Elongation and Desaturation

Cis double bonds can be introduced no farther than C-9 from the carboxylate end in mammals. 

Once fatty acids have been made 16 carbons long, they can be lengthened by adding 2 carbon atoms at a time with malonyl-CoA in a reaction that looks a lot like the first step of fatty acid synthesis. However, the elongation reaction is carried out on the fatty acyl-CoA and by an enzyme that is different from fatty acid synthase.  

Notice that elongation doesn t change the number of carhon atoms between the double bond and the CH3 group at the left end. If a double bond is closer than 7 carbon atoms to the CH3 group (numbering the CH3 as 1, the first double bond you bump into would start at carbon 7), a plant must have made it. 

If you ever have to interconvert between these two nomenclatures, it may be easier for you to write down a representation of the structure rather than to try to figure out the relationships between the length, number of double bonds, and how you add and subtract what to get whatever. 

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Historically, many attempts have been made to systematize the arrangement of fatty acids in the glyceride molecule. The even (34), random (35), restricted random (36), and 1,3-random (37) hypotheses were developed to explain the methods nature utilized to arrange fatty acids in fats. Invariably, exceptions to these theories were encountered. Plants and animals were found to biosynthesize fats and oils very differently. This realization has led to closer examination of biosynthetic pathways, such as chain elongation and desaturation, in individual genera and species. 

From TCA and mitochondria through citrate to C16 fatty acid Through C16-acyl-CoA to elongation and desaturation pathways Through Ci6-acyl-CoA to triglycerides... 

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 FAS multi-enzyme complex synthesizes saturated C16 fatty acids, but cells and tissues need unsaturated and longer chain fatty acids. The palmitoyl-CoA can be modified by either chain elongation and/or oxidation in order to produce different fatty acid molecules. Both elongation and desaturation occur within the smooth endoplasmic reticulum (SER, microsomal fraction) of the cell. 

Fatty acyl CoA may be elongated and desaturated (to a limited extent in humans) using enzymes associated with the smooth endoplasmic reticulum (SER). Cytochrome is involved in the desaturation reactions. These enzymes carmot introduce double bonds past position 9 in the fetty add. 

The reduced coenzyme NADPH is required for the reduction reactions shown in Figure 11.5. It is also required for elongation and desaturation of fatty acids. The major source of NADPH for these reactions is the pentose phosphate pathway, which is described in detail in Chapter 6. 

Although these are termed essential fatty acids, they are, in fact, precursors for the major polyunsaturated fatty acids that have essential roles in the body but are present only in small amounts in the diet. Linoleic acid is converted, via elongation and desaturation reactions, to dihomo-y-linolenic (20 3n-6) and then to arachidonic (20 4n-6) acid. a-Linolenic is converted to eicosapentaenoic (20 5n-3) and then docosahexae-noic (22 6n-3). The pathways for formation of these latter fatty acids, from their dietary precursors, are presented in Figures 11.11 and 11.12. Full details of one pathway are provided, as an example, in Appendix 11.4. For comparison of the two pathways, they are presented side by side in Figure 11.13. 

Figure 20.3 Essential fatty acids in the diet, production of physiological essential acids and their roles in the cell cycle. Essential fatty adds in the diet are mainly linoleic and a-linolenic but they are converted by desaturation and elongation reactions to the essential acids that are used in phospholipid formation and synthesis of eicosanoids. (For details of the elongation and desaturation reactions and eicosanoid formation, see Chapter 11.).

Dietary intake is of great importance. Linoleic acid (C18 2o)6) and a-linolenic acid (C18 3o)3) are the parent essential fatty acids for humans. Both fatty acids derive from vegetable oils. Higher fatty acids are then produced by chain elongation and desaturation. In addition, some of the prime essential fatty acids, AA (C20 4o)6), EPA (C20 5w3) and DHA (C22 6w3), can be obtained directly from the diet. Meat and eggs are rich in AA, whereas fish is a rich source of EPA and DHA [14]. 

The dietary precursor of the prostaglandins is the essential fatty acid, linoleic acid. It is elongated and desaturated to arachidonic acid, the immediate precursor of the predominant class of prostaglandins (those with two double bonds) in humans (Figure 17.22). [Note Arachidonic acid is released from membrane-bound phospholipids by phospholipase Ap in response to a variety of signals (Figure 17.23).]... 

