arachidonic acid

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In chemical structure, arachidonic acid is a carboxylic acid with a 20-carbon chain and four cis-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 acids. However, almost all writings in biology, medicine, and nutrition limit the term to all cis-5,8,11,14-eicosatetraenoic acid.

Arachidonic acid is a polyunsaturated fatty acid present in the phospholipids (especially phosphatidylethanolamine, phosphatidylcholine, and phosphatidylinositides) of membranes of the body's cells, and is abundant in the brain, muscles, and liver. Skeletal muscle is an especially active site of arachidonic acid retention, accounting for roughly 10–20% of the phospholipid fatty acid content typically.{{cite journal |last1=Smith |first1=GI |last2=Atherton |first2=P |last3=Reeds |first3=DN |last4=Mohammed |first4=BS |last5=Rankin |first5=D |last6=Rennie |first6=MJ |last7=Mittendorfer |first7=B |title=Omega-3 polyunsaturated fatty acids augment the muscle protein anabolic response to hyperinsulinaemia-hyperaminoacidaemia in healthy young and middle-aged men and women. |journal=Clinical Science |date=Sep 2011 |volume=121 |issue=6 |pages=267–78 |pmid=21501117 |doi=10.1042/cs20100597 |pmc=3499967}}

In addition to being involved in cellular signaling as a lipid second messenger involved in the regulation of signaling enzymes, such as PLC-γ, PLC-δ, and PKC-α, -β, and -γ isoforms, arachidonic acid is a key inflammatory intermediate and can also act as a vasodilator.{{cite book |last=Baynes |first=John W. |author2=Marek H. Dominiczak |title=Medical Biochemistry 2nd. Edition |publisher=Elsevier Mosby |year=2005 |page=[https://archive.org/details/medicalbiochemis0000unse/page/555 555] |isbn=0-7234-3341-0 |url-access=registration |url=https://archive.org/details/medicalbiochemis0000unse/page/555}} (Note separate synthetic pathways, as described in section below.)

Image:Eicosanoid synthesis.svg

Arachidonic acid is freed from phospholipid by hydrolysis, catalyzed by the phospholipase A₂ (PLA₂).

Arachidonic acid for signaling purposes appears to be derived by the action of group IVA cytosolic phospholipase A₂ (cPLA₂, 85 kDa), whereas inflammatory arachidonic acid is generated by the action of a low-molecular-weight secretory PLA₂ (sPLA₂, 14-18 kDa).

Arachidonic acid is a precursor to a wide range of eicosanoids:

