Arachidonic acid

Arachidonic acid
Names
	Preferred IUPAC name (5Z,8Z,11Z,14Z)-Icosa-5,8,11,14-tetraenoic acid
	Other names 5,8,11,14-all-cis-Eicosatetraenoic acid; all-cis-5,8,11,14-Eicosatetraenoic acid
Identifiers
CAS Number	506-32-1 ;
3D model (JSmol)	Interactive image;
3DMet	B00061;
Beilstein Reference	1713889
ChEBI	CHEBI:15843 ;
ChEMBL	ChEMBL15594 ;
ChemSpider	392692 ;
DrugBank	DB04557 ;
ECHA InfoCard	100.007.304
EC Number	208-033-4;
Gmelin Reference	58972
IUPHAR/BPS	2391;
KEGG	C00219 ;
MeSH	Arachidonic+acid
PubChem CID	444899;
RTECS number	CE6675000;
UNII	27YG812J1I ;
CompTox Dashboard (EPA)	DTXSID4040420 ;
	InChI InChI=1S/C20H32O2/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-20(21)22/h6-7,9-10,12-13,15-16H,2-5,8,11,14,17-19H2,1H3,(H,21,22) Key: YZXBAPSDXZZRGB-UHFFFAOYSA-N ; InChI=1S/C20H32O2/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-20(21)22/h6-7,9-10,12-13,15-16H,2-5,8,11,14,17-19H2,1H3,(H,21,22)/b7-6-,10-9-,13-12-,16-15-; Key: YZXBAPSDXZZRGB-DOFZRALJSA-N;
	SMILES CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O;
Properties
Chemical formula	C20H32O2
Molar mass	304.474 g·mol−1
Density	0.922 g/cm3
Melting point	−49 °C (−56 °F; 224 K)
Boiling point	169 to 171 °C (336 to 340 °F; 442 to 444 K) at 0.15 mmHg
log P	6.994
Acidity (pKa)	4.752
Hazards
	GHS labelling:
Pictograms
Signal word	Warning
Hazard statements	H302, H312, H315, H319, H332, H335
Precautionary statements	P261, P264, P270, P271, P280, P301+P312, P302+P352, P304+P312, P304+P340, P305+P351+P338, P312, P321, P322, P330, P332+P313, P337+P313, P362, P363, P403+P233, P405, P501
NFPA 704 (fire diamond)	1 1 0
Flash point	113 °C (235 °F; 386 K)
Related compounds
Related compounds	Eicosatetraenoic acid
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). verify (what is ?) Infobox references

Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega−6 fatty acid 20:4(ω−6), or 20:4(5,8,11,14).^[2]^[3] If its precursors or diet contains linoleic acid it is formed by biosynthesis and can be deposited in animal fats. It is a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes.^[4]

Together with omega−3 fatty acids and other omega−6 fatty acids, arachidonic acid provides energy for body functions, contributes to cell membrane structure, and participates in the synthesis of eicosanoids, which have numerous roles in physiology as signaling molecules.^[2]^[5]

Its name derives from the ancient Greek neologism arachis 'peanut', although peanut oil does not contain any arachidonic acid.^[6] Arachidonate is the name of the derived carboxylate anion (conjugate base of the acid), salts, and some esters.

Chemistry

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.

Biology

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.^[7]

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.^[8] (Note separate synthetic pathways, as described in section below.)

Biosynthesis and cascade in humans

Arachidonic acid is freed from phospholipid by hydrolysis, catalyzed by the phospholipase A₂ (PLA₂).^[8]

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).^[8]

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).^[9]^[10]
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).^[11]
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;^[12]^[13]^[14] 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.^[15]
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.^[16]
Arachidonic acid is also a precursor to anandamide.^[17]
Some arachidonic acid is converted into hydroxyeicosatetraenoic acids (HETEs) and epoxyeicosatrienoic acids (EETs) by epoxygenase.^[18]

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.

