There are two major classes of polyunsaturated fatty acids (PUFAs): the omega-3 (n-3) and the omega-6 (n-6) fatty acids, where the number corresponds to the position of the first double bond proximate to the methyl end of the fatty acid. Omega-3 and omega-6 fatty acids are considered essential fatty acids. Humans cannot synthesize them, instead they are supplied through diet. Linoleic acid (LA, 18:2(n-6)), a major component of omega-6 fatty acids and alpha-linolenic acid (ALA, 18:2(n-3)) a major component of omega-3 fatty acids are the two main dietary essential fatty acids (EFAs) in humans. ALA and LA obtained from diet are converted in the body into their longer chain and more unsaturated omega-3 and omega-6 products by a series of desaturation and elongation steps. Metabolism of ALA and LA to their corresponding products is mediated via common enzyme systems. In humans ALA is finally converted to docosahexaenoic acid (DHA, C22:6(n-3)), and LA is converted to docosapentaenoic acid (DPA, C22:5(n-6)). The intermediary omega-3 and omega-6 series fatty acids play a significant role in health and disease by generating potent modulatory molecules for inflammatory responses, including eicosanoids (prostaglandins, and leukotrienes), and cytokines (interleukins) and affecting the gene expression of various bioactive molecules (Kapoor & Huang 2006, Sprecher 2002, Burdge 2006).
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3-hydroxy tetracosahexaenoyl-CoA undergoes dehydrogenation to form 1-(3-oxo-6Z,9Z,12Z,15Z,18Z,21Z-tetracosahexaenoyl)-CoA, catalysed by DBP. DBP is a bifunctional enzyme, involved in the hydration of a variety of trans-2,3-dehydroacyl-CoA's but also mediating dehydrogenation of a variety of 3-hydroxyacyl-CoA's (Jiang et al. 1997).
The 24-carbon tetracosahexaenoyl-CoA (6,9,12,15,18,21-24:6(n-3) is transported to peroxisomes to undergo a putative single cycle of peroxisomal beta-oxidation, producing Docosahexaenoic Acid (DHA) (Sprecher 2002, Luthria et al. 1996).
SDA-CoA (6,9,12,15-18:4(n-3)) is rapidly elongated by two carbon atoms to 8,11,14,17-eicosatetraenoyl-CoA (8,11,14,17-20:4(n-3), ETA-CoA). The NADPH-consuming enzyme long-chain fatty acyl elongase (ELOVL5) mediates this reaction which and adds malonyl-CoA to the SDA-CoA and releases carbon dioxide and free CoA (Leonard et al. 2004).
One cycle of peroxisomal beta-oxidation shortens C24:5(n-6) to C22:5(n-6), releasing one molecules of acetyl-CoA. Peroxisomal acyl-coenzyme A oxidase 1 (AOX), D-bifunctional protein (DBP/MFE2), and either peroxisomal 3-oxoacyl-CoA thiolase (Th) or SCPx thiolase (SCPx) enzymes have been proposed to be responsible for this partial beta-oxidation (Infante & Huszagh 1998, Su et al. 2001).
Docosatetraenoyl-CoA is elongated to tetracosatetraenoyl-CoA (TTA-CoA, 9,12,15,18-tetracosatetraenoic acid, 9,12,15,18-24:4(n-6)) by the elongase enzyme ELOVL2.
