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Fatty Acids: Polyunsaturated with Methylene-Interrupted Double Bonds



1. Structure and Nomenclature

Structural formula for methylene-interrupted double bondsThe lipids of all higher organisms contain appreciable quantities of polyunsaturated fatty acids ('PUFA') with methylene-interrupted double bonds, i.e. with two or more double bonds of the cis-configuration separated by a single methylene group; the term ‘homo-allylic’ may also be used to describe this molecular feature. Most bacteria, other than Cyanobacteria, cannot produce polyunsaturated fatty acids. In higher plants, the number of double bonds in fatty acids seldom exceeds three, but in algae and animals there can be up to six (very rarely more in some marine organisms). Two principal families of polyunsaturated fatty acids occur in nature that are derived biosynthetically from linoleic (9-cis,12-cis-octadecadienoic) and α-linolenic (9-cis,12-cis,15-cis-octadecatrienoic) acids.

Structural formulae of linoleic and linolenic acids

In the shorthand nomenclature, these are designated 9c,12c-18:2 and 9c,12c,15c-18:3, respectively. The number before the colon specifies the number of carbon atoms, and that after the colon, the number of double bonds. The position of the terminal double bond can be denoted in the form (n-x), where n is the chain-length of the fatty acid and x is the number of carbon atoms from the last double bond, assuming that all the other double bonds are methylene-interrupted. Thus linoleate and α-linolenate are 18:2(n-6) and 18:3(n-3), respectively (18:2ω6 and 18:3ω3 in the older literature).

Both of these parent fatty acids can be synthesised in plants, but not in animal tissues, and they are therefore essential dietary components (see below). Polyunsaturated fatty acids can be found in most lipid classes, but they are especially important as constituents of the phospholipids, where they appear to confer distinctive properties to the membranes, in particular by decreasing their rigidity. The exception is the sphingolipids, where they are rarely detected in other than trace amounts. In both animals and plants, they are key precursors of the oxylipins.


2. The (n-6) Family of Polyunsaturated Fatty Acids

Linoleic acid is a ubiquitous component of plant lipids, and of all the seed oils of commercial importance. For example, corn, sunflower and soybean oils usually contain over 50% of linoleate, and safflower oil contains up to 75%. Although all the linoleate in animal tissues must be acquired from the diet, it is usually the most abundant dienoic fatty acid in mammals (and in most lipid classes), typically at levels of 15 to 25%, although it can amount to as much as 75% of the total fatty acids of heart cardiolipin. It is also a significant component of fish oils, although fatty acids of the (n-3) family tend to predominate in this instance.

Analogues of linoleic acid with trans-double bonds are occasionally found in seed oils. For example, 9c,12t-18:2 is reported from Dimorphotheca and Crepis species, and 9t,12t-18:2 is found in Chilopsis linearis.

Scottish thistleThe remaining members of the (n-6) family of fatty acids are synthesised from linoleate in animal and plant tissues by a sequence of elongation and desaturation reactions as described below. These metabolites can function as essential fatty acids also. Shorter-chain components may be produced by alpha or beta-oxidation.

γ-Linolenic acid ('GLA' or 6-cis,9-cis,12-cis-octadecatrienoic acid or 18:3(n-6)) is usually a minor component of animal tissues in quantitative terms (< 1%), as it is rapidly converted to higher metabolites. It is found in a few seed oils, and those of evening primrose, borage and blackcurrant have some commercial importance. Evening primrose oil contains about 10% GLA, and is widely used both as a nutraceutical and a medical/veterinary product.

11-cis,14-cis-Eicosadienoic acid (20:2(n-6)) is a common minor component of animal tissues. 8-cis,11-cis,14-cis-Eicosatrienoic acid (dihomo-γ-linolenic acid or 20:3(n-6)) is the immediate precursor of arachidonic acid, and of a family of eicosanoids (PG1 prostaglandins), but it does not accumulate to a significant extent in animal tissue lipids and is typically about 1-2% of the phospholipid fatty acids.

