Skip to main content
SpringerLink
Log in

Leukotriene A4 hydrolase: A key enzyme in chemotactic leukotriene formation

  • Chapter
Novel Inhibitors of Leukotrienes

Part of the book series: Progress in Inflammation Research ((PIR))

Abstract

Leukotrienes are considered as important mediators in a variety of allergic and inflammatory disorders. As discussed elsewhere in this volume, these lipid mediators exert a wide range of biological effects, for example activation of leukocytes and contraction of smooth muscles, particularly in the airways, and microcirculation. In the biosynthesis of leukotrienes, free arachidonic acid is converted by 5-lipoxygenase into 5(S)-trans-5,6-oxido-7,9-trans-11,14-cis-eicosatetraenoic acid, termed leukotriene A4 (LTA4). This highly unstable epoxide intermediate may subsequently be hydrolyzed into 5(S),12(R)-dihydroxy-6,14-cis-8,10-trans-eicosatetraenoic acid (LTB4), a reaction catalyzed by LTA4 hydrolase. Alternatively, LTA4 may be conjugated with glutathione, by LTC4 synthase, to produce 5(S)-hydroxy-6(R)-S-glutathionyl-7,9-trans-11,14-cis-eicosatetraenoic acid (LTC4). This review will focus on the biochemistry and molecular biology of LTA4 hydrolase, the enzyme catalyzing the final step in the biosynthesis of the potent chemotaxin LTB4, an important mediator of inflammation.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Wetterholm A, Blomster M, Haeggström JZ (1996) Leukotriene A4 hydrolase: a key enzyme in the biosynthesis of leukotriene B4. In: G Folco, B Samuelsson, J Maclouf, GP Velo (eds): Eicosanoids: From biotechnology to therapeutic applications. Plenum Press, New York, 1–12

    Google Scholar 

  2. Rybina IV, Liu H, Gor Y, Feinmark SJ (1997) Regulation of leukotriene A4 hydrolase activity in endothelial cells by phosphorylation. J Biol Chem 272: 31865–31871

    Article  PubMed  CAS  Google Scholar 

  3. Strömberg F, Hamberg M, Rosenqvist U, Dahlén S-E, Haeggström JZ (1996) Formation of a novel metabolite of leukotriene A4 in tissues of Xenopus laevis. Eur J Biochem 238: 599–605

    Article  Google Scholar 

  4. Gut J, Goldman DW, Jamieson GC, Trudell JR (1987) Conversion of leukotriene A4 to leukotriene B4: Catalysis by human liver microsomes under anaerobic conditions. Arch Biochem Biophys 259: 497–509

    Article  PubMed  CAS  Google Scholar 

  5. Haeggström JZ (1997) The molecular biology of the leukotriene A4 hydrolase. In: S Holgate, S-E Dahlén (eds): SRS-A to leukotrienes, the dawning of a new treatment. Blackwell Science, Oxford, 85–100

    Google Scholar 

  6. Mancini JA, Evans JF (1995) Cloning and characterization of the human leukotriene A4 hydrolase gene. Eur J Biochem 231: 65–71

    Article  PubMed  CAS  Google Scholar 

  7. Jendraschak E, Kaminski WE, Kiefl R, von Schacky C (1996) The human leukotriene A4 hydrolase gene is expressed in two alternatively spliced mRNA forms. Biochem J 314: 733–737

    PubMed  CAS  Google Scholar 

  8. Malfroy B, Kado-Fong H, Gros C, Giros B, Schwartz J-C, Hellmiss R (1989) Molecular cloning and amino acid sequence of rat kidney aminopeptidase M: A member of a super family of zinc-metallohydrolases. Biochem Biophys Res Commun 161: 236–241

    Article  PubMed  CAS  Google Scholar 

  9. Vallee BL, Auld DS (1990) Zinc coordination, function, and structure of zinc enzymes and other proteins. Biochemistry 29: 5647–5659

    Article  PubMed  CAS  Google Scholar 

  10. Haeggström JZ, Wetterholm A, Shapiro R, Vallee BL, Samuelsson B (1990) Leukotriene A4 hydrolase: A zinc metalloenzyme. Biochem Biophys Res Commun 172: 965–970

    Article  PubMed  Google Scholar 

  11. Minami M, Ohishi N, Mutoh H, Izumi T, Bito H, Wada H, Seyama Y, Toh H, Shimizu T (1990) Leukotriene A4 hydrolase is a zinc-containing aminopeptidase. Biochem Biophys Res Commun 173: 620–626

