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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

References

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  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]
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  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]
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