Structural formula of arachidonic acidArachidonic acid (5-cis,8-cis,11-cis,14-cis-eicosatetraenoic acid or 20:4(n-6)) is the most important metabolite of linoleic acid in animal tissues, both in quantitative and biological terms. It is often the most abundant polyunsaturated component of the phospholipids, and can comprise as much as 40% of the fatty acids of phosphatidylinositol. As such, it has an obvious role in regulating the physical properties of membranes, but the free acid is also involved in the mechanism by which apoptosis is regulated. Meat is the main dietary source in humans. While arachidonate is present in all fish oils, polyunsaturated fatty acids of the (n-3) families tend to be present in much larger amounts. Arachidonic acid is frequently found as a constituent of mosses, liverworts and ferns, but there appears to be only one definitive report of its occurrence in a higher plant (Agathis robusta). The fungus Mortierella alpina is a commercial source or arachidonate via a fermentation process.

Several families of eicosanoids are derived from arachidonate, including prostaglandins (PG2 series), thromboxanes, leukotrienes, and lipoxins, with phosphatidylinositol being the primary source. These have an enormous range of essential biological functions that are discussed in elsewhere in these web pages. In addition, 2-arachidonoylglycerol and anandamide (N-arachidonoylethanolamine) have important biological properties as endocannabinoids, although they are minor lipids in tissues in quantitative terms.

4,7,10,13,16-Docosapentaenoic acid (22:5(n-6)) is usually a relatively minor component of animal lipids, but it is the main C22 polyunsaturated fatty acid in the phospholipids of testes, where it can amount to 70% of the lysobisphosphatidic acid in this tissue, for example. In this instance, C22 fatty acids of the (n-3) family are present at relatively low levels, in contrast to most other reproductive tissues.

Other fatty acids of the (n-6) family that are found in animal tissues include 22:3(n-6) and 22:4(n-6), and the latter, 7,10,13,16-docosatetraenoic or adrenic acid, is a significant component of the phospholipids of the adrenal glands and of testes. Tetra- and pentaenoic fatty acids of the (n-6) family from C24 to C30 have been found in testes, where they are essential for male fertility and sperm maturation, while even longer homologues occur in retina. Very-long-chain fatty acids of this type were first reported from human brain in patients with the rare inherited disorder, Zellweger's syndrome, but it is now established that such fatty acids with up to 38 carbon atoms and with from 3 to 6 methylene-interrupted double bonds are present at low levels in the brains of normal young humans, with 34:4(n-6) and 34:5(n-6) tending to predominate. In ceramides and sphingomyelin of rat testes, 28:4(n-6) and 30:5(n-6) fatty acids are the major VLC-PUFAs found, while 32:3(n-6) and 32:4(n-6) are abundant in the lipids of human spermatozoa.

The most highly unsaturated fatty acid of the (n-6) family to have been characterized are 28:7(n-6) (4,7,10,13,16,19,22-octacosaheptaenoate), which has been found in the lipids of marine dinoflagellates and herring muscle, and 4,7,10,13,16,19,22,25,28-tetratriacontanonaenoic acid (34:9(n-6)) from the freshwater crustacean species Bathynella natans.


3. The (n-3) Family of Polyunsaturated Fatty Acids

α-Linolenic acid (9-cis,12-cis,15-cis-octadecatrienoic acid or 18:3(n-3)) is a major component of the leaves and especially of the photosynthetic apparatus of algae and higher plants, where most of it is synthesised. It can amount to 65% of the total fatty acids of linseed oil, where its relative susceptibility to oxidation has practical commercial value in paints and related products. In contrast, soybean and rapeseed oils have up to 7% of linolenate, and this reduces the value of these oils for cooking purposes. α-Linolenic acid is the biosynthetic precursor of oxylipins such as the jasmonates in plants, which appear to have functions that parallel those of the eicosanoids in animals. In animal tissue lipids, α-linolenic acid tends to be a minor component (<1%), the exception being grass-eating non-ruminants such as the horse or goose, where it can amount to as much as 10% of the adipose tissue lipids.

