Arachidonic acid (AA, sometimes ARA) is an
omega-6 fatty acidn−6 fatty acids are a family of unsaturated fatty acids that have in common a final carbon–carbon double bond in the n−6 position, that is, the sixth bond from the end of the fatty acid.The biological effects of the n−6 fatty acids are largely mediated by their conversion to n-6 eicosanoids that...
20:4(ω-6).
It is the counterpart to the saturated
arachidic acidArachidic acid, also called eicosanoic acid, is a saturated fatty acid found in peanut oil. Its name derives from the Latin arachis — peanut....
found in
peanutThe peanut, or groundnut , is a species in the legume family native to South America, Mexico and Central America. It is an annual herbaceous plant growing 30 to 50 cm tall...
oil, (
L. arachis – peanut.)
Chemistry
In
chemical structureA chemical structure includes molecular geometry, electronic structure and crystal structure of a chemical compound. Molecular geometry refers to the spatial arrangement of atoms in a molecule and the chemical bonds that hold the atoms together...
, arachidonic acid is a
carboxylic acidCarboxylic acids are organic acids characterized by the presence of a carboxyl group, which has the formula -COH, usually written -COOH or -CO2H. Carboxylic acids are Brønsted-Lowry acids — they are proton donors. Salts and anions of carboxylic acids are called...
with a 20-carbon chain and four
cisCis may have the following meanings:* "Cis-" as a prefix of Latin origin, meaning "on the same side [as]" or "on this side [of]", with several derived usages:** In chemistry, cis- refers to cis-trans isomerism...
double bonds; the first double bond is located at the sixth carbon from the omega end.
Some chemistry sources define 'arachidonic acid' to designate any of the
eicosatetraenoic acidEicosatetraenoic acid, ETA, designates any straight chain 20:4 fatty acid.Two isomers, both of them essential fatty acids, are of particular interest:* all-cis 5,8,11,14-eicosatetraenoic acid is an ω-6 fatty acid with the trivial name arachidonic acid...
s. However, almost all writings in biology, medicine and nutrition limit the term to all-
cis 5,8,11,14-eicosatetraenoic acid.
Biology
Arachidonic acid is a polyunsaturated fatty acid that is present in the
phospholipidPhospholipids are a class of lipids and are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from...
s (especially
phosphatidylethanolaminePhosphatidylethanolamine is a lipid found in biological membranes. It is synthesized by the addition of CDP-ethanolamine to diglyceride, releasing CMP. S-adenosyl methionine can subsequently methylate the amine of phosphatidyl ethanolamine to yield phosphatidyl choline.Cephalin is a phospholipid,...
,
phosphatidylcholinePhosphatidylcholines are a class of phospholipids that incorporate choline as a headgroup.They are a major component of biological membranes and can be isolated from either egg yolk or soy beans from which they are mechanically extracted or chemically extracted using hexane.Phosphatidylcholine is...
and phosphatidylinositides) of
membraneThe cell membrane is the biological membrane separating the interior of a cell from the outside environment....
s of the body's
cellThe cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of an organism that is classified as living, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos...
s, and is abundant in the
brainThe brain is the center of the nervous system in all vertebrate, and most invertebrate, animals. Some primitive animals such as jellyfish and starfish have a decentralized nervous system without a brain, while sponges lack any nervous system at all...
and muscles.
In addition to being involved in cellular signaling as a lipid second messenger involved in the regulation of signaling enzymes, such as
PLCPhosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
-ɣ,
PLCPhosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
-δ and
PKCProtein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
-α, -β and -ɣ isoforms, arachidonic acid is a key inflammatory intermediate. (Note separate synthetic pathways, as described in section below)
Essential fatty acid
Arachidonic acid is one of the
essential fatty acidEssential fatty acids, or EFAs, are fatty acids that cannot be constructed within an organism from other components by any known chemical pathways, and therefore must be obtained from the diet. The term refers to fatty acids involved in biological processes, and not those which may just play a...
s required by most
mammalMammals are a class of vertebrate animals whose females are characterized by the possession of mammary glands while both males and females are characterized by sweat glands, hair, three middle ear bones used in hearing, and a neocortex region in the brain.Mammals are divided into three main...
s. Some mammals lack the ability to—or have a very limited capacity to—convert
linoleic acidLinoleic acid is an unsaturated omega-6 fatty acid. It is a colorless liquid. In physiological literature, it is called 18:2. Chemically, linoleic acid is a carboxylic acid with an 18-carbon chain and two cis double bonds; the first double bond is located at the sixth carbon from the omega...
into arachidonic acid, making it an essential part of their diet. Since little or no arachidonic acid is found in plants, such animals are obligate
carnivoreA carnivore , meaning 'meat eater' , is an animal that derives its energy and nutrient requirements from a diet consisting mainly or exclusively of vertebrate and/or invertebrate animal tissue, whether through predation or scavenging...
s; the cat is a common example.
