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Pathway Description
Arachidonic Acid Metabolism
Homo sapiens
Metabolic Pathway
Created: 2013-08-01
Last Updated: 2023-10-25
This pathway describes the production and subsequent metabolism of arachidonic acid, an omega-6 fatty acid. In resting cells arachidonic acid is present in the phospholipids (especially phosphatidylethanolamine and phosphatidylcholine) of membranes of the body’s cells, and is particularly abundant in the brain. Typically a receptor-dependent event, requiring a transducing G protein, initiates phospholipid hydrolysis and releases the fatty acid into the intracellular medium. Three enzymes mediate this deacylation reaction including phospholipase A2 (PLA2), phospholipase C (PLC), and phospholipase D (PLD). Once released, free arachidonate has three possible fates: 1) reincorporation into phospholipids, 2) diffusion outside the cell, and 3) metabolism. Arachidonate metabolism is carried out by three distinct enzyme classes: cyclooxygenases, lipoxygenases, and cytochrome P450’s. Specifically, the enzymes cyclooxygenase and peroxidase lead to the synthesis of prostaglandin H2, which in turn is used to produce the prostaglandins, prostacyclin, and thromboxanes. The enzyme 5-lipoxygenase leads to 5-HPETE, which in turn is used to produce the leukotrienes, hydroxyeicosatetraenoic acids (HETEs) and lipoxins. Some arachidonic acid is converted into midchain HETEs, omega-chain HETEs, dihydroxyeicosatrienoic acids (DHETs), and epoxyeicosatrienoic acids (EETs) by cytochrome P450 epoxygenase hydroxylase activity. Several products of these pathways act within neurons to modulate the activities of ion channels, protein kinases, ion pumps, and neurotransmitter uptake systems, affecting processes such as cellular proliferation, inflammation, and hemostasis. The newly formed eicosanoids may also exit the cell of origin and bind to G-protein-coupled receptors present on nearby neurons or glial cells.
References
Arachidonic Acid Metabolism References
Lehninger, A.L. Lehninger principles of biochemistry (4th ed.) (2005). New York: W.H Freeman.
Vance, D.E., and Vance, J.E. Biochemistry of lipids, lipoproteins, and membranes (4th ed.) (2002) Amsterdam; Boston: Elsevier.
Salway, J.G. Metabolism at a glance (3rd ed.) (2004). Alden, Mass.: Blackwell Pub.
Kroetz DL, Zeldin DC: Cytochrome P450 pathways of arachidonic acid metabolism. Curr Opin Lipidol. 2002 Jun;13(3):273-83.
Pubmed: 12045397
Zeldin DC: Epoxygenase pathways of arachidonic acid metabolism. J Biol Chem. 2001 Sep 28;276(39):36059-62. doi: 10.1074/jbc.R100030200. Epub 2001 Jul 12.
Pubmed: 11451964
Ondrey FG: Arachidonic acid metabolism: a primer for head and neck surgeons. Head Neck. 1998 Jul;20(4):334-49.
Pubmed: 9588707
Sigal E: The molecular biology of mammalian arachidonic acid metabolism. Am J Physiol. 1991 Feb;260(2 Pt 1):L13-28. doi: 10.1152/ajplung.1991.260.2.L13.
Pubmed: 1899973
Kikuta Y, Miyauchi Y, Kusunose E, Kusunose M: Expression and molecular cloning of human liver leukotriene B4 omega-hydroxylase (CYP4F2) gene. DNA Cell Biol. 1999 Sep;18(9):723-30. doi: 10.1089/104454999315006.
Pubmed: 10492403
Zhang X, Chen L, Hardwick JP: Promoter activity and regulation of the CYP4F2 leukotriene B(4) omega-hydroxylase gene by peroxisomal proliferators and retinoic acid in HepG2 cells. Arch Biochem Biophys. 2000 Jun 15;378(2):364-76. doi: 10.1006/abbi.2000.1836.
Pubmed: 10860554
Kikuta Y, Kusunose E, Kusunose M: Characterization of human liver leukotriene B(4) omega-hydroxylase P450 (CYP4F2). J Biochem. 2000 Jun;127(6):1047-52. doi: 10.1093/oxfordjournals.jbchem.a022696.
Pubmed: 10833273
Minami M, Ohno S, Kawasaki H, Radmark O, Samuelsson B, Jornvall H, Shimizu T, Seyama Y, Suzuki K: Molecular cloning of a cDNA coding for human leukotriene A4 hydrolase. Complete primary structure of an enzyme involved in eicosanoid synthesis. J Biol Chem. 1987 Oct 15;262(29):13873-6.