As with linoleate, the remaining members of the (n-3) family of fatty acids are synthesised from α-linolenate in animal and plant tissues by a sequence of elongation and desaturation reactions as described below, while shorter-chain components may also be produced by alpha or beta-oxidation. They also are essential fatty acids.

11,14,17-Eicosatrienoic acid (20:3(n-3)) can usually be detected in the phospholipids of animal tissues but rarely at above 1% of the total, although somewhat higher concentrations may be found in fish oils.

Stearidonic acid (6,9,12,15-octadecatetraenoic or 18:4(n-3)) is occasionally found in plants as a minor component, and it occurs in algae and fish oils. 3,6,9,12,15-Octadecapentaenoic acid or 18:5(n-3) is a significant component of the lipids of dinoflagellates, and it can enter the marine food chain from this source.

8,11,14,17-Eicosatetraenoic acid (20:4(n-3)) is found in most fish oils and as a minor component of animal phospholipids. It is frequently encountered in algae and mosses, but rarely in higher plants.

Structural formula of eicosapentaenoic acid5,8,11,14,17-Eicosapentaenoic acid ('EPA' or 20:5(n-3)) is one of the most important fatty acids of the (n-3) family. It occurs widely in algae and in fish oils, which are major commercial sources, but there are few definitive reports of its occurrence in higher plants. It is a key constituent of the phospholipids in animal tissues, especially in brain, and it is the precursor of the PG3 series of prostaglandins and resolvins, which have anti-inflammatory effects (see the appropriate web pages for further discussion). There is currently great interest in the role of this acid in alleviating the symptoms of neurological disorders such as schizophrenia.

7,10,13,16,19-Docosapentaenoic acid (22:5(n-3)) is an important constituent of fish oils, and it is usually present in animal phospholipids at a level of 2 to 5%. While it has received relatively little study, it is known that it can be retro-converted to EPA, and it reacts with lipoxygenases to form distinctive metabolites.

Structural formula of docosahexaenoic acid4,7,10,13,16,19-Docosahexaenoic acid ('DHA' or 22:6(n-3)) is usually the end point of α-linolenic acid metabolism in animal tissues. It is a major component of fish oils, especially from tuna eyeballs, and of animal phospholipids, those of brain synapses and retina containing particularly high proportions. Indeed, there is some evidence that increased levels of this fatty acid are correlated with improved cognitive and behavioural function in the development of the human infant, although this is controversial. DHA is not present in higher plants, but it is found in high concentrations in many species of algae, especially those of marine origin, where it may be the major source of DHA and EPA in fish. Via the food chain, fish contribute substantially to the levels of these fatty acids in terrestrial systems including humans.

As with the (n-6) family, very-long-chain fatty acids (C24 to C38) of the (n-3) families occur in the retina, brain and sperm, where they are derived biosynthetically by elongation of the C20 and C22 polyunsaturated precursors. Perhaps surprisingly, 20:5(n-3) in retina is preferentially elongated in comparison to 22:6(n-3).

Other fatty acids of the (n-3) family that are found in nature include 22:3(n-3) from animal tissues and 16:3(n-3), which is a common constituent of leaf lipids (see our web pages on mono- and digalactosyldiacylglycerols). 16:4(n-3), 16:4(n-3), 21:5(n-3), 24:5(n-3) and 24:6(n-3) are occasionally present in marine organisms, including fish. Trace levels of highly unsaturated fatty acids of the (n-3) family (suggested to be 38:7(n-3) to 44:12(n-3)) have been reported from brains of patients with genetic impairments of peroxisome function, but the most highly unsaturated fatty acid of the (n-3) family to have been characterized from a normal tissue is 4,7,10,13,16,19,22,25-octacosaoctaenoate (28:8(n-3)) from marine dinoflagellates.

Of these fatty acids, DHA appears to have special properties. It is not a substrate for the prostaglandin synthase-cyclooxygenase enzymes, and indeed it inhibits them. However, via the action of lipoxygenases, it is the precursor of the docosanoids, such as the resolvins or protectins (specialized pro-resolving mediators), which are analogous to the eicosanoids but have potent anti-inflammatory and immuno-regulatory actions.

