Arachidonic acid: structure, synthesis, cascade, benefits, food sources

Arachidonic acid: contents in brief

Chemical structure of arachidonic acid

Arachidonic acid is a polyunsaturated fatty acid (PUFA) with 20 carbon atoms and four double bonds in the cis (Z) configuration.
Since the first double bond, with respect to the methyl end, is between carbon 6 and 7, it is an omega-6 or n-6 polyunsaturated fatty acid, and in shorthand notation is referred to as 20:4n-6.
AA also  belongs to the group of very long chain fatty acids or VLCFAs, that is, fatty acids with 20 carbon atoms or more.

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Properties of arachidonic acid

Arachidonic Acid
Fig. 1 – AA

Molecular weight: 304.46688  g/mol
Molecular formula: C20H32O2
IUPAC name: (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoic acid
CAS registry number: 506-32-1
PubChem: 444899

It has a melting point at -49.5 °C (-57.1 °F; 223.6 K), and a boiling point at 170 °C (338 °F; 443.1 K) at 1.50E-01 mm Hg.

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Synonyms of arachidonic acid

AA
Arachidonate
5,8,11,14-Eicosatetraenoic acid
(all-Z)-5,8,11,14-Eicosatetraenoic acid
all-cis-5,8,11,14-Eicosatetraenoic acid
cis-5,8,11,14-Eicosatetraenoic acid
5Z,8Z,11Z,14Z-Eicosatetraenoic acid
(5Z,8Z,11Z,14Z)-Icosa-5,8,11,14-tetraenoic acid

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Arachidonic acid metabolism

Arachidonic Acid
Fig. 2 – The sn Positions of Phospholipids

Mammalian cells and tissues are rich in AA, mostly present in their membrane phospholipids, in which it is arguably the most important polyunsaturated fatty acid, usually localized in the sn-2 position.
In adult humans following a typical Western diet, its content varies in the different cell types. The highest values are found in platelets, where it constitutes about 25% of the phospholipid fatty acids. Lower values are found in mononuclear cells, liver, erythrocytes, skeletal muscle, neutrophils, and cardiac muscle, about 22, 20, 17, 17, 15 and 9% of the phospholipid fatty acids, respectively.

AA can originate from:

  • de novo synthesis;
  • diet, as preformed product.

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De novo synthesis of arachidonic acid

Arachidonic Acid
Fig. 3 – De Novo Synthesis of AA

AA can be synthesized from endogenous precursors, particularly linoleic acid (LA, 18:2n6), an essential fatty acid as well as the main PUFAs in the Western diet.
Its synthesis, which occurs in the endoplasmic reticulum, involves two desaturation steps and an elongation step.

  • In the first step, LA is desaturated to form gamma-linolenic acid (GLA, 18:3n6). The reaction is catalyzed by acyl-CoA 6-desaturase, also referred to as fatty acid desaturase 2 or Δ6-desaturase (EC 1.14.19.3), the rate-limiting enzyme of the pathway.
    Enzyme activity is affected by nutritional deficiencies as well as inflammatory processes.
  • In the second step, GLA is elongated to form dihomo-gamma-linolenic acid (DGLA, 20:3n6), in a reaction catalyzed by elongase 5.
  • Finally, DGLA is desaturated to form AA, in a reaction catalyzed by acyl-CoA (8-3)-desaturase, also referred as FADS1, acyl-CoA 5-desaturase or Δ5 desaturase (E.C. 1.14.19.44).
    The enzyme appears to be potentially rate-limiting during supplementation with γ-linolenic acid, so that most of the DGLA formed in the previous reaction is inserted at the sn-2 position of phospholipids, as for AA.
    Its activity is influenced by nutritional and environmental factors.

Based on animal studies, it has been assumed that in humans, increasing the intake of linoleic acid, the synthesis of AA could increase. For this reason, it has been recommended to limit the intake of dietary LA to reduce tissue levels of AA (see below).
However, it has been shown that there was no dose-response effect between the intake of dietary linoleic acid and AA tissue levels in subjects consuming a Western-type diet. These data are also supported by the observation that, in adults, the rate of conversion of plasma/serum linoleic acid to AA is very low, being between 0.3% and 0.6%. But why?
It seems that the limiting factor is not the saturation of tissue arachidonic  acid content, but the reaction catalyzed by Δ6-desaturase, since, for example, the levels of AA in blood phospholipids increase as a result of administration of γ-linolenic acid and AA itself.