Synthesis and cascade
Arachidonic acid is freed from a
phospholipidPhospholipids are a class of lipids and are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from...
molecule by the enzyme
phospholipase A2Phospholipases A2 are enzymes that releasefatty acids from the second carbon group of glycerol. This particular phospholipase specifically recognizes the sn-2 acyl bond of phospholipids and catalytically hydrolyzes the bond releasing arachidonic acid and lysophospholipids...
(PLA
2), which cleaves off the
fatty acidIn chemistry, especially biochemistry, a fatty acid is a carboxylic acid often with a long unbranched aliphatic tail , which is either saturated or unsaturated...
, but can also be generated from DAG by DAG lipase.
Arachidonic acid generated for signaling purposes appears to be derived by the action of a phosphatidylcholine-specific cytosolic
phospholipase A2Phospholipases A2 are enzymes that releasefatty acids from the second carbon group of glycerol. This particular phospholipase specifically recognizes the sn-2 acyl bond of phospholipids and catalytically hydrolyzes the bond releasing arachidonic acid and lysophospholipids...
(cPLA
2, 85 kDa), whereas inflammatory arachidonic acid is generated by the action of a low-molecular-weight secretory PLA
2 (sPLA
2, 14-18 kDa).
Arachidonic acid is a precursor in the production of
eicosanoidIn biochemistry, eicosanoids are signaling molecules made by oxygenation of twenty-carbon essential fatty acids, .They exert complex control over many bodily systems, mainly in inflammation or immunity, and as messengers in the central nervous system....
s:
- the enzymes cyclooxygenase
Cyclooxygenase is an enzyme that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain...
and peroxidasePeroxidases are a large family of enzymes that typically catalyze a reaction of the form:For many of these enzymes the optimal substrate is hydrogen peroxide, but others are more active with organic hydroperoxides such as lipid peroxides...
lead to Prostaglandin H2Prostaglandin H2 is a type of Prostaglandin which is derived from arachidonic acid and is a precursor for many other biologically significant molecules:It is acted upon by:* prostacyclin synthase to create prostacyclin...
, which in turn is used to produce the prostaglandinA prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....
s, prostacyclinProstacyclin is a member of the family of lipid molecules known as eicosanoids.As a drug, it is also known as "epoprostenol". The terms are sometimes used interchangeably. -History:During the 1960s a U.K...
, and thromboxaneThromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2.Thromboxane is named for its role in clot formation .-Production:...
s.
- the enzyme 5-lipoxygenase leads to 5-HPETE, which in turn is used to produce the leukotriene
Leukotrienes are fatty molecules of the immune system that contribute to inflammation in asthma and bronchitis. Leukotriene antagonists are used to treat asthma and bronchitis....
s.
- arachidonic acid is also used in the biosynthesis of anandamide
Anandamide, also known as N-arachidonoylethanolamine or AEA, is an endogenous cannabinoid neurotransmitter found in animal and human organs, especially in the brain...
.
- some arachidonic acid is converted into hydroxyeicosatetraenoic acids (HETEs) and epoxyeicosatrienoic acid
The Epoxyeicosatrienoic acids or EETs are signaling molecules formed by the action of Cytochrome P450 epoxygenase on 20-carbon essential fatty acids, such as arachidonic acid, from which it is produced by the enzyme epoxygenase....
s (EETs) by epoxygenaseEpoxygenase is an enzyme that produces hydroxyeicosatetraenoic acids and epoxyeicosatrienoic acids from arachidonic acid, causing effects such as cell proliferation and decrease in cyclooxygenase activity. -HETEs:...
.
The production of these derivatives and their action in the body are collectively known as the
arachidonic acid cascade; see
essential fatty acid interactionsThe actions of the ω-3 and ω-6 essential fatty acids are best characterized by their interactions; they cannot be understood separately.Arachidonic acid is a 20-carbon ω-6 essential fatty acid...
for more details.
PLA2 activation
PLA
2, in turn, is activated by ligand binding to receptors, including:
- 5-HT2 receptor
The 5-HT2 receptors are a subfamily of 5-HT receptors that bind the endogenous neurotransmitter serotonin...
s
- mGLUR1
The glutamate receptor, metabotropic 1, also known as GRM1, is a human gene which encodes the metabotropic glutamate receptor 1 protein.-Function:...
- bFGF
Basic fibroblast growth factor, also known as bFGF, FGF2 or FGF-β, is a member of the fibroblast growth factor family.- Function :...
receptor
- INF-α receptor
- INF-γ receptor
The interferon-gamma receptor is a receptor which binds interferon-γ, the sole member of interferon type II.- Structure and function :...
