leukotriene a4

Summary

Summary: (2S-(2 alpha,3 beta(1E,3E,5Z,8Z)))-3-(1,3,5,8-Tetradecatetraenyl)oxiranebutanoic acid. An unstable allylic epoxide, formed from the immediate precursor 5-HPETE via the stereospecific removal of a proton at C-10 and dehydration. Its biological actions are determined primarily by its metabolites, i.e., LEUKOTRIENE B4 and cysteinyl-leukotrienes. Alternatively, leukotriene A4 is converted into LEUKOTRIENE C4 by glutathione-S-transferase or into 5,6-di-HETE by the epoxide-hydrolase. (From Dictionary of Prostaglandins and Related Compounds, 1990)

Top Publications

  1. DuBois R. Leukotriene A4 signaling, inflammation, and cancer. J Natl Cancer Inst. 2003;95:1028-9 pubmed
  2. Dickinson J, Murphy R. Mass spectrometric analysis of leukotriene A4 and other chemically reactive metabolites of arachidonic acid. J Am Soc Mass Spectrom. 2002;13:1227-34 pubmed
    ..of prostaglandins and leukotrienes proceeds through the formation of chemically reactive intermediates leukotriene A4 (LTA4) and prostaglandin H2 (PGH2) which in aqueous solutions have chemical half-lives of 3 s and 3 min, ..
  3. Thangapandian S, John S, Sakkiah S, Lee K. Molecular docking and pharmacophore filtering in the discovery of dual-inhibitors for human leukotriene A4 hydrolase and leukotriene C4 synthase. J Chem Inf Model. 2011;51:33-44 pubmed publisher
    ..Reverse validation was performed to ensure the results of the study. ..
  4. Chen X, Li N, Wang S, Wu N, Hong J, Jiao X, et al. Leukotriene A4 hydrolase in rat and human esophageal adenocarcinomas and inhibitory effects of bestatin. J Natl Cancer Inst. 2003;95:1053-61 pubmed
    ..b>Leukotriene A4 hydrolase (LTA4H), a protein overexpressed in EAC in this model, is a rate-limiting enzyme in the biosynthesis ..
  5. Dickinson Zimmer J, Voelker D, Bernlohr D, Murphy R. Stabilization of leukotriene A4 by epithelial fatty acid-binding protein in the rat basophilic leukemia cell. J Biol Chem. 2004;279:7420-6 pubmed
    ..These results present a novel function for the well studied fatty acid-binding protein as a participant in leukotriene biosynthesis that permits LTA(4) to be available for further enzymatic processing in various cellular regions. ..
  6. Thompson M, Archer E, Romer C, Seipelt R. A conserved tyrosine residue of Saccharomyces cerevisiae leukotriene A4 hydrolase stabilizes the transition state of the peptidase activity. Peptides. 2006;27:1701-9 pubmed
    Saccharomyces cerevisiae leukotriene A4 hydrolase (LTA4H) is a bifunctional aminopeptidase/epoxide hydrolase and a member of the M1 family of metallopeptidases...
  7. Habib A, Maclouf J. Comparison of leukotriene A4 metabolism into leukotriene C4 by human platelets and endothelial cells. Arch Biochem Biophys. 1992;298:544-52 pubmed
    ..These results show that platelets and HUVEC possess similar enzymes for the production of LTC4 from LTA4; however, platelets seem to have a higher efficiency than HUVEC in performing this reaction. ..
  8. Agarwal R, Raza H, Allyn D, Bickers D, Mukhtar H. Glutathione S-transferase-dependent conjugation of leukotriene A4-methyl ester to leukotriene C4-methyl ester in mammalian skin. Biochem Pharmacol. 1992;44:2047-53 pubmed
    The glutathione S-transferase (GST)-dependent conjugation of reduced glutathione (GSH) with leukotriene A4 (LTA4)-methyl ester in rodent and human skin was investigated...
