Linoleic acid metabolic pathway

Kelavkar U, Lin Y, Landsittel D, Chandran U, Dhir R. The yin and yang of 15-lipoxygenase-1 and delta-desaturases dietary omega-6 linoleic acid metabolic pathway in prostate. J Carcinog. 5 (2006) 9-13. 

M. Moghaddam, K. Motoba, B. Borhan, F. Pinot, B. D. Hammock, Novel Metabolic Pathways for Linoleic and Arachidonic Acid Metabolism , Biochim. Biophys. Acta 1996, 1290, 327 - 339. 

The carboxylic acids can be subdivided into nonvolatile fatty acids, volatile fatty acids, hydroxy acids, dicarboxylic acids, and aromatic acids (Fig. 3). The nonvolatile fatty acids are molecules with more than five carbon atoms, such as stearic and palmitic acids, which are the degradation products of fats and triglycerides. Three different 18-C fatty acids that are important constituents of plants include oleic and linoleic acids that are abundant in plant seeds, and linolenic acid, which is abundant in plant leaves. Volatile fatty acids are short-chain molecules with one to five carbon atoms, such as acetic and valeric acid, associated with anaerobic metabolism. The hydroxy-acids are common intermediates in biochemical pathways, including the tricarboxylic acid cycle. The excretion of hydroxyacids by algae, such as the... 

According to the reports describing metabolic pathways involved in the conversion of linoleic acid to trihydroxy fatty acids, several intermediate reaction products, such as trihydroxy-, hydroperoxy-, dihydroxy-, and hydroxyepoxy-octadecenoate, were involved (Kato et al., 1984,1986). Those metabolites of linoleic acid showed distinct biological functions according to their intermediate structures, including mono-, di-, trihydroxy-octadecenoic acid, and hydroperoxy-, epoxy-forms (Kato et al., 1984 Blair, 2001 Gobel et al., 2002 Hou and Forman, 2000). In an effort to understand the overall mechanism involved in the varied biological functions of the complicated reaction metabolites of bio-converted polyunsaturated fatty acids, Kim et al. (2006) studied the oxidative activities on fish oil, of crude extracts produced by PR3 from... 

Linoleic acid and ot-linolenic acid are essential fatty acids and are the important fatty acids involved in the metabolic pathway of prostaglandin synthesis. 

Figure 1. Metabolic pathway for linoleic acid. COX, Cycloozygenase, LOX, Lipoxygenase, PGEi, Prostaglandin Ej, PGE2, Prostaglandin E2, PGI2, Prostaglandin l2,TXA2, Thromboxane A2, 15-HETrE, 15-hydroxy eicosatrienoic acid, LTB4, Leukotriene B4.

The reaction catalyzed by delta-6-desaturase enzyme is the slowest reaction in the metabolic pathway of LA and is considered as a rate-limiting step (4, 5). Activity of this enzyme further decreases with age and in people suffering from various diseases, including arthritis, diabetes, hypertension, eczema, psoriasis, and so on. Lifestyle factors like stress, smoking, excessive consumption of alcohol, linoleic acid (6), saturated and trans-fatty acids and nutritional deficiencies of Vitamin B6, zinc (7), and magnesium inhibit this desaturase. As a result of limitations in in vivo production of GLA, supplementation with preformed GLA is becoming important. This has led to interest in development and commercialization of the sources of GLA. 

Complete metabolic pathways may not be operational in certain animal species and in human fat metabolism disorders. Some animals require linoleic and arachi-donic acid supplementation, although both are members of the n-6 family. Some carnivorous fish require eicosapentaenoic acid (EPA 5,8,ll,14,17-20 5n-3) and docosahexaenoic acid (DHA 4,7,10,13,16,19-22 6n-3) rather than linolenic acid (9,12,15-18 3n-3) alone. 

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. 

Until recently, the commonly accepted pathway for the metabolic conversion of LNA (18 3n-3) to DHA (22 6n-3), and the corresponding conversion of dietary linoleic acid (18 2n-6) to 22 5n-6, involved the sequential utilization of delta 6-, 5-, and 4-desaturases along with elongation reactions (2-carbon additions) as depicted in Figure 10.2. The more recent and pioneering work of Dr. Howard... 

The precursors of both n-6 and n-3 polyunsaturated fatty acids (PUFAs), linoleic acid and (/.-linolenic acid, respectively, are essential for mammals as they are required for normal physiological function and cannot be synthesized de novo (Holman, 1968). They can only be accumulated by placental transfer or by dietary intake. Once accretion of these fatty acids has occurred, metabolic, conservation and recycling pathways sustain them (B azan et al., 1994). Unlike mammals, plants can synthesize these precursor PUFAs (linoleic and a-linolenic acids) so they are found in abundance in the chloroplast membranes of plants, in certain vegetable oils, and in the tissues of plant-eating animals (Nettleton, 1991). The best sources of a-linolenic acid are vegetable oils, such as perilla (Yoshida et al., 1993) rapeseed (canola), linseed, walnut, and soybean (Nettleton, 1991). They are also abundant in shellfish, fish, and fish products and can be found in low amounts in green, leafy vegetables and baked beans (Nettleton, 1991 Sinclair, 1993). 

