Dihomo-y-linoleic acid

In general for the C20 series, maximal activity is achieved with amides of arachidonic acid (1) [81], mead acid (199) [149], and dihomo-y-linoleic acid (200) [150] (see Table 6.18). Decreasing the unsaturation (201), (202), or abolishment of the n-pentyl chain (203) [150] led to less active or inactive compounds. Variable results were seen with longer chains. The C22 4 n-6 analogue (204) is as active as AEA (1) whereas the C22 6 n-3 analogue (205) is less active than the C20 5 n-3 analogue (203) [150]. Replacement of the double bonds with triple bonds (206) resulted in loss of activity [150] (see Table 6.18). Forcing the fatty acid chain into a hairpin conformation by cyclisation (207) also resulted in inactive compounds [151]. 

The enzymes involved in Scheme 3.3 are the same for the (0-3 and (0-6 PUFAs. The AMesaturase enzyme installs a C6-C7 cis double bond on hnoleic add (4) and a-linolenic acid (5), which forms y-linolenic acid (9) and stearidonic add (10), respectively. Then an elongase transforms these two fatty acids to the two C20 fatty acids dihomo-y-linoleic add (11) and eicosatetraenoic acid (12), respectively. Claisen-type condensation reactions of thioesters are again involved. Desaturation on dihomo-y-linoleic acid (11) by the A -desaturase enzyme installs a C5-C6 cis double bond that leads to arachidonic acid (8). If the A -desaturase enzyme uses eicosatetraenoic acid (12) as the substrate, EPA (6) is formed (Scheme 3.3). 

The question arises whether inhibition of the desaturase for this particular pathway can be overcome. The answer is yes. The product of the A desaturase when desaturating linoleic acid is y-linolenic acid. Supplementation of the diet with y-linolenic acid, which bypasses the A desaturase reaction, has been used to increase the formation of dihomo-y-linolenic acid and arachidonic acid (Figure... 

Experiences in cat nutrition underscore the fallacy of assuming that metabolic pathways found in one species are automatically present in others. Early studies on metabolism of PUFA were conducted on rats, which have high A6 and A5 desa-turase abilities to convert linoleic acid (18 2n-6) to the prostaglandin precursors dihomo-y-linolenic acid (20 3 -6) and arachidonic acid (20 4 -6), respectively. This led to the assumption that other species can desaturate polyunsaturated fatty acids equally well. Over a period of time, it was shown that cats are not able to convert 18 2 -6 to 20 3n-6 or 20 4 -6. The NRC currently recommends the inclusion of 5 g linoleic acid and 0.2 g arachidonic acid/kg diet dry matter. 

A defect in the capability of the enzyme 5-6-desaturase to convert linoleic acid to y-linolenic acid is known to occur in patients with atopic dermatitis (9). Patients with atopic eczema have a dietary deficiency in metabolites of linoleic y-linolenic acid, dihomo-y-linolenic acid, arachidonic acid, adrenic acid, and docosapentaenoic acid caused by a reduced rate of activity in the 5-6-desturase enzyme (8). Galli et al. compared blood samples from babies born to parents who suffered from atopic eczema. Results showed... 

Low levels of linoleic acid and dihomo-y-linolenic acid may predispose coronary heart disease (6,40). For this benefit, linoleic acid needs to be converted by the enzyme 8-6-desaturase to other highly unsaturated, long-change fatty acids, such as y-linolenic acid. OEP contains both linoleic and y-lino-lenic acid, and OEP has been reported to reduce elevated serum cholesterol levels, with y-linolenic acid having a more dramatic effect of the two (6). 