  9. Hankin J, Jones D, Murphy R. Covalent binding of leukotriene A4 to DNA and RNA. Chem Res Toxicol. 2003;16:551-61 pubmed

More Information

Publications62

  1. Chiaro C, Morales J, Prabhu K, Perdew G. Leukotriene A4 metabolites are endogenous ligands for the Ah receptor. Biochemistry. 2008;47:8445-55 pubmed publisher
    ..This work suggests a connection between AHR activation and inflammatory signaling molecules produced by the 5-lipoxygenase pathway. ..
  2. Rakonjac M, Fischer L, Provost P, Werz O, Steinhilber D, Samuelsson B, et al. Coactosin-like protein supports 5-lipoxygenase enzyme activity and up-regulates leukotriene A4 production. Proc Natl Acad Sci U S A. 2006;103:13150-5 pubmed
    ..Furthermore, in stimulated cells, CLP appears to function in a complex together with 5LO and membranes, increasing the capacity of 5LO for leukotriene biosynthesis. ..
  3. Maclouf J, Murphy R. Transcellular metabolism of neutrophil-derived leukotriene A4 by human platelets. A potential cellular source of leukotriene C4. J Biol Chem. 1988;263:174-81 pubmed
    ..They also suggest that such interactions may occur in vivo and that platelets could be an important contribution to the generation of the biologically active LTC4. ..
  4. Claesson H, Haeggstrom J. Human endothelial cells stimulate leukotriene synthesis and convert granulocyte released leukotriene A4 into leukotrienes B4, C4, D4 and E4. Eur J Biochem. 1988;173:93-100 pubmed
    Incubation of human endothelial cells with leukotriene A4 resulted in the formation of leukotrienes B4, C4, D4 and E4...
  5. Rudberg P, Tholander F, Andberg M, Thunnissen M, Haeggstrom J. Leukotriene A4 hydrolase: identification of a common carboxylate recognition site for the epoxide hydrolase and aminopeptidase substrates. J Biol Chem. 2004;279:27376-82 pubmed
    ..In conclusion, Arg(563) and Lys(565) possess distinct roles as carboxylate recognition sites for two chemically different substrates, each of which is turned over in separate enzymatic reactions catalyzed by LTA(4) hydrolase. ..
  6. Chang M, Rao M, Reddanna P, Li C, Tu C, Corey E, et al. Specificity of the glutathione S-transferases in the conversion of leukotriene A4 to leukotriene C4. Arch Biochem Biophys. 1987;259:536-47 pubmed
    ..Surprisingly, purified GSTs from sheep lung and seminal vesicles showed little activity toward these leukotriene epoxides, indicating a lack of the counterpart of rat liver anionic GST isozyme in these tissues. ..
  7. Lam B, Penrose J, Freeman G, Austen K. 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;91:7663-7 pubmed
  8. Zimmer J, Dyckes D, Bernlohr D, Murphy R. Fatty acid binding proteins stabilize leukotriene A4: competition with arachidonic acid but not other lipoxygenase products. J Lipid Res. 2004;45:2138-44 pubmed
  9. Serhan C, Sheppard K. Lipoxin formation during human neutrophil-platelet interactions. Evidence for the transformation of leukotriene A4 by platelet 12-lipoxygenase in vitro. J Clin Invest. 1990;85:772-80 pubmed
    ..Neither stimulus nor cell type alone induced the formation of these products. When leukotriene A4 (LTA4), a candidate for the transmitting signal, was added to platelets, lipoxins were formed...
  10. Murai A, Abe M, Hayashi Y, Sakata N, Katsuragi T, Tanaka K. Comparison study between the mechanisms of allergic asthma amelioration by a cysteinyl-leukotriene type 1 receptor antagonist montelukast and methylprednisolone. J Pharmacol Exp Ther. 2005;312:432-40 pubmed
    ..The different effects on cysLT production between the two drugs may provide a rationale for the use of combination therapy with cysLT(1) receptor antagonists and steroids for the treatment of asthma. ..
  11. Penning T, Russell M, Chen B, Chen H, Liang C, Mahoney M, et al. Synthesis of potent leukotriene A(4) hydrolase inhibitors. Identification of 3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid. J Med Chem. 2002;45:3482-90 pubmed
    ..The efforts leading to the identification of clinical candidate SC-57461A (8d, 3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid) are described. ..
