Skip to main content
SpringerLink
Log in
Book cover

Lipoxygenases in Inflammation pp 31–46Cite as

Leukotriene A4 Hydrolase and Leukotriene C4 Synthase

  • Chapter
  • First Online:

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

Abstract

Leukotrienes are potent proinflammatory and immune modulating lipid mediators synthesized along the 5-lipoxygenase pathway of arachidonic acid metabolism. Leukotriene B4 is one of the most potent chemotactic agents known while leukotriene C4, D4, and E4 are a powerful smooth muscle contracting agents, particularly in the respiratory tract and microcirculation. The committed steps in the biosynthesis of leukotriene B4 and C4 are catalyzed by the key enzymes leukotriene A 4 hydrolase and leukotriene C 4 synthase, respectively. In this chapter we discuss the most recent advances in the understanding of these two enzymes at a structural, functional, and biological level.

This is a preview of subscription content, 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   84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   109.99
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

Learn about institutional subscriptions

References

  1. Haeggstrom JZ, Funk CD (2011) Lipoxygenase and leukotriene pathways: biochemistry, biology, and roles in disease. Chem Rev 111:5866–5898

    Article  PubMed  Google Scholar 

  2. Haeggstrom JZ, Rinaldo-Matthis A, Wheelock CE, Wetterholm A (2010) Advances in eicosanoid research, novel therapeutic implications. Biochem Biophys Res Commun 396:135–139

    Article  PubMed  Google Scholar 

  3. Martinez Molina D, Wetterholm A, Kohl A, McCarthy AA, Niegowski D, Ohlson E, Hammarberg T, Eshaghi S, Haeggström JZ, Nordlund P (2007) Structural basis for synthesis of inflammatory mediators by human leukotriene C4 synthase. Nature 448:613–616

    Article  PubMed  Google Scholar 

  4. Ago H, Kanaoka Y, Irikura D, Lam BK, Shimamura T, Austen KF, Miyano M (2007) Crystal structure of a human membrane protein involved in cysteinyl leukotriene biosynthesis. Nature 448:609–612

    Article  CAS  PubMed  Google Scholar 

  5. Snelgrove RJ, Jackson PL, Hardison MT, Noerager BD, Kinloch A, Gaggar A, Shastry S, Rowe SM, Shim YM, Hussell T, Blalock JE (2010) A critical role for LTA4H in limiting chronic pulmonary neutrophilic inflammation. Science 330:90–94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Thunnissen MM, Nordlund P, Haeggström JZ (2001) Crystal structure of human leukotriene A4 hydrolase, a bifunctional enzyme in inflammation. Nat Struct Biol 8:131–135

    Article  CAS  PubMed  Google Scholar 

  7. Tholander F, Muroya A, Roques BP, Fournié-Zaluski MC, Thunnissen MM, Haeggström JZ (2008) Structure-based dissection of the active site chemistry of leukotriene A4 hydrolase: implications for M1 aminopeptidases and inhibitor design. Chem Biol 15:920–929

    Article  CAS  PubMed  Google Scholar 

  8. Ford-Hutchinson AW (1990) Leukotriene B4 in inflammation. Crit Rev Immunol 10:1–12

    CAS  PubMed  Google Scholar 

  9. Samuelsson B (1983) Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science 220:568–575

    Article  CAS  PubMed  Google Scholar 

  10. Samuelsson B, Dahlen SE, Lindgren JA, Rouzer CA, Serhan CN (1987) Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science 237:1171–1176

    Article  CAS  PubMed  Google Scholar 

  11. Snelgrove RJ (2011) Leukotriene A4 hydrolase: an anti-inflammatory role for a proinflammatory enzyme. Thorax 66:550–551

    Article  PubMed  Google Scholar 

  12. Haeggström JZ (1998) Leukotriene A4 hydrolase. In: Holgate S, Dahlen S-E (eds) 5-lipoxygenase products in asthma. Marcel Dekker, New York, NY, pp 51–76

    Chapter  Google Scholar 

  13. Stsiapanava A, Tholander F, Kumar RB, Qureshi AA, Niegowski D, Hasan M, Thunnissen M, Haeggstrom JZ, Rinaldo-Matthis A (2014) Product formation controlled by substrate dynamics in leukotriene A4 hydrolase. Biochim Biophys Acta 1844:439–446