PLA₂ activation

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

Furthermore, any agent increasing intracellular calcium may cause activation of some forms of PLA₂.^[20]

PLC 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.^[19]

Receptors that activate this pathway include:

PLC may also be activated by MAP kinase. Activators of this pathway include PDGF and FGF.^[20]

In the body

Cell membranes

Along with other omega−6 and omega−3 fatty acids, arachidonic acid contributes to the structure of cell membranes.^[2] When incorporated into phospholipids, the omega fatty acids affect cell membrane properties, such as permeability and the activity of enzymes and cell-signaling mechanisms.^[2]

Brain

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.^[21] Arachidonic acid is involved in the early neurological development of infants.^[22]

Dietary supplement

Arachidonic acid is marketed as a dietary supplement.^[2]^[5] 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.^[23] 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.^[23]

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.^[24] 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.^[25]

References

^ Pubchem. "5,8,11,14-Eicosatetraenoic acid | C20H32O2 - PubChem". pubchem.ncbi.nlm.nih.gov. Retrieved 2016-03-31.
^ ^a ^b ^c ^d ^e "Essential fatty acids". Micronutrient Information Center, Linus Pauling Institute, Oregon State University. June 2019. Retrieved 13 May 2024.
^ "IUPAC Lipid nomenclature: Appendix A: names of and symbols for higher fatty acids". www.sbcs.qmul.ac.uk.
^ "Dorland's Medical Dictionary – 'A'". Archived from the original on 11 January 2007. Retrieved 2007-01-12.
^ ^a ^b "Omega-3 fatty acids". Office of Dietary Supplements, US National Institutes of Health. 15 February 2023. Retrieved 13 May 2024.
^ Truswell A, Choudhury N, Peterson D, Mann J, Agostoni C, Riva E, Giovannini M, Marangoni F, Galli C (1994). "Arachidonic acid and peanut oil". The Lancet. 344 (8928): 1030–1031. doi:10.1016/S0140-6736(94)91695-0. PMID 7999151. S2CID 1522233.
^ Smith GI, Atherton P, Reeds DN, Mohammed BS, Rankin D, Rennie MJ, Mittendorfer B (Sep 2011). "Omega-3 polyunsaturated fatty acids augment the muscle protein anabolic response to hyperinsulinaemia-hyperaminoacidaemia in healthy young and middle-aged men and women". Clinical Science. 121 (6): 267–78. doi:10.1042/cs20100597. PMC 3499967. PMID 21501117.
^ ^a ^b ^c Baynes JW, Marek H. Dominiczak (2005). Medical Biochemistry 2nd. Edition. Elsevier Mosby. p. 555. ISBN 0-7234-3341-0.
^ Wlodawer P, Samuelsson B (1973). "On the organization and mechanism of prostaglandin synthetase". The Journal of Biological Chemistry. 248 (16): 5673–8. doi:10.1016/S0021-9258(19)43558-8. PMID 4723909.
^ Smith WL, Song I (2002). "The enzymology of prostaglandin endoperoxide H synthases-1 and -2". Prostaglandins & Other Lipid Mediators. 68–69: 115–28. doi:10.1016/s0090-6980(02)00025-4. PMID 12432913.
^ Powell WS, Rokach J (Apr 2015). "Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid". Biochim Biophys Acta. 1851 (4): 340–355. doi:10.1016/j.bbalip.2014.10.008. PMC 5710736. PMID 25449650.
^ Brash AR, Boeglin WE, Chang MS (Jun 1997). "Discovery of a second 15S-lipoxygenase in humans". Proc Natl Acad Sci U S A. 94 (12): 6148–52. Bibcode:1997PNAS...94.6148B. doi:10.1073/pnas.94.12.6148. PMC 21017. PMID 9177185.
^ Zhu D, Ran Y (May 2012). "Role of 15-lipoxygenase/15-hydroxyeicosatetraenoic acid in hypoxia-induced pulmonary hypertension". J Physiol Sci. 62 (3): 163–72. doi:10.1007/s12576-012-0196-9. PMC 10717549. PMID 22331435. S2CID 2723454.
^ Romano M, Cianci E, Simiele F, Recchiuti A (Aug 2015). "Lipoxins and aspirin-triggered lipoxins in resolution of inflammation". Eur J Pharmacol. 760: 49–63. doi:10.1016/j.ejphar.2015.03.083. PMID 25895638.
^ Feltenmark S, Gautam N, Brunnström A, Griffiths W, Backman L, Edenius C, Lindbom L, Björkholm M, Claesson HE (Jan 2008). "Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells". Proc Natl Acad Sci U S A. 105 (2): 680–5. Bibcode:2008PNAS..105..680F. doi:10.1073/pnas.0710127105. PMC 2206596. PMID 18184802.
^ Porro B, Songia P, Squellerio I, Tremoli E, Cavalca V (Aug 2014). "Analysis, physiological and clinical significance of 12-HETE: A neglected platelet-derived 12-lipoxygenase product". J Chromatogr B. 964: 26–40. doi:10.1016/j.jchromb.2014.03.015. PMID 24685839.
^ Ueda N, Tsuboi K, Uyama T (May 2013). "Metabolism of endocannabinoids and related N -acylethanolamines: Canonical and alternative pathways". FEBS J. 280 (9): 1874–94. doi:10.1111/febs.12152. PMID 23425575. S2CID 205133026.
^ Walter F., PhD. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 108. ISBN 1-4160-2328-3.
^ ^a ^b ^c ^d ^e ^f Walter F., PhD. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 103. ISBN 1-4160-2328-3.
^ ^a ^b ^c ^d ^e ^f Walter F., PhD. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 104. ISBN 1-4160-2328-3.
^ Crawford MA, Sinclair AJ (1971). "Nutritional influences in the evolution of mammalian brain. In: lipids, malnutrition & the developing brain". Ciba Foundation Symposium: 267–92. doi:10.1002/9780470719862.ch16. PMID 4949878.
^ Crawford MA, Sinclair AJ, Hall B, et al. (July 2023). "The imperative of arachidonic acid in early human development". Progress in Lipid Research. 91: 101222. doi:10.1016/j.plipres.2023.101222. PMID 36746351.
^ ^a ^b Calder PC, Campoy C, Eilander A, Fleith M, Forsyth S, Larsson PO, Schelkle B, Lohner S, Szommer A, van de Heijning BJ, Mensink RP (June 2019). "A systematic review of the effects of increasing arachidonic acid intake on PUFA status, metabolism and health-related outcomes in humans". The British Journal of Nutrition. 121 (11): 1201–1214. doi:10.1017/S0007114519000692. hdl:10481/60184. PMID 31130146.
^ Harris WS, Mozaffarian D, Rimm E, Kris-Etherton P, Rudel LL, Appel LJ, Engler MM, Engler MB, Sacks F (2009). "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". Circulation. 119 (6): 902–7. doi:10.1161/CIRCULATIONAHA.108.191627. PMID 19171857. S2CID 15072227.
^ Chowdhury R, Warnakula S, Kunutsor S, Crowe F, Ward HA, Johnson L, Franco OH, Butterworth AS, Forouhi NG, Thompson SG, Khaw KT, Mozaffarian D, Danesh J, Di Angelantonio E (Mar 18, 2014). "Association of dietary, circulating, and supplement fatty acids with coronary risk: a systematic review and meta-analysis". Annals of Internal Medicine. 160 (6): 398–406. doi:10.7326/M13-1788. PMID 24723079.