    Article  PubMed  CAS  Google Scholar 

  12. Wetterholm A, Macchia L, Haeggström JZ (1994) Zinc and other divalent cations inhibit purified leukotriene A4 hydrolase and leukotriene B4 biosynthesis in human polymorphonuclear leukocytes. Arch Biochem Biophys 311: 263–271

    Article  CAS  Google Scholar 

  13. Haeggström JZ, Wetterholm A, Vallee BL, Samuelsson B (1990) Leukotriene A4 hydro-lase: An epoxide hydrolase with peptidase activity. Biochem Biophys Res Commun 173: 431–437

    Article  PubMed  Google Scholar 

  14. Wu Q, Lahti JM, Air GM, Burrows PD, Cooper MD (1990) Molecular cloning of the murine BP-1/6C3 antigen: A member of the zinc-dependent metallopeptidase family. Proc Natl Acad Sci USA 87: 993–997

    Article  PubMed  CAS  Google Scholar 

  15. Ménard A, Mock M, Montecucco C (1995) Similarities between the lethal factor of bacillus anthracis and leukotriene A4 hydrolase. Mol Microbiol 18: 991–992

    Article  Google Scholar 

  16. Cadel S, Foulon T, Viron A, Balogh A, Midol-Monnet S, Noel N, Cohen P (1997) Aminopeptidase B from the rat testis is a bifunctional enzyme structurally related to leukotriene A4 hydrolase. Proc Natl Acad Sci USA 94: 2963–2968

    Article  PubMed  CAS  Google Scholar 

  17. Nasr F, Bécam AM, Herbert CJ (1996) The sequence of 12.8 kb from the left arm of chromosome XIV reveals a sigma element, a pro-tRNA and six complete open reading frames, one of which encodes a protein similar to the human leukotriene A4 hydrolase. Yeast 12: 493–499

    Article  PubMed  CAS  Google Scholar 

  18. Wetterholm A, Haeggström JZ (1992) Leukotriene A4 hydrolase: an anion activated peptidase. Biochim Biophys Acta 1123: 275–281

    Article  PubMed  CAS  Google Scholar 

  19. Orning L, Gierse JK, Fitzpatrick FA (1994) The bifunctional enzyme leukotriene-A4 hydrolase is an arginine aminopeptidase of high efficiency and specificity. J Biol Chem 269: 11269–11273

    PubMed  CAS  Google Scholar 

  20. Griffin KJ, Gierse J, Krivi G, Fitzpatrick FA (1992) Opioid peptides are substrates for the bifunctional enzyme LTA4 hydrolase/aminopeptidase. Prostaglandins 44: 251–257

    Article  PubMed  CAS  Google Scholar 

  21. Nissen JB, Iversen L, Kragballe K (1995) Characterization of the aminopeptidase activity of epidermal leukotriene A4 hydrolase against the opioid dynorphin fragment 1–7. Br J Dermatol 133: 742–749

    Article  PubMed  CAS  Google Scholar 

  22. Mueller MJ, Samuelsson B, Haeggström JZ (1995) Chemical modification of leukotriene A4 hydrolase. Indications for essential tyrosyl and arginyl residues at the active site. Biochemistry 34: 3536–3543

    Article  PubMed  CAS  Google Scholar 

  23. Örning L, Fitzpatrick FA (1992) Albumins activate peptide hydrolysis by the bifunctional enzyme LTA4 hydrolase/aminopeptidase. Biochemistry 31: 4218–4223

    Article  PubMed  Google Scholar 

  24. Fitzpatrick FA, Haeggström J, Granström E, Samuelsson B (1983) Metabolism of leukotriene A4 by an enzyme in blood plasma: A possible leukotactic mechanism. Proc Natl Acad Sci USA 80: 5425–5429

    Article  PubMed  CAS  Google Scholar 

  25. Munafo DA, Shindo K, Baker JR, Bigby TD (1994) Leukotriene A4 hydrolase in human bronchoalveolar lavage fluid. J Clin Invest 93: 1024–1050

    Article  Google Scholar 

  26. Örning L, Krivi G, Fitzpatrick FA (1991) Leukotriene A4 hydrolase: Inhibition by bestatin and intrinsic aminopeptidase activity establish its functional resemblance to metallohydrolase enzymes. J Biol Chem 266: 1375–1378