Scottish thistleThe concentration of DHA in tissues has been correlated with a number of human disease states, and it is essential to many neurological functions. Particular attention has been given to its role in the retina, where it is a major structural component of the photoreceptor outer segment membranes. For example, it binds strongly to specific sites on rhodopsin, the primary light receptor in the eye, modifying its stability and activity. It affects signalling mechanisms involved in photo-transduction, enhancing activation of membrane-bound retinal proteins, and it may be involved in rhodopsin regeneration. In some cases, sight defects have been ameliorated with DHA supplementation. It is intimately involved with phosphatidylserine metabolism in neuronal tissue. Similarly, N-docosahexaenoylethanolamide or 'synaptamide' is a significant component of brain tissue and is an important signalling molecule that induces neurogenesis, neuritogenesis and synaptogenesis in developing neurons. This is a further mechanism by which DHA promotes brain development and function.

DHA is believed to have specific effects on gene transcription that regulate a number of proteins involved in fatty acid synthesis and desaturation, for example. It has been demonstrated to have beneficial effects upon inflammatory disorders of the intestine and in reducing the risk of colon cancer, which may be mediated through associations with specific signalling proteins in membranes.

As a phospholipid constituent, it has profound effects on the properties of membranes, modulating their structure and function. In such an environment, DHA is believed to be more compact than more saturated chains with an average length of 8.2Å at 41°C compared to 14.2Å for oleic chains. This is the result of the adoption of a conformation with pronounced twists of the chain, which reduce the distance between the ends. The methyl group with its extra bulk is located in the interior region. In mixed-chain phospholipids, a further consequence is a marked increase in the conformational disorder of the saturated chain. There appears to be an incompatibility between the rigid structure of cholesterol and the highly flexible chains of DHA, promoting the lateral segregation of membranes into PUFA-rich/cholesterol-poor and PUFA-poor/cholesterol-rich regions. The latter may ultimately become the membrane microdomains known as rafts. PUFA-rich/cholesterol-poor membrane microdomains are technically less easy to study than rafts, but they may also contain particular proteins and have important biological functions. It has been proposed that changes in the conformation of signalling proteins when they move between these very different domains may have the potential to modulate cell function in a manner that may explain some of the health benefits of dietary consumption of DHA.


4. The (n-9) Family of Polyunsaturated Fatty Acids

Oleate can be chain elongated and desaturated in animal tissues with 5,8,11-eicosatrienoic acid (20:3(n-9) or 'Mead's acid') as the most important product, but this only accumulates in tissues when the animals are suffering from essential fatty acid deficiency (see below). In this condition, 18:2(n-9), 20:2(n-9) and 22:3(n-9) are other fatty acids of this family that may be found at low levels.


5. Other Families of Polyunsaturated Fatty Acids

9,12-Hexadecadienoic acid (16:2(n-4)) is found in marine microorganisms and is presumably the biosynthetic precursor of other fatty acids with an (n-4) terminal structure, i.e. 18:2(n-4), 20:2(n-4), 16:3(n-4) and 18:3(n-4). Fatty acids of an (n-1) family, also found in marine organisms, are believed to be derived biosynthetically by further desaturation (Δ15) of 6,9,12-hexadecatrienoic acid (16:3(n-4)). The main naturally occurring fatty acids of this type are 16:4(n-1) and 18:4(n-1), but 18:5(n-1) has also been detected. Similarly, trace amounts of polyunsaturated fatty acids of an (n-7) family are occasionally encountered in marine organisms and are presumably metabolites of 9-16:1.


6. Biosynthesis of Linoleic and Linolenic Acids in Plants

Linoleic and α-linolenic acids are synthesised in plant tissues from oleic acid by the introduction of double bonds between the existing double bond and the terminal methyl group by the sequential action of Δ12- and Δ15-desaturases.

