Leukotriene A4 Hydrolase: A Key Enzyme in the Biosynthesis of Leukotriene B4

  • Anders Wetterholm
  • Martina Blomster
  • Jesper Z. Haeggström
Chapter
Part of the NATO ASI Series book series (NSSA, volume 283)

Abstract

LTA4 hydrolase (EC 3.3.2.6) catalyzes the conversion of the unstable epoxide intermediate LTA4 into the dihydroxy acid LTB4, 5(S), 12(R)-dihydroxy-6,14-cis-8,10-trans-eicosatetraenoic acid. Purified LTA4 hydrolase from human leukocytes was characterized as a monomeric enzyme (Mr ≈ 69,000) without cofactor requirement and distinct from other epoxide hydrolases (Rådmark et al., 1984). Since then, LTA4 hydrolase has been purified from a number of different cells and tissues, e.g., human erythrocytes (McGee and Fitzpatrick, 1985), human lung (Ohishi et al., 1987), the B-cell line Raji (Odlander et al., 1991), rat neutrophils (Evans et al., 1985), guinea pig lung (Bito et al., 1989), and guinea pig liver (Haeggström et al., 1988). The catalytic properties and physicochemical characteristics are similar for the different enzymes (for a review see Rådmark and Haeggström, 1990). Different methods, such as enzyme activity determinations and/or immunological detection, have shown that LTA4 hydrolase is widely distributed and the enzyme has been found in practically all cells, organs and tissues examined in man (Haeggström et al., 1985; Bigby et al., 1989; Fu et al., 1989), rat (Medina et al., 1988), and guinea pig (Izumi et al., 1986; Ohishi et al., 1990). The enzyme has been detected even in cells apparently devoid of 5-lipoxygenase activity and therefore unable to provide the substrate LTA4, e.g., erythrocytes (Fitzpatrick et al., 1984), T-cell lines (Fu et al, 1988), fibroblasts (Medina et al., 1990), endothelial cells (Claesson and Haeggström, 1988), keratinocytes (Iversen et al., 1993), and airway epithelial cells (Bigby et al., 1989; Bigby et al., 1994). Also cell free fluids such as blood plasma from several mammals (Fitzpatrick et al., 1983) and bronhoalveolar lavage fluid (Munafo et al., 1994) was found to exhibit LTA4 hydrolase activity.

Keywords

Peptidase Activity Wild Type Enzyme Epoxide Hydrolase Zinc Binding Human Polymorphonuclear Leukocyte 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Bigby, T.D., Lee, D.M., Meslier, N. and Gruenert, D.C., 1989, Leukotriene A4 hydrolase activity of human airway epithelial cells, Biochem. Biophys. Res. Commun. 164:1–7.PubMedCrossRefGoogle Scholar
  2. Bigby, T.D., Lee, D.M., Minami, M., Ohishi, N., Shimizu, T. and Baker, J.R., 1994, Characterization of human airway epithelial cell leukotriene A4 hydrolase, Am. J. Respir. Cell Mol Biol. 11:615–624.PubMedCrossRefGoogle Scholar
  3. Bito, H., Ohishi, N., Miki, I., Minami, M., Tanabe, T., Shimizu, T. and Seyama, Y., 1989, Leukotriene A4hydrolase from guinea pig lung: The presence of two catalytically active forms, J. Biochem. 105:261–264.PubMedGoogle Scholar
  4. Blomster, M., Wetterholm, A., Mueller, M.J. and Haeggström, J.Z., 1995, Evidence for a catalytic role of tyrosine 383 in the peptidase reaction of leukotriene A4 hydrolase, Eur. J. Biochem. 231:528–534.PubMedCrossRefGoogle Scholar
  5. Claesson, H.-E. and Haeggström, J., 1988, Human endothelial cells stimulate leukotriene synthesis and convert granulocyte released leukotriene A4 into leukotrienes B4, C4, D4 and E4, Eur. J. Biochem. 173:93–100.PubMedCrossRefGoogle Scholar
  6. Evans, J.F., Dupuis, P. and Ford-Hutchinson, A.W., 1985, Purification and characterisation of leukotriene A4 hydrolase from rat neutrophils, Biochim. Biophys. Acta 840:43–50.PubMedCrossRefGoogle Scholar