    Article  CAS  PubMed  Google Scholar 

  14. Helgstrand C, Hasan M, Uysal H, Haeggstrom JZ, Thunnissen MM (2011) A leukotriene A4 hydrolase-related aminopeptidase from yeast undergoes induced fit upon inhibitor binding. J Mol Biol 406:120–134

    Article  CAS  PubMed  Google Scholar 

  15. Sala A, Folco G, Murphy RC (2010) Transcellular biosynthesis of eicosanoids. Pharmacol Rep 62:503–510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Barret AJ, Rawlings ND, Woessner JF (eds) (1998) Handbook of proteolytic enzymes. Academic, London, San Diego

    Google Scholar 

  17. Haeggstrom JZ (2000) Structure, function, and regulation of leukotriene A4 hydrolase. Am J Respir Crit Care Med 161:S25–31

    Article  CAS  PubMed  Google Scholar 

  18. Orning 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

    CAS  PubMed  Google Scholar 

  19. Stsiapanava A, Olsson U, Wan M, Kleinschmidt T, Rutishauser D, Zubarev RA, Samuelsson B, Rinaldo-Matthis A, Haeggstrom JZ (2014) Binding of Pro-Gly-Pro at the active site of leukotriene A4 hydrolase/aminopeptidase and development of an epoxide hydrolase selective inhibitor. Proc Natl Acad Sci USA 111:4227–4232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Byrum RS, Goulet JL, Snouwaert JN, Griffiths RJ, Koller BH (1999) Determination of the contribution of cysteinyl leukotrienes and leukotriene B4 in acute inflammatory responses using 5-lipoxygenase- and leukotriene A4 hydrolase-deficient mice. J Immunol 163:6810–6819

    CAS  PubMed  Google Scholar 

  21. Barchuk W, Lambert J, Fuhr R, Jiang JZ, Bertelsen K, Fourie A, Liu X, Silkoff PE, Barnathan ES, Thurmond R (2014) Effects of JNJ-40929837, a leukotriene A4 hydrolase inhibitor, in a bronchial allergen challenge model of asthma. Pulm Pharmacol Ther 29:15–23

    Article  CAS  PubMed  Google Scholar 

  22. Lam BK, Owen WF Jr, Austen KF, Soberman RJ (1989) The identification of a distinct export step following the biosynthesis of leukotriene C4 by human eosinophils. J Biol Chem 264:12885–12889

    CAS  PubMed  Google Scholar 

  23. Leier I, Jedlitschky G, Buchholz U, Cole SP, Deeley RG, Keppler D (1994) The MRP gene encodes an ATP-dependent export pump for leukotriene C4 and structurally related conjugates. J Biol Chem 269:27807–27810

    CAS  PubMed  Google Scholar 

  24. Wijnholds J, Evers R, van Leusden MR, Mol CA, Zaman GJ, Mayer U, Beijnen JH, van der Valk M, Krimpenfort P, Borst P (1997) Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug resistance-associated protein. Nat Med 3:1275–1279

    Article  CAS  PubMed  Google Scholar 

  25. Murphy RC, Sala A, Voelkel N, Maclouf J (1991) Appearance of urinary metabolites of LTE4 in human subjects. Ann N Y Acad Sci 629:105–111

    Article  CAS  PubMed  Google Scholar 

  26. Feldberg W, Kellaway CH (1938) Liberation of histamine and formation of lysocithin-like substances by cobra venom. J Physiol 94:187–226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Murphy RC, Hammarstrom S, Samuelsson B (1979) Leukotriene C: a slow-reacting substance from murine mastocytoma cells. Proc Natl Acad Sci USA 76:4275–4279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lam BK, Austen KF (2002) Leukotriene C4 synthase: a pivotal enzyme in cellular biosynthesis of the cysteinyl leukotrienes. Prostaglandins Other Lipid Mediat 68–69:511–520

    Article  PubMed  Google Scholar 

  29. Soderstrom M, Mannervik B, Garkov V, Hammarstrom S (1992) On the nature of leukotriene C4 synthase in human platelets. Arch Biochem Biophys 294:70–74