Biosynthesis of alpha-linolenic acid in plants

As described in our web page dealing with saturated fatty acids most fatty acid synthesis occurs in the plastids, with palmitoyl-ACP and then stearoyl-ACP as the primary products of fatty acid synthases. The latter is desaturated to form oleoyl-ACP, which must be hydrolysed to oleic acid (see our web page on monoenes) and then converted to oleoyl-CoA for transport across the plastid envelope. 1-Acyl,2-oleoyl-phosphatidylcholine (PC) is formed by an acyl transferases, and this is the main substrate for the membrane-bound Δ12-desaturase in the endoplasmic reticulum with formation of 1-acyl,2-linoleoyl-PC. How the diacylglycerol moiety of the latter is transferred back into the plastid in not yet known; it may be that a phospholipid transfer protein is able to transport the intact PC across the membrane or hydrolysis to form diacylglycerols (DAG) may occur for transport. The next certain product in the plastid is linoleoyl-monogalactosyldiacylglycerol (MGDG), and this is the substrate for the Δ15-desaturase with formation of α-linolenoyl-MGDG. As more plant species are investigated, further desaturases with variations in their substrates and sub-cellular distributions continue to be discovered. Those plants that produce significant amounts of 16:3(n-3) add further complications to the problem, and it is evident that much remains to be learned of the overall process.

Biosynthesis of linoleate and linolenate in leaves of plants

In fact, two distinct desaturases have been characterized that can insert the Δ12-double bond, i.e. a plastidial enzyme (FAD6), which uses the terminal methyl group as a reference point and is an ω6-desaturase as it introduces the double bond six carbons from the terminal carbon, and secondly an extra-plastidial oleate Δ12-desaturase (FAD2) that is selective for C12,13-desaturation independently of chain length. The latter is related closely to an enzyme in the seeds of castor oil (Ricinus communis) that converts oleate to (R)-12-hydroxystearate. Indeed, whether the product is a hydroxyl group or a double bond may depend on the nature of only four amino acid residues. Less is known of the desaturase (FAD3) that converts linoleate to α-linolenate, but it is argued that it should be considered as an ω3- rather than as a Δ15-enzyme. It also has much in common with hydroxylase enzymes.

Infrequently in plants, a double bond is inserted between an existing double bond and the carboxyl group as in the biosynthesis of γ-linolenic acid in evening primrose and borage seed oils. In this instance, the double in position 6 is inserted after those in positions 9 and 12. Plant Δ6-desaturases contain the donor of reduced equivalents, cytochrome b5, physically fused to the N-terminus; it is sometimes termed a 'front-end' desaturase.

Biosynthesis of gamma-linolenic acid in plants

Algae are capable of synthesising C20 and C22 polyunsaturated fatty acids of both the n-6 and n-3 families. Obviously, they contain a much wider range of desaturases and elongases than are present in higher plants, and it is apparent that these are distributed between plastids and extra-plastid cellular compartments with involvement of various lipid substrates. Both eukaryotic-like (C20/C20, C18/C18) and prokaryotic-like (C18/C16, C20/C16) species of complex lipids are formed (see our web page on plant galactolipids).


7. Biosynthesis of the (n-6) Family of Polyunsaturated Fatty Acids in Animals

In animal tissues, additional double bonds can only be inserted between an existing double bond and the carboxyl group. The linoleic acid, which is the primary precursor molecule for the (n-6) family of fatty acids, must come from the diet. Biosynthesis of polyunsaturated fatty acids requires a sequence of chain elongation and desaturation steps, as illustrated below, and the various enzymes require the acyl-coenzyme A esters as substrates not intact lipids (unlike plants), with the liver as the main organ involved in the process.