• The enzymes cyclooxygenase-1 and -2 (i.e. prostaglandin G/H synthase 1 and 2 [⁠PTGS1 and PTGS2]) convert arachidonic acid to prostaglandin G₂ and prostaglandin H₂, which in turn may be converted to various prostaglandins, to prostacyclin, to thromboxanes, and to the 17-carbon product of thromboxane metabolism of prostaglandin G₂/H₂, 12-hydroxyheptadecatrienoic acid (12-HHT).{{cite journal |pmid=4723909 |year=1973 |last1=Wlodawer |first1=P |title=On the organization and mechanism of prostaglandin synthetase |journal=The Journal of Biological Chemistry |volume=248 |issue=16 |pages=5673–8 |last2=Samuelsson |first2=B |doi=10.1016/S0021-9258(19)43558-8 |doi-access=free}}{{cite journal |pmid=12432913 |year=2002 |last1=Smith |first1=W. L. |title=The enzymology of prostaglandin endoperoxide H synthases-1 and -2 |journal=Prostaglandins & Other Lipid Mediators |volume=68–69 |pages=115–28 |last2=Song |first2=I |doi=10.1016/s0090-6980(02)00025-4}}
• The enzyme 5-lipoxygenase catalyzes the oxidation of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which in turn converts to various leukotrienes (i.e., leukotriene B₄, leukotriene C₄, leukotriene D₄, and leukotriene E₄) as well as to 5-hydroxyeicosatetraenoic acid (5-HETE) which may then be further metabolized to 5-HETE's more potent 5-keto analog, 5-oxo-eicosatetraenoic acid (5-oxo-ETE) (also see 5-hydroxyeicosatetraenoic acid).{{cite journal |date=Apr 2015 |title=Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid |journal=Biochim Biophys Acta |volume=1851 |issue=4 |pages=340–355 |doi=10.1016/j.bbalip.2014.10.008 |pmid=25449650 |last1=Powell |first1=W. S. |last2=Rokach |first2=J |pmc=5710736}}
• The enzymes 15-lipoxygenase-1 (ALOX15) and 15-lipoxygenase-2 (ALOX15B). ALOX15B catalyzes the oxidation of arachidonic acid to 15-hydroperoxyeicosatetraenoic acid (15-HPETE), which may then be further converted to 15-hydroxyeicosatetraenoic acid (15-HETE) and lipoxins;{{cite journal |date=Jun 1997 |title=Discovery of a second 15S-lipoxygenase in humans |journal=Proc Natl Acad Sci U S A |volume=94 |issue=12 |pages=6148–52 |pmid=9177185 |pmc=21017 |last1=Brash |first1=A. R. |last2=Boeglin |first2=W. E. |last3=Chang |first3=M. S. |doi=10.1073/pnas.94.12.6148 |bibcode=1997PNAS...94.6148B |doi-access=free}}{{cite journal |date=May 2012 |title=Role of 15-lipoxygenase/15-hydroxyeicosatetraenoic acid in hypoxia-induced pulmonary hypertension |journal=J Physiol Sci |volume=62 |issue=3 |pages=163–72 |doi=10.1007/s12576-012-0196-9 |pmid=22331435 |last1=Zhu |first1=D |last2=Ran |first2=Y |s2cid=2723454 |doi-access=free|pmc=10717549 }}{{cite journal |date=Aug 2015 |title=Lipoxins and aspirin-triggered lipoxins in resolution of inflammation |journal=Eur J Pharmacol |volume=760 |pages=49–63 |doi=10.1016/j.ejphar.2015.03.083 |pmid=25895638 |last1=Romano |first1=M |last2=Cianci |first2=E |last3=Simiele |first3=F |last4=Recchiuti |first4=A}} 15-Lipoxygenase-1 may also further metabolize 15-HPETE to eoxins in a pathway analogous to (and presumably using the same enzymes as used in) the pathway which metabolizes 5-HPETE to leukotrienes.{{cite journal |date=Jan 2008 |title=Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells |journal=Proc Natl Acad Sci U S A |volume=105 |issue=2 |pages=680–5 |doi=10.1073/pnas.0710127105 |pmid=18184802 |pmc=2206596 |last1=Feltenmark |first1=S |last2=Gautam |first2=N |last3=Brunnström |first3=A |last4=Griffiths |first4=W |last5=Backman |first5=L |last6=Edenius |first6=C |last7=Lindbom |first7=L |last8=Björkholm |first8=M |last9=Claesson |first9=H. E. |bibcode=2008PNAS..105..680F |doi-access=free}}
• The enzyme 12-lipoxygenase (ALOX12) catalyzes oxidation of arachidonic acid to 12-hydroperoxyeicosatetraenoic acid (12-HPETE), which may then be metabolized to 12-hydroxyeicosatetraenoic acid (12-HETE) and to hepoxilins.{{cite journal |date=Aug 2014 |title=Analysis, physiological and clinical significance of 12-HETE: A neglected platelet-derived 12-lipoxygenase product |journal=J Chromatogr B |volume=964 |pages=26–40 |doi=10.1016/j.jchromb.2014.03.015 |pmid=24685839 |last1=Porro |first1=B |last2=Songia |first2=P |last3=Squellerio |first3=I |last4=Tremoli |first4=E |last5=Cavalca |first5=V}}
• Arachidonic acid is also a precursor to anandamide.{{cite journal |date=May 2013 |title=Metabolism of endocannabinoids and related N -acylethanolamines: Canonical and alternative pathways |journal=FEBS J. |volume=280 |issue=9 |pages=1874–94 |doi=10.1111/febs.12152 |pmid=23425575 |last1=Ueda |first1=Natsuo |last2=Tsuboi |first2=Kazuhito |last3=Uyama |first3=Toru |s2cid=205133026 |doi-access=free}}
• Some arachidonic acid is converted into hydroxyeicosatetraenoic acids (HETEs) and epoxyeicosatrienoic acids (EETs) by epoxygenase.{{cite book |author=Walter F., PhD. Boron |title=Medical Physiology: A Cellular And Molecular Approaoch |publisher=Elsevier/Saunders |year=2003 |page=108 |isbn=1-4160-2328-3}}

The production of these derivatives and their actions in the body are collectively known as the "arachidonic acid cascade"; see Essential fatty acid interactions and the enzyme and metabolite linkages given in the previous paragraph for more details.

{{Further|Phospholipase A2#Regulation}}

PLA₂, in turn, is activated by ligand binding to receptors, including:

• 5-HT2 receptors {{cite book |author=Walter F., PhD. Boron |title=Medical Physiology: A Cellular And Molecular Approaoch |publisher=Elsevier/Saunders |year=2003 |page=103 |isbn=1-4160-2328-3}}
• mGLUR1
• bFGF receptor
• IFN-α receptor
• IFN-γ receptor

Furthermore, any agent increasing intracellular calcium may cause activation of some forms of PLA₂.

{{Further|Phospholipase C#Activation}}

Alternatively, arachidonic acid may be cleaved from phospholipids after phospholipase C (PLC) cleaves off the inositol trisphosphate group, yielding diacylglycerol (DAG), which subsequently is cleaved by DAG lipase to yield arachidonic acid.

Receptors that activate this pathway include:

• A₁ receptor{{cite book |author=Walter F., PhD. Boron |title=Medical Physiology: A Cellular And Molecular Approaoch |publisher=Elsevier/Saunders |year=2003 |pages=104 |isbn=1-4160-2328-3}}
• D₂ receptor
• α₂ adrenergic receptor
• 5-HT1 receptor

PLC may also be activated by MAP kinase. Activators of this pathway include PDGF and FGF.

