Fatty acids chain lengthening

ER fatty acid chain elongation, which uses two-carbon units provided by mal-onyl-CoA, is a cycle of condensation, reduction, dehydration, and reduction reactions similar to those observed in cytoplasmic fatty acid synthesis. In contrast to the cytoplasmic process, the intermediates in the ER elongation process are CoA esters. These reactions can lengthen both saturated and unsaturated fatty acids. Reducing equivalents are provided by NADPH. 

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... 

The liver is the most important organ involved in fatty acid and triglyceride synthesis. It is able to modify body fats by lengthening or shortening and saturating or unsaturating the fatty acid chains. The only fatty acids that cannot be synthesized by the body are those that are polyunsaturated. However, linoleic acid (two double bonds) and linolenic acid (three double bonds) from the diet can be converted to other polyunsaturated fatty acids. This utilization of linoleic and linolenic acids as sources of other polyunsaturated fatty acids is the basis for classifying them as essential fatty acids for humans (Section 8.2). 

The malonic ester synthesis might seem like an arcane technique that only an organic chemist would use. Still, it is much like the method that cells use to synthesize the long-chain fatty acids found in fats, oils, waxes, and cell membranes. Figure 22-4 outlines the steps that take place in the lengthening of a fatty acid chain by two carbon atoms at a time. The growing acid derivative (acyl-CoA) is activated as its thioester with coenzyme A (structure on page 1027). A malonic ester acylation adds two of the three carbons of malonic acid (as malonyl-CoA), with the third carbon lost in the decarboxylation. A )8-ketoester results. Reduction of the ketone, followed by dehydration and reduction of... 

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. 

Although the de novo synthesis of fatty acids is essentially a cytoplasmic process, pre-existing fatty acid chains may be lengthened by two different enzyme systems, one occurring in the mitochondria and the other in the endoplasmic reticulum. Both show significant differences from the pathway described above but both have a requirement for reduced NADP. Between... 

The study of the absorption of long-chain fatty acids of an odd number of carbons was stimulated by their supposed antiketogenic activity. Various investigators claim that from 75% to 90% of heptadecanoic acid (seventeen carbons) is absorbed by normal and diabetic patients fed tri-heptadecanoin. " " It has also been shown, in nonisotopic experiments, that a fed fatty acid of the odd series may be incorporated into the body fat of rats. " A recent study with pentadecanoic acid-5-C illustrates that such odd-carbon fatty acids are indeed readily absorbed (see Table XVI). Nearly all of the C from pentadecanoic acid-5-C was found in the fifteen-carbon fatty acid fraction of the mixed fatty acids of lymph. This indicates that, during the transport of pentadecanoic acid across the intestinal wall, a lengthening or shortening of the fatty acid chain does not occur. 

The preparation of long-chain fatty acids has been carried out in this way because cleavage of 115 with strong sodium hydroxide gives the ketoacid (116), which is easily reduced by the Wolf-Kishner method to the saturated acid. A similar sequence of reactions can be carried out starting with the cyclopentanone enamine, and this method allows lengthening the chain... 

Biosynthesis of unsatutated long-chain fatty acids is achieved by desaturase and elongase enzymes, which introduce double bonds and lengthen existing acyl chains, respectively. 

The direct hydrogenation to deoxidize fatty acid esters results in hydrocarbons with one carbon atom less than the number present in the hydrocarbon chain of the original ester. The reaction can be carried out quantitatively, but it is a relatively drastic chemical operation. In the Grignard method the hydrocarbon chain of the molecule is lengthened the reactions are executed at relatively low temperatures the overall yield amounts to 70-90% of the theory. 

Traube s rule does not hold for adsorption from organic solvents. While, on charcoal, from aqueous solution, the adsorption of organic compounds increases as the hydrocarbon chains are lengthened,2 this rule is reversed in the case of fatty acids on silica. Holmes and McKelvey3 found much greater adsorption of the shortest chain acids, from toluene on silica, than of longer chain acids and Bartell and Fu4 obtained similar results with solutions in carbon tetrachloride. 

Elongation by two carbon atoms occurs commonly in fatty acid biosynthesis. It is a variant of de novo chain-lengthening and occurs with acetyl or malonyl CoA or ACP derivatives. The substrate is any preformed saturated or unsaturated acid. For example, erucic (22 1) in high-emcic acid rapeseed oil and nervonic acid (24 1) in seed oil are formed from oleic acid by two and three elongations, respectively ... 