Biosynthesis of the n-6 family of polyunsaturated fatty acids

The first step is believed to be rate limiting and involves desaturation with the introduction of a double bond in position 6 to form γ-linolenic acid. Chain elongation by a two-carbon unit gives 20:3(n-6), which is converted to arachidonic acid by a Δ5-desaturase. This is the main end product of the process. However, two further chain-elongation steps yield first 22:4(n-6) and then 24:4(n-6), which can be further desaturated by a Δ6-desaturase to 24:5(n-6). At least three elongases, designated ELOVL2, 4, and 5, have been characterized of which ELOVL4 is especially important in the retina and ELOVL5 in liver. ELOVL4 is responsible for the formation of very-long-chain polyunsaturated fatty acids (up to C38) in brain, retina and testes (see our web pages on saturated fatty acids for a more detailed discussion of elongases). All the enzymes to this stage are located in the endoplasmic reticulum of the cell, but the last fatty acid must be transferred to the peroxisomes for retro-conversion (β-oxidation) to 22:5(n-6). However, a recent study reports direct desaturation of 22:4(n-6) to 22:5(n-6) by a desaturase produced by the FAD2 gene in human cells in vitro. The relative importance of the two pathways is not known.

The Δ5- and Δ6-desaturases are membrane bound with cytochrome b5 physically fused to the N-terminus, and with three histidine boxes, characteristic of membrane desaturases, and two membrane spanning regions. They use molecular oxygen and an electron transport system as described in our web page dealing with the biosynthesis of monoenoic fatty acids.

The marine parasitic protozoon Perkinus marinus (and at least three other unrelated unicellular organisms) synthesises arachidonic acid by an alternative pathway in which elongation of linoleic to 11,14-eicosadienoic acid is followed by sequential desaturation by Δ8- and Δ5-desaturases. These enzymes are now known to be present in mammals, although the extent of their participation in synthesis of polyunsaturated fatty acids in vivo is uncertain.


8. Biosynthesis of the (n-3) Family of Polyunsaturated Fatty Acids in Animals

Again, the α-linolenic acid, which is the primary precursor molecule for the (n-3) family of fatty acids in animal tissues, must come from the diet. The main pathway to the formation of docosahexaenoic acid (22:6(n-3)) requires a sequence of chain elongation and desaturation steps (Δ5 and Δ6 desaturases), as illustrated below, with acyl-coenzyme A esters as substrates. Thus, α-linolenic acid is sequentially elongated and desaturated, with double bonds being inserted between existing double bonds and the carboxyl group, as far as 24:6(n-3).

Biosynthesis of the n-3 family of polyunsaturated fatty acids

The final steps of what has been termed the ‘Sprecher’ pathway (after Prof. Howard Sprecher of Ohio State University) involve retro-conversion, i.e. removal of the first two carbon atoms by a process of β-oxidation, and take place in the peroxisomes of the cell (as in the case of the (n-6) family of fatty acids). However, as with the latter, a recent study reports direct desaturation of 22:5(n-3) to 22:6(n-3) by a Δ4-desaturase produced by the FAD2 gene in human cells in vitro, with evidence suggesting that the process may occur in mitochondria. This enzyme can also act as a Δ6- or Δ8-desaturase depending on the substrate. Again, the relative importance of the two pathways for the synthesis of 22:6(n-3) in rodents and humans has still to be determined.

A single gene in the rabbitfish codes for an enzyme that performs both Δ5 and Δ4 desaturation to synthesize 22:6(n-3) directly. Similarly, Δ4-, Δ5- and Δ8-desaturases have been found in certain micro-algae of marine origin (e.g. Pavlova salina), suggesting that a more direct route to DHA may exist in these organisms, including desaturation of 22:5(n-3). On the other hand, marine invertebrates such as molluscs and cephalopods appear to lack some of the key desaturases and elongases and produce polyunsaturated fatty acids of both the (n-3) and (n-6) families by unconventional routes.

All the various intermediates may be found in tissues, especially those of fish, but eicosapentaenoic (20:5(n-3)), docosapentaenoic (22:5(n-3)) and docosahexaenoic (22:6(n-3)) acids tend to be by far the most abundant. In human tissues, the measured rates of conversion of α-linoleic acid to longer-chain metabolites are very low, suggesting that a high proportion of the latter must come from the diet (meat, eggs and fish) in normal circumstances. The rate of DHA synthesis in particular is so low that it has been argued that dietary supplementation is essential to maintain sufficient levels in brain and retina, although vegans do not appear to suffer any deficiency symptoms. On the other hand, much of the α-linoleic acid in the diet is directed to long-term storage in adipose tissue, and may be made available slowly for DHA synthesis, thus leading to misleading experimental data. During the natural processes of turnover and renewal of cell membranes in retinal cells, mechanisms exist to ensure that DHA is conserved.