Furthermore, any agent increasing intracellular
calciumCalcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft grey alkaline earth metal, and is the fifth most abundant element by mass in the Earth's crust...
may cause activation of some forms of PLA
2.
PLC activation
Alternatively, arachidonic acid may be cleaved from phospholipid by
phospholipase CPhosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
(PLC), yielding diacylglycerol (DAG), which subsequently is cleaved by
DAG lipaseDiacylglycerol lipase, also known as DAG lipase, DAGL or DGL, is a key enzyme in the biosynthesis of the endocannabinoid 2-arachidonoylglycerol. It catalyzes the hydrolysis of diacylglycerol releasing a free fatty acid and monoacylglycerol....
to yield arachidonic acid.
Receptors that activate this pathway include:
- A1 receptor
The adenosine A1 receptor is one member of the adenosine receptor group of G protein-coupled receptors with adenosine as endogenous ligand.-Biochemistry:...
- D2 receptor
Dopamine receptor D2, also known as D2R, is a protein which in humans is encoded by the DRD2 gene.- Function :This gene encodes the D2 subtype of the dopamine receptor. This G-protein coupled receptor inhibits adenylyl cyclase activity...
- α-2 adrenergic receptor
-Effect:The α2 receptor has several, general, functions in common with other α-receptors, but also has individual effects.-General:Common effects include:* Vasodilation of arteries...
- 5-HT1 receptor
The 5-HT1 receptors are a subfamily of 5-HT receptors that bind the endogenous neurotransmitter serotonin...
PLC may also be activated by MAP kinase. Activators of this pathway include PDGF and
FGFFibroblast growth factors, or FGFs, are a family of growth factors involved in angiogenesis, wound healing, and embryonic development. The FGFs are heparin-binding proteins and interactions with cell-surface associated heparan sulfate proteoglycans have been shown to be essential for FGF signal...
.
Arachidonic Acid and Muscle Growth
Arachidonic acid is necessary for the repair and growth of skeletal muscle tissue. One of the lead researchers of the Baylor study on arachidonic acid, Mike Roberts MS, CSCS, has authored an article published under the title
Arachidonic Acid, The New Mass Builder explaining the role of this nutrient in muscle anabolism, and its potential for the enhancement of muscle size and strength.
http://www.bodybuilding.com/fun/llewellyn2.htm.
Roberts claims that for optimal muscle growth a training stimulus must elicit localized inflammation and soreness. He also shows that arachidonic acid (AA, 20:4n-6) is an essential Omega-6 (1-6) polyunsaturated fatty acid that is abundant in skeletal muscle membrane phospholipids (figure 2). It is also the body's principle building block for the production of prostaglandins, which are known to have various physiological roles including a close involvement in inflammation. Also, the prostaglandin isomer PGF2a has a potent ability to stimulate muscle growth. As such, Roberts says that arachidonic acid is a regulator of localized muscle inflammation, and he claims that it may be a central nutrient controlling the intensity of the anabolic/tissue-rebuilding response to weight training.
Arachidonic Acid and the Brain
Arachidonic acid is one of the most abundant fatty acids in the brain, and is present in similar quantities to DHA (docosahexaenoic acid). The two account for approximately 20% of its fatty acid content. Like DHA, neurological health is reliant upon sufficient levels of arachidonic acid. Among other things, arachidonic acid helps to maintain hippocampal cell membrane fluidity. It also helps protect the brain from oxidative stress by activating perioxisomal proliferator-activated receptor-y. ARA also activates syntaxin-3 (STX-3), a protein involved in the growth and repair of neurons.
Arachidonic acid is also involved in early neurological development. In one study funded by the U.S. National Institute of Child Health and Human Development, infants (18 months) given supplemental arachidonic acid for 17 weeks demonstrated significant improvements in intelligence, as measured by the Mental Development Index (MDI). This effect is further enhanced by the simultaneous supplementation of DHA and ARA.
In adults, the disturbed metabolism of ARA may be associated with neurological disorders such as Alzheimer’s Disease and Bipolar Disorder. This may involve the increased consumption of ARA at the cellular level, and significant alterations in its conversion to other bioactive molecules (overexpression or disturbances in the ARA enzyme cascade). The increased consumption of dietary arachidonic acid is not believed to cause these neurological disorders.
In the Journal of Lipid Research, an American Society for Biochemical and Molecular Biology journal, a study dated 2005-05-25 used the Flinders Sensitive Line rats to investigate the link between omega-3 fatty acids and depression. An examination of the brains of depressed rats compared them with brains from normal rats. Surprisingly, they found that the main difference between the two types of rats was in omega-6 fatty acid levels and not omega-3 fatty acid levels. Specifically, they discovered that brains with depression had higher concentrations of arachidonic acid, a long-chain unsaturated metabolite of omega-6 fatty acid. The findings suggest that it is not a lack of omega-3 fatty acids but a higher increase of arachidonic that is implicated in depression.