  7. Evans, J.F. and Kargman, S., 1992, Bestatin inhibits covalent coupling of [3[H]LTA4 to human leukocyte LTA4 hydrolase, FEBS Lett. 297:139–142.PubMedCrossRefGoogle Scholar
  8. Evans, J.F., Nathaniel, D.J., Zamboni, R.J. and Ford-Hutchinson, A.W., 1985, Leukotriene A3: A poor substrate but a potent inhibitor of rat and human neutrophil leukotriene A4 hydrolase, J. Biol. Chem. 260:10966–10970.PubMedGoogle Scholar
  9. Fitzpatrick, F.A., Haeggström, J., Granström, E. and 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.PubMedCrossRefGoogle Scholar
  10. Fitzpatrick, F.A., Liggett, W.F., McGee, J., Bunting, S., Morton, D. and Samuelsson, B., 1984, Metabolism of leukotriene A4 by human erythrocytes. A novel cellular source of leukotriene B4., J. Biol. Chem. 259:11403–11407.PubMedGoogle Scholar
  11. Fu, J.Y., Haeggström, J., Collins, P., Meijer, J. and Rådmark, O., 1989, Leukotriene A4 hydrolase: Analysis of some human tissues by radioimmunoassay, Biochim. Biophys. Acta 1006:121–126.PubMedCrossRefGoogle Scholar
  12. Fu, J.Y., Medina, J.F., Funk, C.D., Wetterholm, A. and Rådmark, O., 1988, Leukotriene A4, conversion to leukotriene B4 in human T-cell lines, Prostaglandins 36:241–248.PubMedGoogle Scholar
  13. Funk, C.D., Rådmark, O., Fu, J.Y., Matsumoto, T., Jörnvall, H., Shimizu, T. and Samuelsson, B., 1987, Molecular cloning and amino acid sequence of leukotriene A4 hydrolase, Proc. Natl. Acad. Sci. USA 84:6677–6681.PubMedCrossRefGoogle Scholar
  14. Gorter, J. and Gruber, M., 1970, Cathepsin C: An allosteric enzyme, Biochim. Biophys. Acta 198:546–555.PubMedCrossRefGoogle Scholar
  15. Griffin, K.J., Gierse, J., Krivi, G. and Fitzpatrick, F.A., 1992, Opioid peptides are substrates for the bifunctional enzyme LTA4 hydrolase/aminopeptidase, Prostaglandins 44:251–257.PubMedGoogle Scholar
  16. Haeggström, J., Bergman, T., Jörnvall, H. and Rådmark, O., 1988, Guinea-pig liver leukotriene A4 hydrolase: Purification, characterization and structural properties, Eur. J. Biochem. 174:717–724.PubMedCrossRefGoogle Scholar
  17. Haeggström, J., Rådmark, O. and Fitzpatrick, F.A., 1985, Leukotriene A4-hydrolase activity in guinea pig and human liver, Biochim.Biophys.Acta 835:378–384.PubMedCrossRefGoogle Scholar
  18. Haeggström, J.Z., Wetterholm, A., Shapiro, R., Vallee, B.L. and Samuelsson, B., 1990, Leukotriene A4 hydrolase: A zinc metalloenzyme, Biochem. Biophys. Res. Commun. 172:965–970.PubMedCrossRefGoogle Scholar
  19. Haeggström, J.Z., Wetterholm, A., Vallee, B.L. and Samuelsson, B., 1990, Leukotriene A4 hydrolase: An epoxide hydrolase with peptidase activity, Biochem. Biophys. Res. Commun. 173:431–437.PubMedCrossRefGoogle Scholar
  20. Holmquist, B. and Vallee, B.L., 1974, Metal substitutions and inhibition of thermolysin: Spectra of the cobalt enzyme, J. Biol. Chem. 249:4601–4607.PubMedGoogle Scholar
  21. Hopsu, V.K., Mäkinen, K.K. and Glenner, G.G., 1966, Characterization of aminopeptidase B: Substrate specificity and affector studies, Arch. Biochem. Biophys. 114:567–575.PubMedCrossRefGoogle Scholar
  22. Iversen, L., Fogh, K., Ziboh, V.A., Kristensen, R, Schmedes, A. and Kragballe, K., 1993, Leukotriene B4 formation during human neutrophil keratinocyte interactions: Evidence for transformation of leukotriene A4 by putative keratinocyte leukotriene A4 hydrolase, J. Invest. Dermatol. 100:293–298.PubMedCrossRefGoogle Scholar
  23. Izumi, T., Shimizu, T., Seyama, Y., Ohishi, N. and Takaku, F., 1986, Tissue distribution of leukotriene A4 hydrolase activity in guinea pig, Biochem. Biophys. Res. Commun. 135:139–145.PubMedCrossRefGoogle Scholar