Gamma-linolenoyl-CoA (6,9,12-20:3(n-6)) is rapidly elongated to dihomo-gamma-linolenoyl-CoA (DGL-CoA; 8,11,14-20:3(n-6)) by the action of C18-PUFA-specific elongase 5 (ELOVL5). Two carbon atoms are added during this reaction. DGL-CoA later undergoes desaturation to form arachidonic acid (AA, 5,8,11,14-20:4(n-6)). Depending on the cell type, DGL-CoA can also be metabolized by cyclooxygenases and lipoxygenases to produce anti-inflammatory eicosanoids (prostaglandins of series 1 (PGE1) and 15-hydroxyeico- satrienoic acid (15-HETrE)). GLA and these two oxidative metabolites exert clinical effects in a variety of diseases, including suppression of chronic inflammation, vasodilation and lowering of blood pressure, inhibition of platelet aggregation and thrombosis. (Fan et al. 2001, Fan & Chapkin 1998, Kapoor & Huang. 2006)
Retroconversion of C24:6(n-3) to docosahexaenoic acid (22:6(n-3) involves the initial oxidation of tetracosahexaenoyl-CoA to an intermediate 1-(2E,6Z,9Z,12Z,15Z,18Z,21Z-tetracosaheptaenoyl)-CoA (delta2-THA-CoA). This step is catalysed by the peroxisomal enzyme Straight-chain acyl-CoA oxidase (SCOX) (Ferdinandusse et al. 2001).
DHA-CoA preferentially moves back to the ER, perhaps as a free fatty acid. This conversion is usually catalysed by acyl-CoA thioesterases (ACOTs). No specific acyl-CoA thioesterase enzyme has been identified for the peroxisomal metabolism of DHA-CoA, but the peroxisomal ACOT8 has a wide substrate specificity and is likely to be responsible (Ferdinandusse et al. 2003, Hunt & Alexson. 2008).
The final step in the beta-oxidation process is the thiolytic cleavage of 1-(3-oxo-6Z,9Z,12Z,15Z,18Z,21Z-tetracosahexaenoyl)-CoA to form docosahexaenoyl-CoA (DHA-CoA). This step is catalysed by both sterol carrier protein X (SCPx) (this reaction) and the classic 3-ketoacyl-CoA thiolase (Ferdinandusse et al. 2001).
The final step in the beta-oxidation process is the thiolytic cleavage of 1-(3-oxo-6Z,9Z,12Z,15Z,18Z,21Z-tetracosahexaenoyl)-CoA to form docosahexaenoyl-CoA (DHA-CoA). This step is catalysed by both sterol carrier protein X (SCPx) and the classic 3-ketoacyl-CoA thiolase (this reaction) (Ferdinandusse et al. 2001).
Eicosapentaenoyl-CoA (EPA-CoA) is transformed to docosapentaenoyl-CoA (DPA-CoA/clupanodonic acid; 7,10,13,16,19-22:5(n-3)) by addition of two carbon atoms from malanoyl-CoA. This reaction is catalyzed by the enzymes ELOVL5/2 (Leonard et al. 2004). DPA is quite high in seal oil and may act as an anti-atherogenic factor. DPA has 10-fold greater endothelial cell migration ability than EPA, which is important in wound-healing processes. DPA may act as a precursor for production of the DPA-related D-series of resolvins or neuroprotectins (Kaur et al. 2011).
DGL-CoA (8,11,14-eicosatrienoyl-CoA) undergoes desaturation by delta 5-desaturase (D5-desaturase) forming arachidonoyl-CoA (AA-CoA, 5,8,11,14-Eicosatetraenoic acid). D5-desaturase has 62% sequence identity with D6-desaturase but desaturates a different carbon atom, adding a double bond at position C5 in arachidonoyl-CoA (AA-CoA). AA can be metabolized by variety of oxygenases (including cyclo-oxygenase and lipoxygenase systems) to form a family of varying products known as eicosanoids, prostaglandins, leukotrines and thromboxanes thus playing important role in inflamation response.
DHA is transported back to the ER, where it is incorporated into membrane lipids instead of being further beta-oxidized in the peroxisome (Ferdinandusse et al. 2003).
Arachidonyl-CoA undergoes a two-carbon chain elongation on the carboxyl end to form docosatetraenoyl-CoA (DTA-CoA/Adrenic acid/7,10,13,16-docosatetraenoic acid (7,10,13,16-22:4(n-6)). This reaction is catalyzed by the enzymes ELOVL5 or ELOVL2. Malanoyl-CoA provides the additional two carbons required for elongation. Docosatetraenoyl-CoA is further metabolized by cyclooxygenases (COX), lipoxygenases (LO) and cytochrome P450s (CYP450s) to dihomo (DH) eicosanoids (Kopf et al. 2010, Leonard et al. 2004).