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Arachidonic acid derivatives and inflammation

Arachidonic Acid
Fig. 4 – AA Derivatives

The analysis of the metabolome of AA highlights the presence of a constellation of metabolites, such as PUFAs with higher degree of unsaturation and longer carbon chain, as well as many bioactive lipids, some with pro-inflammatory activity, and others with anti-inflammatory activity or able to promote the resolution of inflammatory injuries. Indeed, there are many different bioactive lipids; for example, ligands for endocannabinoid receptors, such as anandamide and 2-arachidonoylglycerol, nitrated arachidonic acid, which is an inflammatory and vascular signaling molecule, but especially eicosanoids.

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Arachidonic acid and eicosanoids

Eicosanoids, mediators with autocrine and paracrine activity, are a group of oxygenated 20 carbon fatty acids. Their main precursor is arachidonic acid; others are LA, DGLA, and EPA.
Their biosynthesis, like that of the other bioactive lipids seen previously, is preceded by the release of AA from membrane phospholipids in a reaction catalyzed by phospholipase A2. A second, minor, pathway for the release of AA is the hydrolysis of diacylglycerol or DAG, in a reaction catalyzed by DAG lipase.
The pathways leading to the biosynthesis of eicosanoids from AA are known as “arachidonate cascade“, and three major pathways may be identified, which are named from the enzyme that catalyzes the first step.

  • The cyclooxygenase pathway, in which the first reaction is catalyzed by prostaglandin-endoperoxide synthase or PTGS or cyclooxygenase (E.C. 1.14.99.1).
    There are two cyclooxygenase isoenzymes, referred to as 1, and 2,  or COX-1 and COX-2, and also known as PTGS1 and PTGS2, and prostaglandin G/H synthase 1 and 2.

COX-1 is the constitutive enzyme and is present in most cells, except red blood cells.
COX-2 is the inducible form. It is constitutively expressed in uninflamed tissues and organs, such as heart, kidney, the vasculature, gastric epithelium and brain, but may be induced by inflammatory stimuli in epithelial cells, white blood cells, and smooth muscle cells.

This pathway leads to the synthesis of 2-series prostaglandins (PT), and their derivatives 2-series thromboxanes (TX), so called because they have two double carbon-carbon bonds in their side chains.
Some of these molecules have pro-inflammatory activity, such as prostaglandin E2 or PGE2, others anti-inflammatory activity, such as thromboxane A2 or TXA2.

  • The lipoxygenase pathway, in which the first reaction is catalyzed by the arachidonate 5-lipoxygenase or 5-lipoxygenase o 5-LOX (EC 1.13.11.34). This reaction leads to the formation of 5(S)-hydroperoxy eicosatetraenoic acid or 5S-HPETE (see below).
    This pathway leads to the synthesis of 4-series leukotrienes (LT), so called because they have four double carbon-carbon bonds in their side chains.
    LT are pro-inflammatory signaling molecules, such as leukotriene B4 or LTB4, and are the precursors of the lipoxins (LX), eicosanoids with anti-inflammatory properties, such as lipoxin A4 or LXA4 and lipoxin B4 or LXB4.
  • The epoxygenase pathway, in which the first reaction is catalyzed by a cytochrome P450 epoxygenase.
    This pathway leads to the synthesis of epoxyeicosatrienoic acids or EETs, molecules with vasorelaxant activity, profibrinolytic as well as anti-inflammatory effects. In vivo, EETs are rapidly metabolized to dihydroxyeicosatrienoic acids or DHETs, in reactions catalyzed by soluble epoxy hydrolase. DHETs are less active than EETs.
    Two other series of reactions are grouped into the “epoxygenase pathway”. They are initiated by other cytochrome P450 mixed-function oxidases. These enzymes lead to the synthesis of:

hydroperoxyeicosatetraenoic acids or HPETEs, some of which are epimers of lipoxygenase catalyzed products;
omega-oxidized  monohydroxyeicosatetraenoic acids.

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Omega-6 PUFA derived from arachidonic acid

AA can also be converted into n6-docosapentaenoic acid (22: 5n6), through four reactions, of which the first three occur in the endoplasmic reticulum, whereas the last one in peroxisomes (see fig. 4).