  24. Kester, W.R. and Matthews, B.W., 1977, Crystallographic study of the binding of dipeptide inhibitors to thermolysin: Implications for the mechanism of catalysis, Biochemistry 16:2506–2516.PubMedCrossRefGoogle Scholar
  25. Labaudinière, R., Hilboll, G., Leon-Lomeli, A., Lautenschläger, H.-H., Parnham, M., Kuhl, R and Dereu, N., 1992, ω-[(ω-arylalky)aryl]alkanoic acids: A new class of specific LTA4 hydrolase inhibitors, J. Med. Chem. 35:3156–3169.PubMedCrossRefGoogle Scholar
  26. Labaudinière, R., Hilboll, G., Leon-Lomeli, A., Terlain, B., Cavy, F., Parnham, M., Kuhl, P. and Dereu, N., 1992, ω-[(ω-arylalkyl)thienyl]alkanoic acids: From specific LTA4 hydrolase inhibitors to LTB4 receptor antagonists, J. Med. Chem. 35:3170–3179.PubMedCrossRefGoogle Scholar
  27. Larsen, K.S. and Auld, D.S., 1989, Carboxypeptidase A: Mechanism of zinc inhibition, Biochemistry 28:9620–9625.PubMedCrossRefGoogle Scholar
  28. Larsen, K.S. and Auld, D.S., 1991, Characterization of an inhibitory metal binding site in carboxypeptidase A, Biochemistry 30:2613–2618.PubMedCrossRefGoogle Scholar
  29. Levitzki, A. and Steer, M.L., 1974, The allosteric activation of mammalian α-amylase by chloride, Eur. J. Biochem. 41:171–180.PubMedCrossRefGoogle Scholar
  30. Makita, N., Funk, C.D., Imai, E., Hoover, R.L. and Badr, K.F., 1992, Molecular cloning and functional expression of rat leukotriene A4 hydrolase using the polymerase chain reaction, FEBS Lett. 299:273–277.PubMedCrossRefGoogle Scholar
  31. Malfroy, B., Kado-Fong, H., Gros, C., Giros, B., Schwartz, J.-C. and 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.PubMedCrossRefGoogle Scholar
  32. Mancini, J.A. and Evans, J.F., 1995, Cloning and characterization of the human leukotriene A4 hydrolase gene, Eur. J. Biochem. 231:65–71.PubMedCrossRefGoogle Scholar
  33. Maycock, A.L., Anderson, M.S., DeSousa, D.M. and Kuehl Jr, F.A., 1982, Leukotriene A4: Preparation and enzymatic conversion in a cell-free system to leukotriene B4, J. Biol. Chem. 257:13911–13914.PubMedGoogle Scholar
  34. McGee, J. and Fitzpatrick, F., 1985, Enzymatic hydration of leukotriene A4: Purification and characterization of a novel epoxide hydrolase from human erythrocytes, J. Biol. Chem. 260:12832–12837.PubMedGoogle Scholar
  35. Medina, J.F., Barrios, C., Funk, C.D., Larsson, O., Haeggström, J. and Rådmark, O., 1990, Human fibroblasts show expression of the leukotriene A4 hydrolase gene, which is increased after SV-40 transformation, Eur. J. Biochem 191:27–31.PubMedCrossRefGoogle Scholar
  36. Medina, J.F., Haeggström, J.Z., Kumlin, M. and Rådmark, O., 1988, Leukotriene A4: metabolism in different rat tissues, Biochim. Biophys. Acta 961:203–212.PubMedCrossRefGoogle Scholar
  37. Medina, J.F., Rådmark, O., Funk, C.D. and Haeggström, J.Z., 1991, Molecular cloning and expression of mouse leukotriene A4 hydrolase cDNA, Biochem. Biophys. Res. Commun. 176:1516–1524.PubMedCrossRefGoogle Scholar
  38. Medina, J.F., Wetterholm, A., Rådmark, O., Shapiro, R., Haeggström, J.Z., Vallee, B.L. and Samuelsson, 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.PubMedCrossRefGoogle Scholar
  39. Minami, M., Bito, H., Ohishi, N., Tsuge, H., Miyano, M., Mori, M., Wada, H., Mutoh, H., Shimada, S., Izumi, T., Abe, K. and Shimizu, T., 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.PubMedCrossRefGoogle Scholar
  40. Minami, M., Minami, Y., Emori, Y, Kawasaki, H., Ohno, S., Suzuki, K., Ohishi, N., Shimizu, T. and Seyama, Y., 1988, Expression of human leukotriene A4 hydrolase cDNA in Escherichia coli, FEBS Lett. 229:279–282.CrossRefGoogle Scholar