Pubmed: 3654641
Funk CD, Radmark O, Fu JY, Matsumoto T, Jornvall H, Shimizu T, Samuelsson B: Molecular cloning and amino acid sequence of leukotriene A4 hydrolase. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6677-81. doi: 10.1073/pnas.84.19.6677.
Pubmed: 2821541
Mancini JA, Evans JF: Cloning and characterization of the human leukotriene A4 hydrolase gene. Eur J Biochem. 1995 Jul 1;231(1):65-71. doi: 10.1111/j.1432-1033.1995.tb20671.x.
Pubmed: 7628486
Lam BK, Penrose JF, Freeman GJ, Austen KF: Expression cloning of a cDNA for human leukotriene C4 synthase, an integral membrane protein conjugating reduced glutathione to leukotriene A4. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7663-7. doi: 10.1073/pnas.91.16.7663.
Pubmed: 8052639
Welsch DJ, Creely DP, Hauser SD, Mathis KJ, Krivi GG, Isakson PC: Molecular cloning and expression of human leukotriene-C4 synthase. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9745-9. doi: 10.1073/pnas.91.21.9745.
Pubmed: 7937884
Penrose JF, Spector J, Baldasaro M, Xu K, Boyce J, Arm JP, Austen KF, Lam BK: Molecular cloning of the gene for human leukotriene C4 synthase. Organization, nucleotide sequence, and chromosomal localization to 5q35. J Biol Chem. 1996 May 10;271(19):11356-61. doi: 10.1074/jbc.271.19.11356.
Pubmed: 8626689
Rajpert-De Meyts E, Heisterkamp N, Groffen J: Cloning and nucleotide sequence of human gamma-glutamyl transpeptidase. Proc Natl Acad Sci U S A. 1988 Dec;85(23):8840-4. doi: 10.1073/pnas.85.23.8840.
Pubmed: 2904146
Sakamuro D, Yamazoe M, Matsuda Y, Kangawa K, Taniguchi N, Matsuo H, Yoshikawa H, Ogasawara N: The primary structure of human gamma-glutamyl transpeptidase. Gene. 1988 Dec 15;73(1):1-9. doi: 10.1016/0378-1119(88)90307-1.
Pubmed: 2907498
Pitot HC, Goodspeed D, Dunn T, Hendrich S, Maronpot RR, Moran S: Regulation of the expression of some genes for enzymes of glutathione metabolism in hepatotoxicity and hepatocarcinogenesis. Toxicol Appl Pharmacol. 1989 Jan;97(1):23-34. doi: 10.1016/0041-008x(89)90052-5.
Pubmed: 2563599
Forsberg L, de Faire U, Morgenstern R: Low yield of polymorphisms from EST blast searching: analysis of genes related to oxidative stress and verification of the P197L polymorphism in GPX1. Hum Mutat. 1999;13(4):294-300. doi: 10.1002/(SICI)1098-1004(1999)13:4<294::AID-HUMU6>3.0.CO;2-5.
Pubmed: 10220143
Kote-Jarai Z, Durocher F, Edwards SM, Hamoudi R, Jackson RA, Ardern-Jones A, Murkin A, Dearnaley DP, Kirby R, Houlston R, Easton DF, Eeles R: Association between the GCG polymorphism of the selenium dependent GPX1 gene and the risk of young onset prostate cancer. Prostate Cancer Prostatic Dis. 2002;5(3):189-92. doi: 10.1038/sj.pcan.4500569.
Pubmed: 12496980
Sukenaga Y, Ishida K, Takeda T, Takagi K: cDNA sequence coding for human glutathione peroxidase. Nucleic Acids Res. 1987 Sep 11;15(17):7178. doi: 10.1093/nar/15.17.7178.
Pubmed: 3658677
Miyata A, Hara S, Yokoyama C, Inoue H, Ullrich V, Tanabe T: Molecular cloning and expression of human prostacyclin synthase. Biochem Biophys Res Commun. 1994 May 16;200(3):1728-34. doi: 10.1006/bbrc.1994.1652.
Pubmed: 8185632
Chevalier D, Cauffiez C, Bernard C, Lo-Guidice JM, Allorge D, Fazio F, Ferrari N, Libersa C, Lhermitte M, D'Halluin JC, Broly F: Characterization of new mutations in the coding sequence and 5'-untranslated region of the human prostacylcin synthase gene (CYP8A1). Hum Genet. 2001 Feb;108(2):148-55. doi: 10.1007/s004390000444.
