-phosphate.

The types of fatty acids obtained through dietary intake and de novo synthesis are insufficient to meet the varied demands of cells, so there is substantial metabolism and rearrangement in the structures of the fatty acids as development, growth, and aging proceed. Knowledge of how the array of fatty acyl chains is derived and modified, and what regulates the metabolism of fatty acyl chains by elongation and desaturation are described in the sections that follow. 

The desaturation of fatty acids is usually assayed by incubating radioactive fatty acids with microsomes in the presence of appropriate cofactors. This general protocol has been used by many investigators to assay A9, A6, and A5 desaturase activities. It was thus assumed that 7,10,13,16-22 4 and 7,10,13,16,19-22 5 were desaturated by a microsomal A4 desaturase. In 1991, we showed that when rat liver microsomes were incubated with [1- C]7,10,13,16,19-22 5, it was not desaturated to 4,7,10,13,16,19-22 6. However, when malonyl-CoA was included in the incubation, the substrate was chain elongated to 9,12,15,18,21-24 5, which was then desaturated, at position-6, to yield 6,9,12,15,18,21-24 6. When [1- C]7,10,13,16,19-22 5 and the two [3- C]-labeled 24-carbon acids were incubated with hepatocytes, all three acids were metabolized to esterified [1- C]4,7,10, 13,16,19-22 6 (19). The findings implied that 4,7,10,13,16, 19-22 6 was made from 9,12,15-18 3 as follows ... 

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.

Chapkin, R. S., and Ziboh, V. A. (1986) Metabolism of Essential Fatty Acids by Human Epidermal Enzyme Preparations Evidence of Chain Elongation, J. Lipid Res. 27, 945-954. 

The metabolic transformation of the C,s essential fatty acids to their longer chain fatty acid derivatives has been studied mainly in the liver and to some extent in the brain. Animals and tissues vary greatly in their efficiency of desaturation and chain elongation [18,414,415]. Thus young rats have a particularly active system whereas cats are unable to perform this metabolic reaction. The failure of the cat family to desaturate linoleic acid has been suggested to be a possible reason behind the cats evolution to carnivorous animals [416] (e.g. eating rats). Humans occupy an intermediate position. 

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