  41. Minami, M., Ohishi, N., Mutoh, H., Izumi, T., Bito, H., Wada, H., Seyama, Y., Toh, H. and Shimizu, T., 1990, Leukotriene A4 hydrolase is a zinc-containing aminopeptidase, Biochem. Biophys. Res. Commun. 173:620–626.PubMedCrossRefGoogle Scholar
  42. Minami, M., Ohno, S., Kawasaki, H., Rådmark, O., Samuelsson, B., Jörnvall, H., Shimizu, T., Seyama, Y. and Suzuki, K., 1987, Molecular cloning of a cDNA coding for human leukotriene A4 hydrolase, J. Biol. Chem. 262:13873–13876.PubMedGoogle Scholar
  43. Mueller, M.J., Samuelsson, B. and Haeggström, J.Z., 1995, Chemical modification of leukotriene A4 hydrolase. Indications for essential tyrosyl and arginyl residues at the active site, Biochemistry 34:3536–3543.PubMedCrossRefGoogle Scholar
  44. Munafo, D.A., Shindo, K., Baker, J.R. and Bigby, T.D., 1994, Leukotriene A4 hydrolase in human bronchoalveolar lavage fluid, J. Clin. Invest. 93:1024–1050.CrossRefGoogle Scholar
  45. Myrbäck, K., 1926, Über Verbindungen einiger Enzyme mit inakivierenden Stoffen, HoppeSeyler’s Z. Physiol. Chem. 159:1–84.CrossRefGoogle Scholar
  46. Odlander, B., Claesson, H.-E., Bergman, T., Rådmark, O., Jörnvall, H. and Haeggström, J.Z., 1991, Leukotriene A4 hydrolase in the human B-lymphocytic cell line Raji: Indications of catalytically divergent forms of the enzyme, Arch. Biochem. Biophys. 287:167–174.PubMedCrossRefGoogle Scholar
  47. Ohishi, N., Izumi, T., Minami, M., Kitamura, S., Seyama, Y., Ohkawa, S., Terao, S., Yotsumoto, H., Takaku, F. and Shimizu, T., 1987, Leukotriene A4 hydrolase in the human lung: Inactivation of the enzyme with leukotriene A4 isomers, J. Biol. Chem. 262:10200–10205.PubMedGoogle Scholar
  48. Ohishi, N., Minami, M., Kobayashi, J., Seyama, Y., Hata, J., Yotsumoto, H., Takaku, F. and Shimizu, T., 1990, Immunological quantitation and immunohistochemical localization of leukotriene A4 hydrolase in guinea pig tissues, J. Biol. Chem. 265:7520–7525.PubMedGoogle Scholar
  49. Örning, L. and Fitzpatrick, F.A., 1992, Albumins activate peptide hydrolysis by the bifunctional enzyme LTA4 hydrolase/aminopeptidase, Biochemistry 31:4218–4223.PubMedCrossRefGoogle Scholar
  50. Örning, L., Gierse, J., Duffin, K., Bild, G., Krivi, G. and Fitzpatrick, F.A., 1992, Mechanism-based inactivation of leukotriene A4 hydrolase/aminopeptidase by leukotriene A4. Mass spectrometric and kinetic characterization, J. Biol. Chem. 267:22733–22739.PubMedGoogle Scholar
  51. Orning, L., Gierse, J.K. and Fitzpatrick, F.A., 1994, The bifunctional enzyme leukotriene-A4 hydrolase is an arginine aminopeptidase of high efficiency and specificity, J. Biol. Chem. 269:11269–11273.PubMedGoogle Scholar
  52. Örning, L., Jones, D.A. and Fitzpatrick, F.A., 1990, Mechanism-based inactivation of leukotriene A4 hydrolase during leukotriene B4 formation by human erythrocytes, J. Biol. Chem. 265:14911–14916.PubMedGoogle Scholar
  53. Örning, L., Krivi, G., Bild, G., Gierse, J., Aykent, S. and Fitzpatrick, F. A., 1991, Inhibition of leukotriene A4 hydrolase/aminopeptidase by Captopril, J. Biol. Chem. 266:16507–16511.PubMedGoogle Scholar
  54. Örning, L., Krivi, G. and Fitzpatrick, F.A., 1991, Leukotriene A4 hydrolase: Inhibition by bestatin and intrinsic aminopeptidase activity establish its functional resemblance to metallohydrolase enzymes, J. Biol. Chem. 266:1375–1378.PubMedGoogle Scholar
  55. Pangburn, M.K. and Walsh, K.A., 1975, Thermolysin and neutral protease: Mechanistic considerations, Biochemistry 14:4050–4054.CrossRefGoogle Scholar