The metabolic pathways for synthesis of n-6 and n-3 families of polyunsaturated fatty acids from the essential fatty acids, linoleic acid (LA) (18 2 [n-6]) and a-linolenic acid (18 3 [n-3]), respectively, are showninFig. 2. Conversion of LA to arachidonic acid (AA) occurs via A6 desaturation to yield y-linolenic acid (GLA), then an elongation step to produce dihomo-y-linolenic acid (DHGL A) and A5 desaturation, to form AA. The A6 and A5 microsomal desaturases have been reported to utilize both NADH and NADPH as cofactors in vitro (Brenner 1977). Whether there is a more stringent pyridine nucleotide requirement in vivo is not known with certainty. Desaturase activities are especially abundant in the liver. 

Prostaglandins (PGs), leukotrienes (LTs), and related compounds are called eicosanoids,/rom the Greek eikosi ( twenty ). Precursor essential fatty acids containlO carbons and three, four, or five double bonds 8,11,14-eicosatrienoic acid (dihomo-y-linolenic acid), 5,8,11,14-eicosatetraenoic acid (arachidonic acid [AA] Figure 25—1), and 5,8,11,14,17-eicosapentaenoic acid (EPA). AA, the most abundant precursor, is either derived from dietary linoleic acid (9,12-octadecadienoic acid) or ingested directly as a dietary constituent. EPA is a major constituent of oils from fatty fish such as salmon. 

Arachidonic acid is present in high concentrations in ester form in most animal fats and so can be assimilated by man directly in his diet. Alternatively, mammals may biosynthesize arachidonic acid from linoleic acid via desaturation to y-linolenic acid, chain elongation to dihomo-y-linolenic acid, and then further desaturation to arachidonic acid. 

Fig. 5. Metabolism of dietary linoleic acid (LA) and y-linolenic acid (GLA) in epidermis. Abbreviations DGLA, dihomo-y-linolenic acid AA, arachidonic acid 15-LOX, 15-lipoxyge-nase 13-HODE, 13-hydroxyoctadecadienoic COX, cyclooxygenase PGE, prostaglandin E, 15-HETrE, 15-hydroxyeicosatrienoic acid.

A common chemical property of polyunsatured fatty acids, which are needed to maintain animals in healthy condition, seems to be cis double bonds at the w6 and w9 positions [14]. Important essential fatty acids in the diet are linoleic (18 2w6) and a-linoleic (18 3w3) acids, which both occur in plants. In the mammalian organism, these fatty acids can be desaturated and elongated to form the derived essential fatty acids, dihomo-y-linolenic acid (20 3w6), arachidonic acid (20 4 6) and timnodonic acid (20 5to3), the three precursor acids of prostaglandins (Fig. 2, see also Fig. 11). The derived essential fatty acids can also be obtained in the diet. Arachidonic and dihomo-y-linolenic acids occur in animal tissues timnodonic acid in fish. The mammalian organism cannot introduce double bonds at the co3 and <06 positions of long-chain fatty acids, which partly explains why fatty acids of the w3 and w6 series must be provided in the diet (see refs. 15-18 for reviews). These fatty acids are also essential to man, however, deficiency states can only be induced by... 

AU-ds5,8,ll,14- Eicosatetraenoic Arachidonic 20 4n-6 Synthesized from linoleic acid via y-linolenic and dihomo-y-linolenic acids Meat... 

Linoleic (A 2 octadecadienoic) acid Dihomo-y-linolenic (A8.ii.i4-eicosatrienoic) acid... 

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. 

A6 9-octadecadienoate rather than linoleate. However, animals need linoleate for the biosynthesis of dihomo-y-linolenate (A81114-eicosatrienoate) and arachidonate (A5 81114-eicosatetraenoate), C20 polyunsaturated fatty acid precursors of... 

Narce, M., and Poisson, J. -P. (1984) In Vitro Study of Linoleic and Dihomo-y-Linolenic Fatty Acid A6- and A5-Desaturations During the Development of High Blood Pressure in Relation with Age in Spontaneously Hypertensive Rats (SHR) Comparatively to Normotensive Rats (WKY), CR. Soc. Biol. 178,458-466. 

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