In mice, the fatty acid elongase ELOVL2 has been shown to be important for the synthesis of endogenous DHA in the liver and may be a factor in the control of lipogenesis de novo and many other aspects of lipid metabolism. As with the (n-6) family, the fatty acid elongase designated ELOVL4 is responsible for the biosynthesis of the very-long-chain polyunsaturated fatty acids of the (n-3) family found in the retina, brain, testis and skin.

In contrast to higher plants and mammals, the nematode Caenorhabditis elegans possesses all of the enzymes required for the synthesis of 20:4(n-6) and 20:5(n-3) fatty acids de novo, feats that can also be accomplished by the fungus, Mortierella alpina, and some mosses and red algae.


9. Biosynthesis of Polyunsaturated Fatty Acids by Polyketide Synthase (PKS)

With acetyl-CoA as the primary precursor, the synthesis of 22:6(n-3) by the route described above involves approximately 30 distinct enzymes and 70 reactions. However, an entirely different and much simpler pathway catalysed by a polyketide synthase has been found in marine bacteria, especially Shewanella species, and in fungal-like protoists. The conventional view of polyketides is of secondary metabolites consisting of multiple building blocks of ketide groups (–CH2–CO–), which are synthesised by a polyketide synthase ('PUFA synthase'). This is an enzyme system similar to the fatty acid synthase in bacteria in that it uses acyl carrier protein as a covalent attachment for chain synthesis and proceeds in iterative cycles adding C2 units and double bonds. In contrast to the elongation-desaturation pathway, the double bonds are introduced during the process of fatty acid synthesis. Thus, aerobic desaturation is not required for introducing double bonds into the existing acyl chain, and this is sometimes termed an ‘anaerobic’ pathway, although it has been found in aerobic organisms such as the micro alga Schizochytrium sp. Much remains to be learned of this process in relation to EPA and DHA synthesis, but it is evident that it proceeds via different intermediates from the well-established aerobic pathway as illustrated.

Intermediates in the polyketide pathway to DHA

It is believed that as the chain elongates the ketones groups are reduced to hydroxyls, and this is followed by dehydration reactions to introduce the double bonds. For this purpose, six enzymes are required: 3-ketoacyl synthase, 3-ketoacyl-ACP-reductase, dehydrase, enoyl reductase, dehydratase/2-trans 3-cis isomerase, dehydratase/2-trans, and 2-cis isomerase. Similar reactions occur is some terrestrial bacteria such as the myxobacterial genus Aetherobacter, but the biosynthetic pathways differ somewhat from those in marine organisms in terms of gene organization and structures of the enzyme components of the PUFA synthases. In contrast to the aerobic method of fatty acid synthesis, the polyketide biosynthesis pathways can modify the intermediates in the growing polyketone chain by re-arranging the order and combinations of the various enzymes to produce many different final products including antibiotics, toxins and pigments.


10. Catabolism

Polyunsaturated fatty acids of all families are broken down in animal tissues to produce energy by a multi-step process of β-oxidation. This is discussed in our web page on carnitines. In addition, some very-long-chain fatty acids are oxidized in peroxisomes or 'microbodies, especially in the kidney and liver; the products are medium-chain fatty acids, which are transported to mitochondria for further oxidation. In plants, glyoxysomes in germinating seeds can break down fatty acids rapidly to acetyl-CoA, while β-oxidation occurs in leaves mainly in peroxisomes but also in mitochondria.


11. Essential Fatty Acids

Most fatty acids have important properties that are not easily replaced. For example, many different fatty acids in the unesterified (free) state, but especially the polyunsaturated components, interact with multiple G protein-coupled receptors for free fatty acids (FFAR) on cell surfaces and have important roles in the regulation of nutrition (see our web page on free fatty acids).