Fig. 1. The n-3/n-6 metabolic pathways. Precursors of the n-3 (18 3n-3, linolenic acid) and n-6 (18 2n-6, (/.-linoleic acid) are converted by a series of desaturation and (adding double bonds) and elongation (adding carbon atoms to the hydrocarbon backbone) reactions. Note that the same enzymes catalyze n-3 and n-6 desaturation and elongation reactions. Major metabolites are indicated. PUFAs with 20-carbon backbones (20 4n-6, arachidonic acid, and 20 5n-3, eicosapentaenoic acid) are precursors to the eicosanoids (prostaglandins, leukotrienes, thromboxanes). Docosahexaenoic acid (22 6n-3) is also indicated. Note that only a limited part of the metabolic pathway is shown in this figure.

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. 

Moghaddam et al. (13) reported that linoleic acid and arachidonic acid can be metabolized to their dihydroxy-THFA (tetrahydrofuran-diols) in vitro by microsomal cytochrome P450 epoxidations, followed by microsomal epoxide hydrolase. In their metabolic pathways, saturated dihydroxy-THFA are produced because 9,10(12,13)-dihydroxy-12,13(9,10)-epoxy-octadecanoate converted from linoleic acid methyl ester are cyclized (13). These saturated dihydroxy-THFA exhibit cytotoxic activity and mitogenic activity for breast cancer and... 

HETE. The 15-lipoxygenase (15-LOX) has been the most extensively characterized pathway in the reticulocytes, leukocytes, and airway epidermal cells (24-27). An outline in Figure 5 shows that 15-LOX can, on the one hand, catalyze the abstraction of a proton from C-13 of 20-carbon AA to produce 155-hydroperoxyeicosatetraenoic acid (155-HPETE), whereas on the other hand, the 18-carbon linoleic acid is converted mainly to 13-hydroperoxyoctadecadienoic acid (13-HPODE) and 9-hydroperoxy-10,12- , Z-octadecadienoic acid (9-HPODE) in the ratio of 10 1 (28). Both the 155-HPETE (intermediate) from AA and 13-HPODE (intermediate) from linoleic acid can be further metabolized by glutathione peroxidase to mainly monohydroxylated 15S-HETE and 13-hydroxy-octadecadienoic acid (HODE), respectively. 

Fig. 1. Metabolic pathway converting linoleic acid to arachidonic acid and hence, eicosanoids. COX, cyclooxygenase PA-1, plasmin activator-l 2-AQ, 2-arachidonyl glycerol PC, prostaglandin.

The starting point of their biosynthesis is linoleic acid, an essential dietary constituent for Man. This is converted to arachidonic acid (4.68) (a 20-carbon aliphatic acid with four double bonds) which is stored as a phospholipid in cell membranes. From these it is liberated, on demand, by phospholipase A2. Arachidonic acid is further metabolized by two pathways. In the first of these, it... 

Since AA is only a minor fatty acid in higher plants, eicosanoids are not of major importance for plant physiology. However, the oxygenation metabolites of linoleic acid and a-linolenic acid, called oxylipins [5,6], do play a role in plant defence reactions, in the formation of phytohormones and in the synthesis of cutin monomers [6,40-43]. Oxylipins constitute a family of lipids that are formed from free fatty acids by a cascade of reactions involving at least one step of dioxygen-dependent oxidation. The biosynthesis of oxylipins proceeds via a large number of metabolic pathways, most of which involve an unsaturated hydroperoxy fatty acid as intermediate (Scheme 10). Conversion of the hydroperoxide via the peroxide lyase pathway, the allene oxide pathway and the recently discovered peroxygenase pathway, leads to a complex pattern of oxidized lipid mediators. 

Oxidative Metabolism. Because CLA are fatty acids, they are substrate for energy production through oxidative metabolism. However, few studies have been conducted to consider this metabolic pathway. One study was published on carbon dioxide production during 24 h after a bolus intragastric delivery of labeled CLA isomers compared with linoleic acid (16). It appeared (Fig. 15.2) that both CLA isomers studied were more oxidized than linoleic acid. In that study, 70% of the radioactivity was recovered as CO2, a value close to what was previouly observed with linolenic acid (17). However, when looking at the mechanisms involved in mitochondrial oxidation, Clouet et al. (18) showed that mitochondrial respiration with rumenic acid was lower than that with linoleic acid. These difference between both fatty acids may be due to a lower camitine-acylcamitine translocase activity. 

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