  12. Topol E, Smith J, Plow E, Wang Q. Genetic susceptibility to myocardial infarction and coronary artery disease. Hum Mol Genet. 2006;15 Spec No 2:R117-23 pubmed
    ..Although the population attributable risk for any of the genes identified to date is limited, such discovery is likely to be accelerated in the future. ..
  13. Daly K, Digby M, Lefevre C, Nicholas K, Deane E, Williamson P. Identification, characterization and expression of cathelicidin in the pouch young of tammar wallaby (Macropus eugenii). Comp Biochem Physiol B Biochem Mol Biol. 2008;149:524-33 pubmed publisher
    ..Such expression of antimicrobial peptides may form part of the immune strategies of marsupials for neonatal survival during their post-partum development...
  14. Ishii K, Zaitsu M, Yonemitsu N, Kan Y, Hamasaki Y, Matsuo M. 5-lipoxygenase pathway promotes cell proliferation in human glioma cell lines. Clin Neuropathol. 2009;28:445-52 pubmed
    ..The 5-LO-LTA4 pathway might play roles in the proliferation of human glioma cells. ..
  15. Karelina T, Zhudenkov K, Demin O, Svetlichny D, Agoram B, Fairman D, et al. Regulation of leukotriene and 5oxoETE synthesis and the effect of 5-lipoxygenase inhibitors: a mathematical modeling approach. BMC Syst Biol. 2012;6:141 pubmed publisher
    ..Despite both redox and non-redox inhibitors suppressing leukotriene A4 (LTA4) synthesis, redox inhibitors are predicted to increase oxoETE production, thus compromising efficacy...
  16. Paige M, Wang K, Burdick M, Park S, Cha J, Jeffery E, et al. Role of leukotriene A4 hydrolase aminopeptidase in the pathogenesis of emphysema. J Immunol. 2014;192:5059-68 pubmed publisher
    The leukotriene A4 hydrolase (LTA4H) is a bifunctional enzyme with epoxy hydrolase and aminopeptidase activities...
  17. Prakash C, Sweetman B, Sivakumar R, Taffer I, Zipkin R, Blair I. Preparation of omega trideuterated sulfidopeptide leukotrienes: analysis by FAB/MS. Prostaglandins. 1989;37:251-8 pubmed
    C-20 Trideuterated leukotriene A4 methyl ester was prepared by Wittig condensation of a deuterated C9-phosphonium salt with a C11-epoxydienal. It was then treated separately with glutathione, cysteinylglycine and cysteine...
  18. Petric R, Nicholson D, Ford Hutchinson A. Renal leukotriene C4 synthase: characterization, partial purification and alterations in experimental glomerulonephritis. Biochim Biophys Acta. 1995;1254:207-15 pubmed
    ..05). These results suggest a potential mechanism for enhanced cysteinyl LT formation in the development of experimental GN and further support their causal role in the etiology of this disease. ..
  19. Bestmann H, Roder T. Syntheses of leukotriene-derivatives. Eicosanoids. 1992;5 Suppl:S1-3 pubmed
    ..The compounds were tested in a LT-inhibition assay using a monoclonal antibody. ..
  20. Liminga M, Oliw E. Studies of lipoxygenases in the epithelium of cultured bovine cornea using an air interface model. Exp Eye Res. 2000;71:57-67 pubmed
    ..7 kb. The two enzymes were also detected in human corneal epithelium by reverse transcription-polymerase chain reaction. ..
  21. Fierro I, Kutok J, Serhan C. Novel lipid mediator regulators of endothelial cell proliferation and migration: aspirin-triggered-15R-lipoxin A(4) and lipoxin A(4). J Pharmacol Exp Ther. 2002;300:385-92 pubmed
    ..Together, these results identify a novel and potent previously unappreciated action of aspirin-triggered 15-epi-LX. ..