  • In the first step, AA is elongated to form adrenic acid (22: 4n6), in the reaction catalyzed by elongase 2 or Elovl2 (EC 2.3.1.199) or elongase 5 or Elovl5.
  • Adrenic acid is elongated to n6-tetracosatetraenoic acid (24: 4n6), in the reaction catalyzed by elongase 2.
  • n6-Tetracosatetraenoic acid is desaturated to form n6-tetracosapentaenoic acid (24: 5n6), in the reaction catalyzed by Δ6-desaturase (EC 1.14.19.3).
  • In the last step, n6-tetracosapentaenoic acid undergoes peroxisomal β-oxidation, to form n6-docosapentaenoic acid (22: 5n6).

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Arachidonic acid: harmful or helpful

The idea that AA may be harmful is derived from the following observations.

  • Many AA-derived mediators are involved in many pathologies, having pro-inflammatory action.
  • Free arachidonic acid itself is an immunosuppressant, induces inflammatory responses, and is a potent platelet aggregator.
  • Many health benefits of omega-3 PUFAs involve an “antagonism” of AA: often, in fact, they partly replace it in membrane phospholipids and inhibit its metabolism to eicosanoids.
  • A study published in 1975, in which 6 g/day of AA were administered to healthy volunteers, was stopped because of a marked increase in ex vivo platelet aggregation, a pro-thrombotic event.

However, it is important to keep in mind that the aforementioned effects were only observed in certain tissues or cells, and often under non-physiological conditions, such as the study conducted in 1975. Therefore these effects, as their effectiveness under physiological conditions remain to be defined.
Conversely, in subjects receiving 1.5 g/day of arachidonic acid, no effects have been observed on inflammatory markers, a range of immune functions, platelet reactivity, and bleeding time. All this indicates that AA intake up to 1.5 g/day by healthy adults does not appear to have any adverse effects.
Finally, it should be emphasized that infant formulas containing AA in combination with DHA are associated with improved growth and development, and in premature infants, with a development of the immune system similar to that of breastfed infants, reducing also the risk of necrotizing enterocolitis. Therefore, AA seems to have an important role for the proper growth and development of infants.

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Dietary sources of arachidonic acid

Important dietary sources of arachidonic acid are listed below.

  • Meat.
    It is found both in lean cuts, where it is concentrated in phospholipids, and in visible fat.
    The highest concentration is found in pork fat, for example about 11 mg/g of AA in lard, whereas among lean cuts the richest source is duck.
    Lamb and beef meat, both lean cuts and visible fat, are those that contain the lowest level of AA.
  • Eggs.
  • Fish.
    For example about 3 mg/g of AA in tuna and salmon, and 0.4 mg/g in herring.

The average daily intake for an adult following a Western diet is estimated to be between 50 and 300 mg.

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References

Calder P. C. Dietary arachidonic acid: harmful, harmless or helpful? Br J Nutr  2007; 98:451-53. doi:10.1017/S0007114507761779

Farvid M.S., Ding M., Pan A., Sun Q., Chiuve S.E., Steffen L.N., Willett W.C., Hu F.B. Dietary linoleic acid and risk of coronary heart disease: a systematic review and meta-analysis of prospective cohort studies. Circulation 2014;130:1568-78. doi:10.1161/CIRCULATIONAHA.114.010236

Gregory M.K., Gibson R.A., Cook-Johnson R.J., Cleland L.G., James M.J. Elongase reactions as control points in long-chain polyunsaturated fatty acid synthesis. PLoS One 2011;6(12):e29662. doi:10.1371/journal.pone.0029662

Harris W.S., Shearer G.C. Omega-6 fatty acids and cardiovascular disease. Friend, not foe? Circulation 2014;130:1562-64. doi:10.1161/CIRCULATIONAHA.114.012534

Lee J.M., Lee H., Kang S. 3 and Park W.J. Fatty acid desaturases, polyunsaturated fatty acid regulation, and biotechnological advances. Nutrients 2016;8(1):23. doi:10.3390/nu8010023

Li D., Ng A, Mann N.J., Sinclair A.J. Contribution of meat fat to dietary arachidonic acid. Lipids. 1998;33(4):437-40. doi:10.1007/s11745-998-0225-7

Rett B.S. and Whelan J. Increasing dietary linoleic acid does not increase tissue arachidonic acid content in adults consuming Western-type diets: a systematic review. Nutr Metab (Lond) 2011;8:36. doi:10.1186/1743-7075-8-36

Seyberth H.W., Oelz O., Kennedy T., Sweetman B.J., Danon A., Frolich J.C., Heimberg M. and Oates J.A. Increased arachidonate in lipids after administration to man: effects on prostaglandin biosynthesis. Clin Pharmacol Ther 1975;18:521-29. doi:10.1002/cpt1975185part1521


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