Arachidonic Acid as a Bodybuilding Supplement
Arachidonic acid is marketed under patent (#6,841,573) as an anabolic bodybuilding supplement in products such as X-Factor (Molecular Nutrition), Halodrol Liquigels (Gaspari Nutrition), Animal Test (Universal Nutrition), Hemodraulix (Axis Labs), Mass Caps (IDS), Max Out (iForce), and Thermaphoria (EST Nutrition).
The first clinical study concerning the use of arachidonic acid as a sport supplement was conducted at Baylor University and published in the 'Journal of the International Society of Sports Nutrition'."
The performance data results from the paper include the following statistically significant improvement, and statistically strong trends:
A significant group × time interaction for relative Wingate peak power was observed among groups (P = 0.02) with gains in peak power being significantly greater in the AA group (0.3 ± 1.2 W·kg-1) vs. PLA (0.2 ± 0.7 W·kg-1, Figure 1). Using repeated measures ANOVA with delta scores, AA experienced significantly greater increases in comparison to the PLA group at day 50 (P < 0.05). Statistical trends were seen in Wingate total work (AA: 1,292 ± 1,206 vs. PLA: 510 ± 1,249 J, P = 0.09, ηp 2 = 0.052), favoring the AA group.
WIth regard to inflammation, the paper reported a statistiically significant reduction in resting IL-6 levels (a central regulator of inflammation):
IL-6 levels experienced a significant group × time interaction (P = 0.04) among groups with subsequent post-hoc analyses revealing that IL-6 was significantly lower at day 25 of the study. One way ANOVA of IL-6 delta values at day 25 revealed significantly greater increases in PLA when compared to AA group (AA: 0.8 ± 13.5 pg·ml-1 vs. PLA: 52.5 ± 1.6 pg·ml-1, P = 0.01; Figure 2)
Arachidonic acid was shown to improve peak muscle power, reduce resting IL-6 levels, and produce statistically strong trends of improvements in muscle endurance, average power, and bench press 1-rep maximum lift. This study provides preliminary evidence supporting the use of arachidonic acid in sports nutrition. Further research is needed.
Effects of arachidonic acid supplementation on training adaptations
in resistance-trained males
Dietary Arachidonic Acid and Inflammation
Under normal metabolic conditions, the increased consumption of arachidonic acid is unlikely to increase inflammation. ARA is metabolized to both pro-inflammatory and anti-inflammatory molecules. Studies giving between 840 mg and 2,000 mg per day to healthy individuals for up to 50 days have shown no increases in inflammation or related metabolic activities. Increased arachidonic acid levels are actually associated with reduced pro-inflammatory IL-6 and IL-1 levels, and increased anti-inflammatory tumor-necrosis factor-beta. This may reduce inflammation under certain conditions.
Arachidonic acid does still play a central role in inflammation related to many diseased states. How it is metabolized in the body dictates its inflammatory or anti-inflammatory activity. Individuals suffering from joint pains or active inflammatory disease may find that increased arachidonic acid consumption exacerbates symptoms, probably because it is being more readily converted to inflammatory compounds. Likewise, high arachidonic acid consumption is not advised for individuals with a history of inflammatory disease, or that are in compromised health. It is also of note that while ARA supplementation does not appear to have pro-inflammatory effects in healthy individuals, it may counter the anti-inflammatory effects of omega-3 EFA supplementation.
Health Effects of Arachidonic Acid Supplementation
Arachidonic acid supplementation in daily dosages of 1,000-1,500 mg for 50 days has been well tolerated during several clinical studies, with no significant side effects reported. All common markers of health including kidney and liver function, serum lipids, immunity, and platelet aggregation appear to be unaffected with this level and duration of use. Furthermore, higher concentrations of ARA in muscle tissue may be correlated with improved insulin sensitivity. Arachidonic acid supplementation by healthy adults appears to offer no toxicity or significant safety risk. The safety of arachidonic acid supplementation in patients suffering from inflammatory or other diseased states is unknown, and is not recommended.
See also
- Polyunsaturated fat
In nutrition, polyunsaturated fat, or polyunsaturated fatty acid, are fatty acids in which more than one double bond exists within the representative molecule. That is, the molecule has two or more points on its structure capable of supporting hydrogen atoms not currently part of the structure...
- Polyunsaturated fatty acid
Polyunsaturated fatty acids are those that contain more than one double bond.- Methylene-Interrupted Polyenes :These fatty acids have 2 or more cis double bonds that are separated from each other by a single methylene group...
- Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication....
- inhibits cyclooxygenaseCyclooxygenase is an enzyme that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain...
enzyme to prevent the conversion of arachidonic acid to other signal molecules
External links