Pubmed: 11281454
Deloukas P, Matthews LH, Ashurst J, Burton J, Gilbert JG, Jones M, Stavrides G, Almeida JP, Babbage AK, Bagguley CL, Bailey J, Barlow KF, Bates KN, Beard LM, Beare DM, Beasley OP, Bird CP, Blakey SE, Bridgeman AM, Brown AJ, Buck D, Burrill W, Butler AP, Carder C, Carter NP, Chapman JC, Clamp M, Clark G, Clark LN, Clark SY, Clee CM, Clegg S, Cobley VE, Collier RE, Connor R, Corby NR, Coulson A, Coville GJ, Deadman R, Dhami P, Dunn M, Ellington AG, Frankland JA, Fraser A, French L, Garner P, Grafham DV, Griffiths C, Griffiths MN, Gwilliam R, Hall RE, Hammond S, Harley JL, Heath PD, Ho S, Holden JL, Howden PJ, Huckle E, Hunt AR, Hunt SE, Jekosch K, Johnson CM, Johnson D, Kay MP, Kimberley AM, King A, Knights A, Laird GK, Lawlor S, Lehvaslaiho MH, Leversha M, Lloyd C, Lloyd DM, Lovell JD, Marsh VL, Martin SL, McConnachie LJ, McLay K, McMurray AA, Milne S, Mistry D, Moore MJ, Mullikin JC, Nickerson T, Oliver K, Parker A, Patel R, Pearce TA, Peck AI, Phillimore BJ, Prathalingam SR, Plumb RW, Ramsay H, Rice CM, Ross MT, Scott CE, Sehra HK, Shownkeen R, Sims S, Skuce CD, Smith ML, Soderlund C, Steward CA, Sulston JE, Swann M, Sycamore N, Taylor R, Tee L, Thomas DW, Thorpe A, Tracey A, Tromans AC, Vaudin M, Wall M, Wallis JM, Whitehead SL, Whittaker P, Willey DL, Williams L, Williams SA, Wilming L, Wray PW, Hubbard T, Durbin RM, Bentley DR, Beck S, Rogers J: The DNA sequence and comparative analysis of human chromosome 20. Nature. 2001 Dec 20-27;414(6866):865-71. doi: 10.1038/414865a.
Pubmed: 11780052
Nagata A, Suzuki Y, Igarashi M, Eguchi N, Toh H, Urade Y, Hayaishi O: Human brain prostaglandin D synthase has been evolutionarily differentiated from lipophilic-ligand carrier proteins. Proc Natl Acad Sci U S A. 1991 May 1;88(9):4020-4. doi: 10.1073/pnas.88.9.4020.
Pubmed: 1902577
White DM, Mikol DD, Espinosa R, Weimer B, Le Beau MM, Stefansson K: Structure and chromosomal localization of the human gene for a brain form of prostaglandin D2 synthase. J Biol Chem. 1992 Nov 15;267(32):23202-8.
Pubmed: 1385416
Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. doi: 10.1038/ng1285. Epub 2003 Dec 21.
Pubmed: 14702039
Penning TM, Burczynski ME, Jez JM, Lin HK, Ma H, Moore M, Ratnam K, Palackal N: Structure-function aspects and inhibitor design of type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3). Mol Cell Endocrinol. 2001 Jan 22;171(1-2):137-49. doi: 10.1016/s0303-7207(00)00426-3.
Pubmed: 11165022
Lovering AL, Ride JP, Bunce CM, Desmond JC, Cummings SM, White SA: Crystal structures of prostaglandin D(2) 11-ketoreductase (AKR1C3) in complex with the nonsteroidal anti-inflammatory drugs flufenamic acid and indomethacin. Cancer Res. 2004 Mar 1;64(5):1802-10.
Pubmed: 14996743
Qin KN, New MI, Cheng KC: Molecular cloning of multiple cDNAs encoding human enzymes structurally related to 3 alpha-hydroxysteroid dehydrogenase. J Steroid Biochem Mol Biol. 1993 Dec;46(6):673-9.
Pubmed: 8274401
Yokoyama C, Miyata A, Ihara H, Ullrich V, Tanabe T: Molecular cloning of human platelet thromboxane A synthase. Biochem Biophys Res Commun. 1991 Aug 15;178(3):1479-84. doi: 10.1016/0006-291x(91)91060-p.
Pubmed: 1714723
Ohashi K, Ruan KH, Kulmacz RJ, Wu KK, Wang LH: Primary structure of human thromboxane synthase determined from the cDNA sequence. J Biol Chem. 1992 Jan 15;267(2):789-93.
Pubmed: 1730669
Miyata A, Yokoyama C, Ihara H, Bandoh S, Takeda O, Takahashi E, Tanabe T: Characterization of the human gene (TBXAS1) encoding thromboxane synthase. Eur J Biochem. 1994 Sep 1;224(2):273-9. doi: 10.1111/j.1432-1033.1994.00273.x.
Pubmed: 7925341
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