External links

Arachidonic+Acid at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

[1] Pubchem. "5,8,11,14-Eicosatetraenoic acid | C20H32O2 - PubChem". pubchem.ncbi.nlm.nih.gov. Retrieved 2016-03-31.

[lpi-2] "Essential fatty acids". Micronutrient Information Center, Linus Pauling Institute, Oregon State University. June 2019. Retrieved 13 May 2024.

[3] "IUPAC Lipid nomenclature: Appendix A: names of and symbols for higher fatty acids". www.sbcs.qmul.ac.uk.

[Dorland-4] "Dorland's Medical Dictionary – 'A'". Archived from the original on 11 January 2007. Retrieved 2007-01-12.

[ods-5] "Omega-3 fatty acids". Office of Dietary Supplements, US National Institutes of Health. 15 February 2023. Retrieved 13 May 2024.

[6] Truswell A, Choudhury N, Peterson D, Mann J, Agostoni C, Riva E, Giovannini M, Marangoni F, Galli C (1994). "Arachidonic acid and peanut oil". The Lancet. 344 (8928): 1030–1031. doi:10.1016/S0140-6736(94)91695-0. PMID 7999151. S2CID 1522233.

[7] Smith GI, Atherton P, Reeds DN, Mohammed BS, Rankin D, Rennie MJ, Mittendorfer B (Sep 2011). "Omega-3 polyunsaturated fatty acids augment the muscle protein anabolic response to hyperinsulinaemia-hyperaminoacidaemia in healthy young and middle-aged men and women". Clinical Science. 121 (6): 267–78. doi:10.1042/cs20100597. PMC 3499967. PMID 21501117.

[Dominiczak-8] Baynes JW, Marek H. Dominiczak (2005). Medical Biochemistry 2nd. Edition. Elsevier Mosby. p. 555. ISBN 0-7234-3341-0.

[9] Wlodawer P, Samuelsson B (1973). "On the organization and mechanism of prostaglandin synthetase". The Journal of Biological Chemistry. 248 (16): 5673–8. doi:10.1016/S0021-9258(19)43558-8. PMID 4723909.

[10] Smith WL, Song I (2002). "The enzymology of prostaglandin endoperoxide H synthases-1 and -2". Prostaglandins & Other Lipid Mediators. 68–69: 115–28. doi:10.1016/s0090-6980(02)00025-4. PMID 12432913.