However, as discussed briefly above, linoleic and linolenic acids cannot be synthesised in animal tissues and must be obtained from the diet, i.e. ultimately from plants, and there is an absolute requirement for these 'essential fatty acids' for growth, reproduction and good health. Young animals deprived of these fatty acids in the diet rapidly display adverse effects, including diminished growth, liver and kidney damage, and dermatitis; these eventually result in death. A key biochemical parameter is the 'triene-tetraene' ratio, i.e. the ratio of 20:3(n-9) to 20:4(n-6) fatty acids in plasma; levels greater than 0.4 reflect essential fatty acid deficiency. While it takes longer for the effects to become apparent in older animals, which may have substantial stores of essential fatty acids in their body fats, symptoms do appear eventually. The effects of essential fatty acid deficiency have been seen in human infants, on adults on parenteral nutrition or with certain genetic disorders. The absolute requirements are dependent on a number of factors, including species and sex (females appear to have a higher requirement for (n-3) fatty acids), but are usually considered to be a minimum of 1 to 2% for linoleate, and somewhat less for linolenate. In contrast, the requirement for α-linolenate in fish is higher than for linoleate. For some years it was believed that cats lacked a Δ6-desaturase and had an absolute requirement for arachidonic acid especially in their diet, i.e. they were obligate carnivores, but this now appears not to be the case.

Scottish thistleIt has sometimes been argued that linoleate and linolenate per se may in fact be less important than their longer-chain metabolites in animal biology, but there is an absolute requirement for linoleate for the proper functioning of ceramides in skin.

It is evident that arachidonic, eicosapentaenoic and docosahexaenoic acids each have distinct functions, some of which are discussed briefly above, which make them essential for healthy animal metabolism. They are precursors of eicosanoids, including prostaglandins (PG1, PG2 and PG3 series), thromboxanes, leukotrienes, and lipoxins, and docosanoids, including resolvins and protectins, which have a variety of important biological properties. In addition, n-3 polyunsaturated fatty acids per se may exert beneficial effects by regulatory actions in signalling processes, especially in T-cells, for example by modulating the activities of membrane receptors or by influencing gene transcription. Polyunsaturated fatty acids confer distinctive attributes on the complex lipids that may be required for their function in membranes, and in esterified form they can also have important biological properties. For example, arachidonic acid is an essential component of the endocannabinoids. On the other hand, there are suggestions that excessive amounts of polyunsaturated fatty acids in tissues, including those of the n-3 family, have the potential to cause harm.

Although the actual requirement for polyunsaturated fatty acids is relatively low, general nutritional advice for the human diet until recently was that they should comprise a substantial part of the daily intake. Over the last 30 years, there has been a large increase in the consumption of linoleic acid because of an increased use of vegetable oils rich in this fatty acid in the diet. By comparison, the intake of n-3 polyunsaturated fatty acids has been reduced because of a relative decrease in the consumption of fish and vegetables. The consequence is that the ratio of n-6 to n-3 fatty acids in the diet is of the order of 20:1, whereas it was probably closer to 2:1 in historical times in western countries. A consensus is emerging that the proportion of n-3 polyunsaturated fatty acids in the diet should be increased. On the other hand, it is recognized that the propensity of all such fatty acids for oxidation can lead to potentially harmful levels of hydroperoxides in tissues, so higher relative proportions of dietary oleate are now often advised (the Mediterranean diet). However, detailed discussion of such a contentious topic is not possible here.


Recommended Reading


I can also recommend the Chapter on fatty acid biosynthesis in the book - Gurr, M.I., Harwood, J.L., Frayn, K.N., Murphy, D.J. and Michell, R.H. Lipids: Biochemistry, Biotechnology and Health (6th Edition). (Wiley-Blackwell) (2016).



Lipid listings Credits/disclaimer Updated: May 23rd, 2017 Author: William W. Christie LipidWeb icon