  22. Hada T, Ueda N, Takahashi Y, Yamamoto S. Catalytic properties of human platelet 12-lipoxygenase as compared with the enzymes of other origins. Biochim Biophys Acta. 1991;1083:89-93 pubmed
    ..acid, raised a question if lipoxins were produced by incubation of the enzyme with leukotriene A4. However, the leukotriene A4 was scarcely transformed to lipoxin isomers by 12-lipoxygenases of human and ..
  23. Maclouf J, Murphy R, Henson P. Transcellular sulfidopeptide leukotriene biosynthetic capacity of vascular cells. Blood. 1989;74:703-7 pubmed
    ..Furthermore, platelets, because of their quantity and reactivity, may play a pivotal role in transcellular biosynthesis of eicosanoids. ..
  24. Fukasawa K, Fukasawa K, Harada M, Hirose J, Izumi T, Shimizu T. Aminopeptidase B is structurally related to leukotriene-A4 hydrolase but is not a bifunctional enzyme with epoxide hydrolase activity. Biochem J. 1999;339 ( Pt 3):497-502 pubmed
    ..However, these mutants, Y408F, N409S and NE409-410SS also did not possess any epoxide hydrolase activity. We concluded that Ap B is an M1-family zinc metallopeptidase without epoxide hydrolase activity. ..
  25. Luscinskas F, Nicolaou K, Webber S, Veale C, Gimbrone M, Serhan C. Ca2+ mobilization with leukotriene A4 and epoxytetraenes in human neutrophils. Biochem Pharmacol. 1990;39:355-65 pubmed
    ..We have examined the capacity of leukotriene A4 (LTA4) and 15S-hydroxy-5,6-oxido-7,9,13-trans-11-cis-eicosatetraenoic acid [5(6)-epoxytetraene] to stimulate ..
  26. Fong L, Jiang Y, Riley M, Liu X, Smalley K, Guttridge D, et al. Prevention of upper aerodigestive tract cancer in zinc-deficient rodents: inefficacy of genetic or pharmacological disruption of COX-2. Int J Cancer. 2008;122:978-89 pubmed
    ..Thus, targeting only the COX-2 pathway in zinc-deficient animals did not prevent UADT carcinogenesis. Our data suggest zinc supplementation should be more thoroughly explored in human prevention clinical trials for UADT cancer. ..
  27. Maury G, Ginestar E, Sraïri D, Thaler Dao H, Dembélé Duchesne M, Lorquin J, et al. Racemic LTA4 methyl ester bioconversion into LTC4 methyl ester by various glutathione S-transferases. Biochem Int. 1987;15:1127-35 pubmed
    ..that various glutathione transferases can synthesize leukotriene C4, or its methyl ester, from glutathione and leukotriene A4. We questioned whether the same enzymes could be used to resolve racemic leukotriene A4 methyl ester (more ..
  28. Folco G, Murphy R. Eicosanoid transcellular biosynthesis: from cell-cell interactions to in vivo tissue responses. Pharmacol Rev. 2006;58:375-88 pubmed
    ..Experiments for transcellular events taking place in vivo that reveal the true complexity of eicosanoid biosynthesis within tissues are also reviewed. ..
  29. Abe M, Hugli T. Characterization of leukotriene C4 synthetase in mouse peritoneal exudate cells. Biochim Biophys Acta. 1988;959:386-98 pubmed
    ..Our results indicate that LTC4 synthetase from mouse peritoneal macrophages is a particulate or membrane-bound enzyme, as was reported by Bach et al.(ABSTRACT TRUNCATED AT 400 WORDS) ..
  30. Reddy C, Bertler C, Hammarstrom S. Conversion of dihomo-gamma-linolenic acid to mono- and dihydroxy acids by potato lipoxygenase: evidence for the formation of 8,9-leukotriene A3. Arch Biochem Biophys. 1990;279:211-7 pubmed
    ..The results suggest that 8,9-LTA3 is synthesized by the sequential action of 8- and 11-lipoxygenase activities associated with the potato enzyme. ..
  31. Ohishi N, Izumi T, Minami M, Kitamura S, Seyama Y, Ohkawa S, et al. Leukotriene A4 hydrolase in the human lung. Inactivation of the enzyme with leukotriene A4 isomers. J Biol Chem. 1987;262:10200-5 pubmed
    b>Leukotriene A4 hydrolase from the human lung was purified to apparent homogeneity...
  32. Enomoto H, Morikawa Y, Miyake Y, Tsuji F, Mizuchi M, Suhara H, et al. Synthesis and biological evaluation of N-mercaptoacylproline and N-mercaptoacylthiazolidine-4-carboxylic acid derivatives as leukotriene A4 hydrolase inhibitors. Bioorg Med Chem Lett. 2008;18:4529-32 pubmed publisher
  33. Prié S, Cadieux A, Sirois P. Removal of guinea pig bronchial and tracheal epithelium potentiates the contractions to leukotrienes and histamine. Eicosanoids. 1990;3:29-37 pubmed
    ..These results suggest that PGE2 and I2 are major components of the epithelium-derived relaxing factor. Our results suggest however that underlying tissues are also responsible for the release of these relaxant prostanoids. ..
  34. Chabannes B, Moliere P, Merhi Soussi F, Poubelle P, Lagarde M. Platelets may inhibit leucotriene biosynthesis by human neutrophils at the integrin level. Br J Haematol. 2003;121:341-8 pubmed
    ..It is concluded that platelets may inhibit the neutrophil 5-lipoxygenase activity at the integrin level and in turn may play a role in slowing down the production of LTB4 in the course of inflammation. ..
  35. Sala A, Folco G, Murphy R. Transcellular biosynthesis of eicosanoids. Pharmacol Rep. 2010;62:503-10 pubmed
  36. Bigby T. The yin and the yang of 5-lipoxygenase pathway activation. Mol Pharmacol. 2002;62:200-2 pubmed
  37. Funk D, Sorg B, Lindner S, Schmeiser H. 32P-postlabeling analysis of DNA adducts formed by leukotriene A4 (LTA4). Environ Mol Mutagen. 2010;51:338-43 pubmed publisher
    ..In summary, the TLC (32)P-postlabeling method is suitable for studying DNA adduct formation by LTA(4) and can be used for further investigations on the link between inflammation and cancer...
  38. Jiang W, Li J, Gallowitsch Puerta M, Tracey K, Pisetsky D. The effects of CpG DNA on HMGB1 release by murine macrophage cell lines. J Leukoc Biol. 2005;78:930-6 pubmed
  39. Wiseman J, Skoog M, Nichols J, Harrison B. Kinetics of leukotriene A4 synthesis by 5-lipoxygenase from rat polymorphonuclear leukocytes. Biochemistry. 1987;26:5684-9 pubmed
    ..The 5-HPETE then partitions between reduction to the 5-hydroxyeicosanoid and conversion to leukotriene A4 (LTA4). Both steps in the formation of LTA4 are catalyzed by the enzyme 5-lipoxygenase...
  40. Tornhamre S, Elmqvist A, Lindgren J. 15-Lipoxygenation of leukotriene A(4). Studies Of 12- and 15-lipoxygenase efficiency to catalyze lipoxin formation. Biochim Biophys Acta. 2000;1484:298-306 pubmed
  41. Shimizu T. Enzymes functional in the syntheses of leukotrienes and related compounds. Int J Biochem. 1988;20:661-6 pubmed
    ..6. I report herein recent progress in studies on arachidonic acid metabolism, with the focus primarily on enzymes linked to the 5-lipoxygenase pathway. ..
  42. Kitamura S, Shimizu T, Miki I, Izumi T, Kasama T, Sato A, et al. Synthesis and structural identification of four dihydroxy acids and 11,12-leukotriene C4 derived from 11,12-leukotriene A4. Eur J Biochem. 1988;176:725-31 pubmed
    ..NMR and mass spectrometry to be (5Z,7E,9E,14Z)-(11S,12S)-11,12-oxido-5,7,9,14-ic osatetraenoic acid (11,12-leukotriene A4) and (5Z,7Z,9E,14Z)-(11S,12S)-11,12-oxido-5,7,9,14-ic osatetraenoic acid (7-cis-11,12-leukotriene A4)...