[11] Powell WS, Rokach J (Apr 2015). "Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid". Biochim Biophys Acta. 1851 (4): 340–355. doi:10.1016/j.bbalip.2014.10.008. PMC 5710736. PMID 25449650.

[12] Brash AR, Boeglin WE, Chang MS (Jun 1997). "Discovery of a second 15S-lipoxygenase in humans". Proc Natl Acad Sci U S A. 94 (12): 6148–52. Bibcode:1997PNAS...94.6148B. doi:10.1073/pnas.94.12.6148. PMC 21017. PMID 9177185.

[13] Zhu D, Ran Y (May 2012). "Role of 15-lipoxygenase/15-hydroxyeicosatetraenoic acid in hypoxia-induced pulmonary hypertension". J Physiol Sci. 62 (3): 163–72. doi:10.1007/s12576-012-0196-9. PMC 10717549. PMID 22331435. S2CID 2723454.

[14] Romano M, Cianci E, Simiele F, Recchiuti A (Aug 2015). "Lipoxins and aspirin-triggered lipoxins in resolution of inflammation". Eur J Pharmacol. 760: 49–63. doi:10.1016/j.ejphar.2015.03.083. PMID 25895638.

[15] Feltenmark S, Gautam N, Brunnström A, Griffiths W, Backman L, Edenius C, Lindbom L, Björkholm M, Claesson HE (Jan 2008). "Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells". Proc Natl Acad Sci U S A. 105 (2): 680–5. Bibcode:2008PNAS..105..680F. doi:10.1073/pnas.0710127105. PMC 2206596. PMID 18184802.

[16] Porro B, Songia P, Squellerio I, Tremoli E, Cavalca V (Aug 2014). "Analysis, physiological and clinical significance of 12-HETE: A neglected platelet-derived 12-lipoxygenase product". J Chromatogr B. 964: 26–40. doi:10.1016/j.jchromb.2014.03.015. PMID 24685839.

[17] Ueda N, Tsuboi K, Uyama T (May 2013). "Metabolism of endocannabinoids and related N -acylethanolamines: Canonical and alternative pathways". FEBS J. 280 (9): 1874–94. doi:10.1111/febs.12152. PMID 23425575. S2CID 205133026.

[boron108-18] Walter F., PhD. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 108. ISBN 1-4160-2328-3.

[boron103-19] ^ ^a ^b ^c ^d ^e ^f Walter F., PhD. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 103. ISBN 1-4160-2328-3.

[boron104-20] ^ ^a ^b ^c ^d ^e ^f Walter F., PhD. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 104. ISBN 1-4160-2328-3.

[21] Crawford MA, Sinclair AJ (1971). "Nutritional influences in the evolution of mammalian brain. In: lipids, malnutrition & the developing brain". Ciba Foundation Symposium: 267–92. doi:10.1002/9780470719862.ch16. PMID 4949878.

[crawford-22] Crawford MA, Sinclair AJ, Hall B, et al. (July 2023). "The imperative of arachidonic acid in early human development". Progress in Lipid Research. 91: 101222. doi:10.1016/j.plipres.2023.101222. PMID 36746351.

[calder-23] Calder PC, Campoy C, Eilander A, Fleith M, Forsyth S, Larsson PO, Schelkle B, Lohner S, Szommer A, van de Heijning BJ, Mensink RP (June 2019). "A systematic review of the effects of increasing arachidonic acid intake on PUFA status, metabolism and health-related outcomes in humans". The British Journal of Nutrition. 121 (11): 1201–1214. doi:10.1017/S0007114519000692. hdl:10481/60184. PMID 31130146.

[Harris-24] Harris WS, Mozaffarian D, Rimm E, Kris-Etherton P, Rudel LL, Appel LJ, Engler MM, Engler MB, Sacks F (2009). "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". Circulation. 119 (6): 902–7. doi:10.1161/CIRCULATIONAHA.108.191627. PMID 19171857. S2CID 15072227.

[25] Chowdhury R, Warnakula S, Kunutsor S, Crowe F, Ward HA, Johnson L, Franco OH, Butterworth AS, Forouhi NG, Thompson SG, Khaw KT, Mozaffarian D, Danesh J, Di Angelantonio E (Mar 18, 2014). "Association of dietary, circulating, and supplement fatty acids with coronary risk: a systematic review and meta-analysis". Annals of Internal Medicine. 160 (6): 398–406. doi:10.7326/M13-1788. PMID 24723079.

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Arachidonic acid

Chemistry

Biology