Along with other omega−6 and omega−3 fatty acids, arachidonic acid contributes to the structure of cell membranes. When incorporated into phospholipids, the omega fatty acids affect cell membrane properties, such as permeability and the activity of enzymes and cell-signaling mechanisms.

Arachidonic acid, one of the most abundant fatty acids in the brain, is present in similar quantities to docosahexaenoic acid, with the two accounting for about 20% of brain fatty-acid content.{{cite book |last1=Crawford |first1=MA |last2=Sinclair |first2=AJ |title=Nutritional influences in the evolution of mammalian brain. In: lipids, malnutrition & the developing brain |journal=Ciba Foundation Symposium |pages=267–92 |year=1971 |doi=10.1002/9780470719862.ch16 |pmid=4949878}} Arachidonic acid is involved in the early neurological development of infants.{{cite journal |vauthors=Crawford MA, Sinclair AJ, Hall B, Ogundipe E, Wang Y, Bitsanis D, Djahanbakhch OB, Harbige L, Ghebremeskel K, Golfetto I, Moodley T, Hassam A, Sassine A, Johnson MR|display-authors=3 |title=The imperative of arachidonic acid in early human development |journal=Progress in Lipid Research |volume=91 |issue= |pages=101222 |date=July 2023 |pmid=36746351 |doi=10.1016/j.plipres.2023.101222 |doi-access=free |hdl=10044/1/103039 |hdl-access=free }}

{{missing information|section|Typical dietary intake — needed to put supplement dose into context|date=February 2025}}

Arachidonic acid is marketed as a dietary supplement. A 2019 review of clinical studies investigating the potential health effects of arachidonic acid supplementation of up to 1500 mg per day on human health found there were no clear benefits.{{cite journal |vauthors=Calder PC, Campoy C, Eilander A, Fleith M, Forsyth S, Larsson PO, Schelkle B, Lohner S, Szommer A, van de Heijning BJ, Mensink RP |title=A systematic review of the effects of increasing arachidonic acid intake on PUFA status, metabolism and health-related outcomes in humans |journal=The British Journal of Nutrition |volume=121 |issue=11 |pages=1201–1214 |date=June 2019 |pmid=31130146 |doi=10.1017/S0007114519000692 |url=https://www.cambridge.org/core/journals/british-journal-of-nutrition/article/systematic-review-of-the-effects-of-increasing-arachidonic-acid-intake-on-pufa-status-metabolism-and-healthrelated-outcomes-in-humans/6A0167CBF8EC148B4855C25D002E4AC4 |hdl=10481/60184 |hdl-access=free }} There were no adverse effects in adults of using high daily doses (1500 mg) of arachidonic acid on several biomarkers of blood chemistry, immune function, and inflammation.

A 2009 review indicated that consumption of 5−10% of food energy from omega−6 fatty acids including arachidonic acid may reduce the risk of cardiovascular diseases compared to lower intakes.{{cite journal |last1=Harris |first1=WS |last2=Mozaffarian |first2=D |last3=Rimm |first3=E |last4=Kris-Etherton |first4=P |last5=Rudel |first5=LL |last6=Appel |first6=LJ |last7=Engler |first7=MM |last8=Engler |first8=MB |last9=Sacks |first9=F |title=Omega-6 fatty acids and risk for cardiovascular disease: a science advisory from the American Heart Association Nutrition Subcommittee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Cardiovascular Nursing; and Council on Epidemiology and Prevention |journal=Circulation |volume=119 |issue=6 |pages=902–7 |year=2009 |pmid=19171857 |doi=10.1161/CIRCULATIONAHA.108.191627 |doi-access=|s2cid=15072227|url=https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.108.191627|url-access=subscription }} A 2014 meta-analysis of possible associations between heart disease risk and individual fatty acids reported a significantly reduced risk of heart disease with higher levels of EPA, DHA, and arachidonic acid.{{cite journal |last1=Chowdhury |first1=R |last2=Warnakula |first2=S |last3=Kunutsor |first3=S |last4=Crowe |first4=F |last5=Ward |first5=HA |last6=Johnson |first6=L |last7=Franco |first7=OH |last8=Butterworth |first8=AS |last9=Forouhi |first9=NG|last10=Thompson|first10=SG |last11=Khaw |first11=KT |last12=Mozaffarian |first12=D |last13=Danesh |first13=J |last14=Di Angelantonio |first14=E |title=Association of dietary, circulating, and supplement fatty acids with coronary risk: a systematic review and meta-analysis. |journal=Annals of Internal Medicine |date=Mar 18, 2014 |volume=160 |issue=6 |pages=398–406 |pmid=24723079 |doi=10.7326/M13-1788}}

{{Div col}}

• Aspirin—inhibits cyclooxygenase enzyme, preventing conversion of arachidonic acid to other signal molecules
• Fish oil
• Juniperonic acid, an isomer
• Polyunsaturated fat

{{div col end}}

{{reflist}}

• {{MeshName|Arachidonic+Acid}}

{{Eicosanoids}}

{{Fatty acids}}

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Category:Fatty acids

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