    PubMed  Google Scholar 

  27. Yuan W, Wong C-H, Haeggström JZ, Wetterholm A, Samuelsson B (1992) Novel tight-binding inhibitors of leukotriene A4 hydrolase. J Am Chem Soc 114: 6552–6553

    Article  CAS  Google Scholar 

  28. Wetterholm A, Haeggström JZ, Samuelsson B, Yuan W, Munoz B, Wong C (1995) Potent and selective inhibitors of leukotriene A4 hydrolase: effects on purified enzyme and human polymorphonuclear leukocytes. J Pharmacol Exp Ther 275: 31–37

    PubMed  CAS  Google Scholar 

  29. Hogg JH, Ollmann IR, Haeggström JZ, Wetterholm A, Samuelsson B, Wong C-H (1995) Amino hydroxamic acids as potent inhibitors of LTA4 hydrolase. Bioorg Med Chem 3: 1405–1415

    Article  PubMed  CAS  Google Scholar 

  30. Penning TD, Askonas LJ, Djuric SW, Haack RA, Yu SS, Michener ML, Krivi GG, Pyla EY (1995) Kelatorphan and related analogs-potent and selective inhibitors of leukotriene A4 hydrolase. Bioorg Med Chem Lett 5: 2517–2522

    Article  CAS  Google Scholar 

  31. Labaudinière R, Hilboll G, Leon-Lomeli A, Lautenschläger H-H, Parnham M, Kuhl P, Dereu N (1992) ω-[(ω-arylalkyl)aryl]alkanoic acids: A new class of specific LTA4 hydro-lase inhibitors. J Med Chem 35: 3156–3169

    Article  PubMed  Google Scholar 

  32. Yuan JH, Birkmeier J, Yang DC, Hribar JD, Liu N, Bible R, Hajdu E, Rock M, Schoen-hard G (1996) Isolation and identification of metabolites of leukotriene A4 hydrolase inhibitor SC-57461 in rats. Drug Metab Dispos 24: 1124–1133

    PubMed  CAS  Google Scholar 

  33. Smith WG, Russell MA, Liang C, Askonas LA, Kachur JF, Kim S, Souresrafil N, Price DV, Clapp NK (1996) Pharmacological characterization of selective inhibitors of leukotriene A4 hydrolase. Prostaglandins Leukot Essent Fatty Acids 55 (Suppl 1): 13

    Google Scholar 

  34. Tsuge H, Ago H, Aoki M, Furuno M, Noma M, Miyano M, Minami M, Izumi T, Shimizu T (1994) Crystallization and preliminary X-ray crystallographic studies of recombinant human leukotriene A4 hydrolase complexed with bestatin. J Mol Biol 238: 854–856

    Article  PubMed  CAS  Google Scholar 

  35. Medina JF, Wetterholm A, Rádmark O, Shapiro R, Haeggström JZ, Vallee BL, Samuels-son B (1991) Leukotriene A4 hydrolase: determination of the three zinc-binding ligands by site directed mutagenesis and zinc analysis. Proc Natl Acad Sci USA 88: 7620–7624

    Article  PubMed  CAS  Google Scholar 

  36. Pangburn MK, Walsh KA (1975) Thermolysin and neutral protease: Mechanistic considerations. Biochemistry 14: 4050–4054

    Article  CAS  Google Scholar 

  37. Kester WR, Matthews BW (1977) Crystallographic study of the binding of dipeptide inhibitors to thermolysin: Implications for the mechanism of catalysis. Biochemistry 16: 2506–2516

    Article  PubMed  CAS  Google Scholar 

  38. Wetterholm A, Medina JF, Rádmark O, Shapiro R, Haeggström JZ, Vallee BL, Samuels-son B (1992) Leukotriene A4 hydrolase: Abrogation of the peptidase activity by mutation of glutamic acid-296. Proc Natl Acad Sci USA 89: 9141–9145

    Article  PubMed  CAS  Google Scholar 

  39. Minami M, Bito H, Ohishi N, Tsuge H, Miyano M, Mori M, Wada H, Mutoh H, Shimada S, Izumi T et al (1992) Leukotriene A4 hydrolase, a bifunctional enzyme. Distinction of leukotriene A4 hydrolase and aminopeptidase activities by site-directed mutagenesis at Glu-297. FEBS Lett 309: 353–357