The first step in de novo fatty acid synthesis is the production of malonyl-CoA from acetyl-CoA and bicarbonate. This committed step is catalyzed by acetyl-CoA carboxylase present in the cytoplasm of liver cells and adipocytes. After replacement of the CoA residue in acetyl-CoA by ACP (acyl carrier protein), malonyl-ACP is used to convert acetyl-ACP to butyryl-ACP by the fatty acid synthase complex. In this multistep reaction, NADPH is used as donor of hydrogen atoms and CO2 is produced. Butyryl-ACP is subsequently elongated to hexanoyl-ACP by a similar process in which malonyl-ACP serves as donor of two carbon atoms required for lengthening of the growing acyl chain. This process is repeated until palmitic acid... 

FIGURE 21.18 A portion of an animal cell, showing the sites of various aspects of fatty-acid metabolism. The cytosol is the site of fatty-acid anabolism. It is also the site of formation of acyl-CoA, which is transported to the mitochondrion for catabolism by the P-oxidation process. Some chainlengthening reactions (beyond Cjg) take place in the mitochondria. Other chain-lengthening reactions take place in the endoplasmic reticulum (ER), as do reactions that introduce double bonds. 

The utility of this methodology is illustrated by the stereoselective synthesis of ( + )-cer-ulenin (759), an antifungal antibiotic first isolated from the culture filtrate of Cephalosporium caerulens. Its ability to inhibit lipid biosynthesis in Escherichia coli by irreversibly binding P-keto-acyl-carrier protein synthetase, the enzyme responsible for the chain lengthening reaction in fatty acid synthesis, has attracted interest in its mechanism of action. D-Tartaric acid... 

C22H34O2, Mr 330.51. Pale yellow liquid, D. 0.937, mp. -78 °C, bp. 331 °C. C. is a docosapentaenoic acid (DPA) of the o)3-series with an unusual distribution of the C=C double bonds it was first isolated from the Japanese sardine Clupanodon melanostica), the oil of which contains ca. 8% C. The DPA of the ft>3-series normally formed in animals is (a//-Z)-7,10,13,16,19-DPA built from eicosapentaenoic acid by chain lengthening. The corresponding fatty acid of the (u6-series is (aH-Z)-4,7,10,13,16-DPA, formed as metabolic product from linoleic acid. Many fish and fish liver oils contain glycerol esters of C. in varying amounts, e.g. sardine oil 2.8%, mackerel oil 0.6%, anchovy oil 1.2%, and herring oil 0.4% as well as cod-liver oil 10%. 

Biological synthesis of fatty acids is analogous to the malonate synthesis of carboxylic acids. The enolate carbanion from malonate acts as a nucleophile in a nucleophilic substitution on the acetyl-CE followed by decarboxylation. Each series puts the three-carbon malonate on the ACP and then decarboxylates the substitution product, resulting in lengthening of the carbon chain by two carbons at a time. Naturally occurring fatty acids are even numbered carboxylic acids. 

Investigations with heterotrophic cell suspension cultures of I. polycarpa at the subcellular level revealed two systems capable of synthesizing cyclo-pentenyl fatty acids (Buchholz and Spener, 1980). One system was located in the proplastids, the organelles responsible for straight-chain fatty acid biosynthesis in cultured plant cells (Nothelfere/a/., 1977) a second system was found in the cytosol. In this fraction acetyl-CoA neither served as a primer for straight-chain fatty acids nor as a chain-lengthening unit for cyclic acids. The latter function was readily fulfilled by malonyl-CoA (Buchholz and Spener, 1980). It remains to be seen whether the biosynthesis of cyclopen-tenyl fatty acids exhibits CoA or AGP dependency. 

Eicosa-9, 12-dienoic acid only differs from linoleic acid by the existence of two additional carbons at the methyl end of the chain. Similarly 20 3 (9, 12, 15) has the structure of a-linolenic acid with two more carbons at the methyl end of the chain. In spite of this, both acids were desaturated by rat liver microsomes to 20 3 (6, 9, 12) and 20 4 (6, 9, 12, 15) respectively. However they were desaturated less efficiently than linoleic and a-linolenic acids showing that A6 desaturase recognizes the additional lengthening of the methyl end of the fatty acids (Table 1). The enzyme also recognizes the number of double bonds in the acids of 20 carbons, as was already shown in the acids of 18 carbons, since 20 3 (9, 12, 15) is a better substrate than 20 2 (9, 12) acid. 

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