In the first step the precursor apha-linolenic (9,12,15-18:3(n-3)) acid is activated to a high energy form known as alpha-linolenoyl-CoA (9Z,12Z,15Z-octadecatrienoyl-CoA) by the iron enzyme long-chain-fatty-acid-CoA-ligase (acyl-CoA synthetase 1, ACSL1) and coenzyme A.
Prior to this reaction all the enzymes involved in the desaturation and elongation of linoleic acid are located in the ER, but for this last step tetracosapentaenoyl-CoA must be transferred to the peroxisomes for partial beta-oxidation to docosapentaenoyl-CoA (DPA-CoA, 4,7,10,13,16-22:5(n-6)) (Su et al. 2001).
The dietary essential fatty acid (EFA) linoleic acid (LA) is activated to a high energy form known as linoleoyl-CoA by the action of long-chain acyl-CoA synthetases (ACSLs). Thioesterification of long-chain fatty acids into their acyl-CoA derivatives is considered to be the first committed step in fatty acid metabolism. Formation of acyl-CoA allows an otherwise non-reactive fatty acid to participate in biosynthetic or catabolic pathways. This acyl CoA form is converted to its longer-chain polyunsaturated products by a series of desaturation and elongation reactions (Ellis et al. 2010, Watkins 2008).
Delta2-THA-CoA is hydrated to 3-hydroxyacyl-CoA intermediate 1-(3-hydroxy-6Z,9Z,12Z,15Z,18Z,21Z-tetracosahexaenoyl)-CoA by HSD17B4/DBP (d-bifunctional protein) dimer.
Tetracosapentaenoyl-CoA (9,12,15,18,21-24:5(n-3)) is further converted by delta 6-desaturase (FADS2) to tetracosahexaenoyl-CoA (6,9,12,15,18,21-24:6(n-3)).
Alpha-linoloyl-CoA is converted to Stearidonoyl-CoA (SDA, 6,9,12,15-18:3(n-3)) by delta-6-destaurase (fatty acid desaturase-2, FADS2). FADS2 uses the cytochrome b5 system to add a double bond at position 6. This is the rate limiting step in alpha-linolenic acid (ALA) metabolism (Horrobin 1993).
Eicosatetraenoyl-CoA (ETA-CoA) is desaturated by an additional carbon-carbon bond to form 5Z,8Z,11Z,14Z,17Z-eicosapentaenoyl-CoA (EPA-CoA, 5,8,11,14,17-20:5(n-3)). Delta-5-desaturase is required for this conversion. EPA-CoA has health benefits due to its anti-inflammatory actions. It is a precursor for the anti-inflammatory series-3 prostaglandins (PG), the series-5 leukotrienes (LT) and the series-3 thromboxanes (TA), which are anti-atherogenic and anti-thrombogenic (Ross et al. 2009).
The first major step in the metabolism of linoleic acid (LA) is desaturation of delta 9,12-octadecadienoyl CoA/linoleoyl CoA (LA-CoA) to delta 6,9,12-octodecatrienoyl CoA/gamma-lenoleoyl CoA (GLA-CoA). This step is catalyzed by delta-6-destaurase (fatty acid desaturase-2, FADS2) which introduces a cis-double bond between carbons 6 and 7. This is the rate limiting step in LA metabolism (Horrobin 1993).
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Depending on the cell type, DGL-CoA can also be metabolized by cyclooxygenases and lipoxygenases to produce anti-inflammatory eicosanoids (prostaglandins of series 1 (PGE1) and 15-hydroxyeico- satrienoic acid (15-HETrE)). GLA and these two oxidative metabolites exert clinical effects in a variety of diseases, including suppression of chronic inflammation, vasodilation and lowering of blood pressure, inhibition of platelet aggregation and thrombosis. (Fan et al. 2001, Fan & Chapkin 1998, Kapoor & Huang. 2006)