    Article  PubMed  CAS  Google Scholar 

  40. Ohishi N, Izumi T, Minami M, Kitamura S, Seyama Y, Ohkawa S, Terao S, Yotsumoto H, Takaku F, Shimizu T (1987) Leukotriene A4 hydrolase in the human lung: Inactivation of the enzyme with leukotriene A4 isomers. J Biol Chem 262: 10200–10205

    PubMed  CAS  Google Scholar 

  41. Maycock AL, Anderson MS, DeSousa DM, Kuehl Jr FA (1982) Leukotriene A4: Preparation and enzymatic conversion in a cell-free system to leukotriene B4. J Biol Chem 257: 13911–13914

    PubMed  CAS  Google Scholar 

  42. Evans JF, Nathaniel DJ, Zamboni RJ, Ford-Hutchinson AW (1985) Leukotriene A3: A poor substrate but a potent inhibitor of rat and human neutrophil leukotriene A4 hydro-lase. J Biol Chem 260: 10966–10970

    PubMed  CAS  Google Scholar 

  43. Örning L, Gierse J, Duffin K, Bild G, Krivi G, Fitzpatrick FA (1992) Mechanism-based inactivation of leukotriene A4 hydrolase/aminopeptidase by leukotriene A4. Mass spectrometric and kinetic characterization. J Biol Chem 267: 22733–22739

    PubMed  Google Scholar 

  44. Evans JF, Kargman S (1992) Bestatin inhibits covalent coupling of [3H]LTA4 to human leukocyte LTA4 hydrolase. FEBS Lett 297: 139–142

    Article  PubMed  CAS  Google Scholar 

  45. Mueller MJ, Wetterholm A, Blomster M, Jörnvall H, Samuelsson B, Haeggström JZ (1995) Leukotriene A4 hydrolase: Mapping of a heneicosapeptide involved in mechanism-based inactivation. Proc Natl Acad Sci USA 92: 8383–8387

    Article  PubMed  CAS  Google Scholar 

  46. Mueller MJ, Blomster M, Opperman UCT, Jörnvall H, Samuelsson B, Haeggström JZ (1996) Leukotriene A4 hydrolase: Protection from mechanism-based inactivation by mutation of tyrosine-378. Proc Natl Acad Sci USA 93: 5931–5935

    Article  PubMed  CAS  Google Scholar 

  47. Mueller MJ, Blomster M, Samuelsson B, Haeggström JZ (1996) Leukotriene A4 hydro-lase: mutation of tyrosine-378 allows conversion of leukotriene A4 into an isomer of leukotriene B4. J Biol Chem 271: 24345–24348

    Article  PubMed  CAS  Google Scholar 

  48. Blomster Andberg M, Hamberg M, Haeggström JZ (1997) Mutation of tyrosine 383 in leukotrienc A4 hydrolase allows formation of 5S,6S-dihydroxy-7,9-trans-11,14-ciseicosatetraenoic acid: Implications for the epoxide hydrolase mechanism. J Biol Chem 272: 23057–23063

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Biochemistry and Biophysics, Division of Chemistry II, Karolinska Institutet, Stockholm, S-171 77, Sweden

    Jesper Z. Haeggström & Anders Wetterholm

Authors
  1. Jesper Z. Haeggström
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anders Wetterholm
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Center for Cardiopulmonary Pharmacology Institute of Pharmacological Sciences, University of Milan, Via Balzaretti 9, Milan, 20133, Italy

    Giancarlo Folco

  2. Department of Medical Biochemistry and Biophysics Division of Physiological Chemistry II, Karolinska Institute, Stockholm, 10401, Sweden

    Bengt Samuelsson

  3. National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO, 80206, USA

    Robert C. Murphy

Rights and permissions

Reprints and permissions

Copyright information

© 1999 Springer Basel AG

About this chapter

Cite this chapter

Haeggström, J.Z., Wetterholm, A. (1999). Leukotriene A4 hydrolase: A key enzyme in chemotactic leukotriene formation. In: Folco, G., Samuelsson, B., Murphy, R.C. (eds) Novel Inhibitors of Leukotrienes. Progress in Inflammation Research. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0348-8703-8_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-0348-8703-8_3

  • Publisher Name: Birkhäuser, Basel

  • Print ISBN: 978-3-0348-9736-5

  • Online ISBN: 978-3-0348-8703-8

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation