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Chemical Compound Review

Leukotriene A4     4-[(2S,3S)-3-[(1E,3E,5Z,8Z)- tetradeca-1,3...

Synonyms: LTA4, CHEMBL69439, AC1NQWZ2, AG-G-83152, CHEBI:15651, ...
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Disease relevance of Leukotriene A4


High impact information on Leukotriene A4

  • The initial enzymatic step in the formation of leukotrienes is the oxidation of arachidonic acid by 5-lipoxygenase (5-LO) to leukotriene A4 [6].
  • Arachidonic acid is released from membrane phospholipids upon cell stimulation (for example, by immune complexes and calcium ionophores) and converted to leukotrienes by a 5-lipoxygenase that also has leukotriene A4 synthetase activity [7].
  • Exposure of HAM to leukotriene A4 (LTA4) resulted in a 2-fold increase in LXA4 and 10-fold increase in LXB4 [8].
  • In contrast, neutrophils did not transform LTA4 to lipoxins [9].
  • IC50 values for the inhibition of the conjugation of 20 microM LTA4-me with 5 mM GSH were 2.1 microM and 0.3 microM for LTC4 and LTC3, respectively [10].

Chemical compound and disease context of Leukotriene A4


Biological context of Leukotriene A4

  • The conversion of LTA4-me to LTC4-me was competitively inhibited by LTA3, LTA4, and LTA5, with respective Ki values of 1.5, 3.3, and 2.8 microM, suggesting that these substrates were recognized by a common active site [10].
  • The recombinant 5-lipoxygenase in 10,000 x g supernatant fractions was able to synthesize large amounts of 5-hydroperoxy-6,8,10,14-icosatetraenoic acid, together with smaller amounts of the nonenzymatic hydrolysis products of leukotriene A4, and exhibited a dependence on Ca2+ and ATP for maximal activity [15].
  • A sensitive fluorescence-linked immunoassay for LTC4 was used to screen a KG-1 cDNA expression library for LTC4 synthase activity after transfection of COS cells and addition of substrate LTA4 [16].
  • The enzymatic reaction obeyed Michaelis-Menten saturation kinetics with respect to varying concentrations of leukotriene A4 [17].
  • They also demonstrate a specific PMNL-endothelial cell interaction in which endothelial cell LTC4 synthesis results from the intercellular transfer of LTA4 produced by PMNL [18].

Anatomical context of Leukotriene A4


Associations of Leukotriene A4 with other chemical compounds


Gene context of Leukotriene A4


Analytical, diagnostic and therapeutic context of Leukotriene A4


  1. Deficient lipoxin synthesis: a novel platelet dysfunction in myeloproliferative disorders with special reference to blastic crisis of chronic myelogenous leukemia. Stenke, L., Edenius, C., Samuelsson, J., Lindgren, J.A. Blood (1991) [Pubmed]
  2. Genetic susceptibility to myocardial infarction and coronary artery disease. Topol, E.J., Smith, J., Plow, E.F., Wang, Q.K. Hum. Mol. Genet. (2006) [Pubmed]
  3. Influence of microvascular adherence on neutrophil leukotriene generation. Evidence for cooperative eicosanoid synthesis. Grimminger, F., Kreusler, B., Schneider, U., Becker, G., Seeger, W. J. Immunol. (1990) [Pubmed]
  4. Eosinophil 15-lipoxygenase is a leukotriene A4 synthase. MacMillan, D.K., Hill, E., Sala, A., Sigal, E., Shuman, T., Henson, P.M., Murphy, R.C. J. Biol. Chem. (1994) [Pubmed]
  5. Leukotriene C synthase in mouse mastocytoma cells. An enzyme distinct from cytosolic and microsomal glutathione transferases. Söderström, M., Hammarström, S., Mannervik, B. Biochem. J. (1988) [Pubmed]
  6. Identification and isolation of a membrane protein necessary for leukotriene production. Miller, D.K., Gillard, J.W., Vickers, P.J., Sadowski, S., Léveillé, C., Mancini, J.A., Charleson, P., Dixon, R.A., Ford-Hutchinson, A.W., Fortin, R. Nature (1990) [Pubmed]
  7. Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Samuelsson, B., Dahlén, S.E., Lindgren, J.A., Rouzer, C.A., Serhan, C.N. Science (1987) [Pubmed]
  8. Human alveolar macrophages have 15-lipoxygenase and generate 15(S)-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid and lipoxins. Levy, B.D., Romano, M., Chapman, H.A., Reilly, J.J., Drazen, J., Serhan, C.N. J. Clin. Invest. (1993) [Pubmed]
  9. Lipoxin formation during human neutrophil-platelet interactions. Evidence for the transformation of leukotriene A4 by platelet 12-lipoxygenase in vitro. Serhan, C.N., Sheppard, K.A. J. Clin. Invest. (1990) [Pubmed]
  10. Properties of highly purified leukotriene C4 synthase of guinea pig lung. Yoshimoto, T., Soberman, R.J., Spur, B., Austen, K.F. J. Clin. Invest. (1988) [Pubmed]
  11. Epidermal cell-polymorphonuclear leukocyte cooperation in the formation of leukotriene B4 by transcellular biosynthesis. Solá, J., Godessart, N., Vila, L., Puig, L., de Moragas, J.M. J. Invest. Dermatol. (1992) [Pubmed]
  12. The biology of 5-lipoxygenase: function, structure, and regulatory mechanisms. Silverman, E.S., Drazen, J.M. Proc. Assoc. Am. Physicians (1999) [Pubmed]
  13. Involvement of leukotriene B4 in murine dermatitis models. Tsuji, F., Miyake, Y., Horiuchi, M., Mita, S. Biochem. Pharmacol. (1998) [Pubmed]
  14. Human melanoma cells generate leukotrienes B4 and C4 from leukotriene A4. Okano-Mitani, H., Ikai, K., Imamura, S. Arch. Dermatol. Res. (1997) [Pubmed]
  15. Native and mutant 5-lipoxygenase expression in a baculovirus/insect cell system. Funk, C.D., Gunne, H., Steiner, H., Izumi, T., Samuelsson, B. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  16. Expression cloning of a cDNA for human leukotriene C4 synthase, an integral membrane protein conjugating reduced glutathione to leukotriene A4. Lam, B.K., Penrose, J.F., Freeman, G.J., Austen, K.F. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  17. Leukotriene A4 hydrolase in human leukocytes. Purification and properties. Rådmark, O., Shimizu, T., Jörnvall, H., Samuelsson, B. J. Biol. Chem. (1984) [Pubmed]
  18. Endothelial cell leukotriene C4 synthesis results from intercellular transfer of leukotriene A4 synthesized by polymorphonuclear leukocytes. Feinmark, S.J., Cannon, P.J. J. Biol. Chem. (1986) [Pubmed]