  43. Cholbi R, Ferrandiz M, Terencio M, de Rosa S, Alcaraz M, Paya M. Inhibition of phospholipase A2 activities and some inflammatory responses by the marine product ircinin. Naunyn Schmiedebergs Arch Pharmacol. 1996;354:677-83 pubmed
    ..Ircinin is a new inhibitor of PLA2 activity and our results suggest a potential role for this marine product as an inhibitor of inflammatory processes. ..
  44. Hamasaki Y, Zaitu M, Tsuji K, Miyazaki M, Hayasaki R, Muro E, et al. (9-[4-acetyl-3-hydroxy-2-n-propylphenoxy) methyl]-3-(1H-tetrazol-5-yl)-4H-pyrido [1,2-a] pyrimidin-4-one), AS-35, inhibits leukotriene synthesis. Int J Immunopharmacol. 2000;22:483-90 pubmed
    ..The results indicate that anti-allergic action of AS-35 is predominantly attributable to its inhibition of LT synthesis by suppressing three consecutive enzymes for LTC(4) synthesis. ..
  45. Pufahl R, Kasten T, Hills R, Gierse J, Reitz B, Weinberg R, et al. Development of a fluorescence-based enzyme assay of human 5-lipoxygenase. Anal Biochem. 2007;364:204-12 pubmed
    ..In addition, we demonstrate the use of the assay in a high-throughput screen of the Pfizer compound collection to identify inhibitors of 5-LOX. ..
  46. Schneider C, Niisuke K, Boeglin W, Voehler M, Stec D, Porter N, et al. Enzymatic synthesis of a bicyclobutane fatty acid by a hemoprotein lipoxygenase fusion protein from the cyanobacterium Anabaena PCC 7120. Proc Natl Acad Sci U S A. 2007;104:18941-5 pubmed
  47. Zhou J, An H, Xu H, Liu S, Cao X. Heat shock up-regulates expression of Toll-like receptor-2 and Toll-like receptor-4 in human monocytes via p38 kinase signal pathway. Immunology. 2005;114:522-30 pubmed
    ..These results suggest that the p38 kinase-mediated up-regulation of TLR2 and TLR4 might be involved in the enhanced response to PAMP in human monocytes induced by heat shock. ..
  48. Romano M, Chen X, Takahashi Y, Yamamoto S, Funk C, Serhan C. Lipoxin synthase activity of human platelet 12-lipoxygenase. Biochem J. 1993;296 ( Pt 1):127-33 pubmed
    Human platelets and megacaryocytes generate lipoxins from exogenous leukotriene A4 (LTA4)...
  49. Gupta N, Gresser M, Ford Hutchinson A. Kinetic mechanism of glutathione conjugation to leukotriene A4 by leukotriene C4 synthase. Biochim Biophys Acta. 1998;1391:157-68 pubmed
    ..The rate equation for the random equilibrium mechanism accommodates the inhibition patterns observed for L-699,333 against both substrates as revealed by kinetic fits of the inhibition data to the overall rate equation. ..
  50. Rinaldo Matthis A, Ahmad S, Wetterholm A, Lachmann P, Morgenstern R, Haeggstrom J. Pre-steady-state kinetic characterization of thiolate anion formation in human leukotriene C? synthase. Biochemistry. 2012;51:848-56 pubmed publisher
  51. Thangapandian S, John S, Lazar P, Choi S, Lee K. Structural origins for the loss of catalytic activities of bifunctional human LTA4H revealed through molecular dynamics simulations. PLoS ONE. 2012;7:e41063 pubmed publisher
    Human leukotriene A4 hydrolase (hLTA4H), which is the final and rate-limiting enzyme of arachidonic acid pathway, converts the unstable epoxide LTA4 to a proinflammatory lipid mediator LTB4 through its hydrolase function...
  52. Schewe T, Kuhn H, Sies H. Flavonoids of cocoa inhibit recombinant human 5-lipoxygenase. J Nutr. 2002;132:1825-9 pubmed
  53. Brost H, Ott H, Pfannenstiel C, Wenzl T, Heimann G. Aspirin intolerance in boy with primary ciliary dyskinesia. Allergy. 2003;58:160 pubmed