  56. Rådmark, O. and Haeggström, J., 1990, Properties of leukotriene A4 hydrolase, Adv. Prostaglandin, Leukotriene Thromboxane Res. 20:35–45.Google Scholar
  57. Rådmark, O., Shimizu, T., Jörnvall, H. and Samuelsson, B., 1984, Leukotriene A4 hydrolase in human leukocytes: Purification and properties, J. Biol. Chem. 259:12339–12345.PubMedGoogle Scholar
  58. Simchowitz, L. and De Weer, P., 1986, Chloride movements in human neutrophils. Diffusion, exchange, and active transport, J. Gen. Physiol. 88:167–194.PubMedCrossRefGoogle Scholar
  59. Skeggs Jr, L.T., Marsh, W.H., Kahn, J.R. and Shumway, N.P., 1954, The existence of two forms of hypertensin, J. Exp. Med. 99:275–282.PubMedCrossRefGoogle Scholar
  60. Tsuge, H., Ago, H., Aoki, M., Furuno, M., Noma, M., Miyano, M., Minami, M., Izumi, T. and Shimizu, T., 1994, Crystallization and preliminary X-ray crystallographic studies of recombinant human leukotriene A4 hydrolase comlpexed with bestatin, J. Mol. Biol 238:854–856.PubMedCrossRefGoogle Scholar
  61. Tsushima, H. and Hopsu-Havu, V.K., 1990, Achloride activated alanine aminopeptidase from a melanoma cell line, Neoplasma 37:415–425.PubMedGoogle Scholar
  62. Vallee, B.L. and Auld, D.S., 1990, Zinc coordination, function, and structure of zinc enzymes and other proteins, Biochemistry 29:5647–5659.PubMedCrossRefGoogle Scholar
  63. Watt, V.M. and Yip, C.C., 1989, Amino acid sequence deduced from rat kidney cDNA suggests it encodes the Zn-peptidase Aminopeptidase N, J. Biol Chem. 264:5480–5487.PubMedGoogle Scholar
  64. Wetterholm, A. and Haeggström, J.Z., 1992, Leukotriene A4 hydrolase: an anion activated peptidase, Biochim. Biophys. Acta 1123:275–281.PubMedCrossRefGoogle Scholar
  65. Wetterholm, A., Haeggström, J.Z., Samuelsson, B., Yuan, W., Munoz, B. and Wong, C., 1995, Potent and selective inhibitors of leukotriene A4 hydrolase: effects on purified enzyme and human polymorphonuclear leukocytes, J. Pharmacol. Exp. Ther. 275:in press.Google Scholar
  66. Wetterholm, A., Macchia, L. and Haeggström, J.Z., 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.PubMedCrossRefGoogle Scholar
  67. Wetterholm, A., Medina, J.F., Rådmark, O., Shapiro, R., Haeggström, J.Z., Vallee, B.L. and Samuelsson, B., 1991, Recombinant mouse leukotriene A4 hydrolase: a zinc metalloenzyme with dual enzymatic activities, Biochim. Biophys. Acta 1080:96–102.PubMedCrossRefGoogle Scholar
  68. Wetterholm, A., Medina, J.F., Rådmark, O., Shapiro, R., Haeggström, J.Z., Vallee, B.L. and Samuelsson, B., 1992, Leukotriene A4 hydrolase: Abrogation of the peptidase activity by mutation of glutamic acid-296, Proc. Natl. Acad. Sci. USA 89:9141–9145.PubMedCrossRefGoogle Scholar
  69. Yuan, W., Munoz, B., Wong, C.-H., Haeggström, J.Z., Wetterholm, A. and Samuelsson, B., 1993, Development of selective tight-binding inhibitors of leukotriene A4 hydrolase, J. Med. Chem. 36:211–220.PubMedCrossRefGoogle Scholar
  70. Yuan, W., Wong, C.-H., Haeggström, J.Z., Wetterholm, A. and Samuelsson, B., 1992, Novel tight-binding inhibitors of leukotriene A4 hydrolase, J. Am. Chem. Soc. 114:6552–6553.CrossRefGoogle Scholar
  71. Yuan, W., Zhong, Z., Wong, C.H., Haeggström, J.Z., Wetterholm, A. and Samuelsson, B., 1991, Probing the inhibition of leukotriene A4 hydrolase based on its aminopeptidase activity, Bioorg. Med. Chem. Lett. 1:551–556*.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Anders Wetterholm
    • 1
  • Martina Blomster
    • 1
  • Jesper Z. Haeggström
    • 1
  1. 1.Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSweden

Personalised recommendations