  19. Single protein from human leukocytes possesses 5-lipoxygenase and leukotriene A4 synthase activities. Rouzer, C.A., Matsumoto, T., Samuelsson, B. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  20. Erythrocyte-neutrophil interactions: formation of leukotriene B4 by transcellular biosynthesis. McGee, J.E., Fitzpatrick, F.A. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  21. Characterization of leukotriene A4 synthase from murine mast cells: evidence for its identity to arachidonate 5-lipoxygenase. Shimizu, T., Izumi, T., Seyama, Y., Tadokoro, K., Rådmark, O., Samuelsson, B. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  22. Metabolism of leukotriene A4 by an enzyme in blood plasma: a possible leukotactic mechanism. Fitzpatrick, F., Haeggström, J., Granström, E., Samuelsson, B. Proc. Natl. Acad. Sci. U.S.A. (1983) [Pubmed]
  23. Peptido-leukotrienes are potent agonists of von Willebrand factor secretion and P-selectin surface expression in human umbilical vein endothelial cells. Datta, Y.H., Romano, M., Jacobson, B.C., Golan, D.E., Serhan, C.N., Ewenstein, B.M. Circulation (1995) [Pubmed]
  24. Leukotriene C4 production by murine mast cells: evidence of a role for extracellular leukotriene A4. Dahinden, C.A., Clancy, R.M., Gross, M., Chiller, J.M., Hugli, T.E. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  25. Enzyme with dual lipoxygenase activities catalyzes leukotriene A4 synthesis from arachidonic acid. Shimizu, T., Rådmark, O., Samuelsson, B. Proc. Natl. Acad. Sci. U.S.A. (1984) [Pubmed]
  26. Evidence for a lipoxygenase mechanism in the biosynthesis of epoxide and dihydroxy leukotrienes from 15(S)-hydroperoxyicosatetraenoic acid by human platelets and porcine leukocytes. Maas, R.L., Brash, A.R. Proc. Natl. Acad. Sci. U.S.A. (1983) [Pubmed]
  27. Identification and characterization of a novel human microsomal glutathione S-transferase with leukotriene C4 synthase activity and significant sequence identity to 5-lipoxygenase-activating protein and leukotriene C4 synthase. Jakobsson, P.J., Mancini, J.A., Ford-Hutchinson, A.W. J. Biol. Chem. (1996) [Pubmed]
  28. Thiopyranol[2,3,4-c,d]indoles as inhibitors of 5-lipoxygenase, 5-lipoxygenase-activating protein, and leukotriene C4 synthase. Hutchinson, J.H., Charleson, S., Evans, J.F., Falgueyret, J.P., Hoogsteen, K., Jones, T.R., Kargman, S., Macdonald, D., McFarlane, C.S., Nicholson, D.W. J. Med. Chem. (1995) [Pubmed]
  29. Leukotriene A4 hydrolase: abrogation of the peptidase activity by mutation of glutamic acid-296. Wetterholm, A., Medina, J.F., Rådmark, O., Shapiro, R., Haeggström, J.Z., Vallee, B.L., Samuelsson, B. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  30. Aminopeptidase B from the rat testis is a bifunctional enzyme structurally related to leukotriene-A4 hydrolase. Cadel, S., Foulon, T., Viron, A., Balogh, A., Midol-Monnet, S., Noël, N., Cohen, P. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  31. Leukotriene A4 hydrolase, insights into the molecular evolution by homology modeling and mutational analysis of enzyme from Saccharomyces cerevisiae. Tholander, F., Kull, F., Ohlson, E., Shafqat, J., Thunnissen, M.M., Haeggström, J.Z. J. Biol. Chem. (2005) [Pubmed]
  32. Leukotriene A4 hydrolase: determination of the three zinc-binding ligands by site-directed mutagenesis and zinc analysis. Medina, J.F., Wetterholm, A., Rådmark, O., Shapiro, R., Haeggström, J.Z., Vallee, B.L., Samuelsson, B. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  33. Leukotriene A4 hydrolase: protection from mechanism-based inactivation by mutation of tyrosine-378. Mueller, M.J., Blomster, M., Oppermann, U.C., Jörnvall, H., Samuelsson, B., Haeggström, J.Z. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  34. Leukotriene A4. Enzymatic conversion into 5,6-dihydroxy-7,9,11,14-eicosatetraenoic acid by mouse liver cytosolic epoxide hydrolase. Haeggström, J., Meijer, J., Rådmark, O. J. Biol. Chem. (1986) [Pubmed]
  35. Molecular cloning and functional expression of a Caenorhabditis elegans aminopeptidase structurally related to mammalian leukotriene A4 hydrolases. Baset, H.A., Ford-Hutchinson, A.W., O'Neill, G.P. J. Biol. Chem. (1998) [Pubmed]
  36. Eicosanoid forming enzyme mRNA in human tissues. Analysis by quantitative polymerase chain reaction. Funk, C.D., FitzGerald, G.A. J. Biol. Chem. (1991) [Pubmed]
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