Sites of further fatty acid elongation and desaturation... 

In 1930, George and Mildred Burr reported that the C18 2 (A9,12) Iinoleic acid, a fatty acid of exclusively plant origin, cured a disease condition observed in rats raised on a highly purified fat-free diet.a b These animals grew poorly, developed a scaly dermatitis, and suffered kidney damage and impaired fertility. The symptoms could be prevented if 1% of the dietary energy was provided by Iinoleic acid. This C18 2 fatty acid can be converted in animals into a series of other fatty acids by chain elongation and desaturation. All of this series have a double bond six carbon atoms from the -CH3 terminus and form an co6 (or n-6) family.c... 

Owen, J.M., Adron, J.W., Middleton, C. and Cowey, C.B. (1975). Elongation and desaturation of dietary fatty acids in turbot Scophthalmus maximus L. and rainbow trout, Salmo gairdnerii Rich. Lipids 10,528-531. 

Saturated fatty acids or unsaturated fatty acids, such as oleic acid (18 1, n-9), can be synthesized by normal mammalian cells that posses elongation and desaturation enzymes (Rosenthal, 1987). However, the polyunsaturated fatty acids of the n-3 and n-6 group, such as linoleic acid (18 2, n-6) or linolenic acid (18 3, n-3), are essential nutrients for animals because they are precursors for the synthesis of eicosanoid hormones such as prostaglandins (Needleman et al., 1986). 

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 HUFAs (AA, EPA, and DHA), required by mammals, are synthesized by the microsomal elongases and A5 and A6 desaturases (8). The substrates for synthesis, LA and LN, are obtained primarily from vegetable oils in the diet. Elongation and desaturation of LA produces AA, whereas elongation and desaturation of LN produces EPA and DHA. Synthesis of DHA, which is concentrated in the brain, proceeds through the elongation and desaturation pathways to the product C24 6 (1)3, which is then the substrate for one cycle of peroxisomal fS-oxidation to yield C22 6 (u3 (8). 

A variety of unsaturated fatty acids can be formed from oleate by a combination of elongation and desaturation reactions. For example, oleate can be elongated to a 20 1 cis-A fatty acid. Alternatively, a second double bond can be inserted to yield an 18 2 cis-A, A fatty acid. Similarly, palmitate (16 0) can be oxidized to palmitoleate (16 1 cis-A ), which can then be elongated to cA-vaccenate (18 1 cis-A H). 

Fatty acids are elongated and desaturated by enzyme systems in the endoplasmic reticulum membrane. Desaturation requires NADH and O2 and is carried out by a complex consisting of a flavoprotein, a cytochrome, and a nonheme iron protein. Mammals lack the enzymes to introduce double bonds distal to C-9, and so they require linoleate and linolenate in their diets. 

Fatty Acids Synthesis, Elongation, and Desaturation. The main objective of feeding fats to animals is to provide a concentrated energy source, not to have the fat stored in the tissues. Recognized EFA requirements are no more than several percent of dry matter at the most, but the critical roles they play in maintaining the metabolic machinery has attracted the majority of current research on dietary fat utilization. 

The RDA for the essential fatty acids is 1 to 2% of total energy intake. Generally, between 5 and 10% of our energy intake consists of EFAs. Because of our ample intake of fat, a deficiency in EFAs is quite rare. The biochemical steps in the modification of nonessential fatty acids, such as oleic add, and essential fatty adds (linoleic add and linolenic acid) are generally the same. These steps include elongation and desaturation. Modification of fatty adds by their repeated desatu-... 

Palmitate, the product released by the fatty acid synthase complex, is converted to a series of other fatty acyl CoAs by elongation and desaturation reactions. 

Palmitate can be elongated and desaturated to form a series of fatty acids. 

A. Arachidonic acid is produced from linoleic acid (an essential fatty acid) by a series of elongation and desaturation reactions. Arachidonic acid is stored in membrane phospholipids, released, and oxidized by a cyclooxygenase (which is inhibited by aspirin) in the first step in the synthesis of prostaglandins, prostacyclins, and thromboxanes. Leukotrienes require a lipoxygenase, rather than a cyclooxygenase, for their synthesis from arachidonic acid. 

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