    Article  CAS  PubMed  Google Scholar 

  30. Mandal AK, Jones PB, Bair AM, Christmas P, Miller D, Yamin TT, Wisniewski D, Menke J, Evans JF, Hyman BT, Bacskai B, Chen M, Lee DM, Nikolic B, Soberman RJ (2008) The nuclear membrane organization of leukotriene synthesis. Proc Natl Acad Sci USA 105:20434–20439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Christmas P, Weber BM, McKee M, Brown D, Soberman RJ (2002) Membrane localization and topology of leukotriene C4 synthase. J Biol Chem 277:28902–28908

    Article  CAS  PubMed  Google Scholar 

  32. Strid T, Svartz J, Franck N, Hallin E, Ingelsson B, Soderstrom M, Hammarstrom S (2009) Distinct parts of leukotriene C4 synthase interact with 5-lipoxygenase and 5-lipoxygenase activating protein. Biochem Biophys Res Commun 381:518–522

    Article  CAS  PubMed  Google Scholar 

  33. Nakamura M, Shimizu T (2011) Leukotriene receptors. Chem Rev 111:6231–6298

    Article  CAS  PubMed  Google Scholar 

  34. Lynch KR, O'Neill GP, Liu Q, Im DS, Sawyer N, Metters KM, Coulombe N, Abramovitz M, Figueroa DJ, Zeng Z, Connolly BM, Bai C, Austin CP, Chateauneuf A, Stocco R, Greig GM, Kargman S, Hooks SB, Hosfield E, Williams DL Jr, Ford-Hutchinson AW, Caskey CT, Evans JF (1999) Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature 399:789–793

    Article  CAS  PubMed  Google Scholar 

  35. Heise CE, O'Dowd BF, Figueroa DJ, Sawyer N, Nguyen T, Im DS, Stocco R, Bellefeuille JN, Abramovitz M, Cheng R, Williams DL Jr, Zeng Z, Liu Q, Ma L, Clements MK, Coulombe N, Liu Y, Austin CP, George SR, O'Neill GP, Metters KM, Lynch KR, Evans JF (2000) Characterization of the human cysteinyl leukotriene 2 receptor. J Biol Chem 275:30531–30536

    Article  CAS  PubMed  Google Scholar 

  36. Kanaoka Y, Maekawa A, Austen KF (2013) Identification of GPR99 protein as a potential third cysteinyl leukotriene receptor with a preference for leukotriene E4 ligand. J Biol Chem 288:10967–10972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Boyce JA, Lam BK, Penrose JF, Friend DS, Parsons S, Owen WF, Austen KF (1996) Expression of LTC4 synthase during the development of eosinophils in vitro from cord blood progenitors. Blood 88:4338–4347

    CAS  PubMed  Google Scholar 

  38. Schroder O, Sjostrom M, Qiu H, Jakobsson PJ, Haeggstrom JZ (2005) Microsomal glutathione S-transferases: selective up-regulation of leukotriene C4 synthase during lipopolysaccharide-induced pyresis. Cell Mol Life Sci 62:87–94

    Article  CAS  PubMed  Google Scholar 

  39. Hsieh FH, Lam BK, Penrose JF, Austen KF, Boyce JA (2001) T helper cell type 2 cytokines coordinately regulate immunoglobulin E-dependent cysteinyl leukotriene production by human cord blood-derived mast cells: profound induction of leukotriene C4 synthase expression by interleukin 4. J Exp Med 193:123–133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ali A, Ford-Hutchinson AW, Nicholson DW (1994) Activation of protein kinase C down-regulates leukotriene C4 synthase activity and attenuates cysteinyl leukotriene production in an eosinophilic substrain of HL-60 cells. J Immunol 153:776–788

    CAS  PubMed  Google Scholar 

  41. Sjolinder M, Tornhamre S, Werga P, Edenius C, Lindgren JA (1995) Phorbol ester-induced suppression of leukotriene C4 synthase activity in human granulocytes. FEBS Lett 377:87–91

    Article  CAS  PubMed  Google Scholar 

  42. Tornhamre S, Edenius C, Lindgren JA (1995) Receptor-mediated regulation of leukotriene C4 synthase activity in human platelets. Eur J Biochem/FEBS 234:513–520

    Article  CAS  Google Scholar 

  43. Esser J, Gehrmann U, Salvado MD, Wetterholm A, Haeggstrom JZ, Samuelsson B, Gabrielsson S, Scheynius A, Radmark O (2011) Zymosan suppresses leukotriene C4 synthase activity in differentiating monocytes: antagonism by aspirin and protein kinase inhibitors. FASEB J 25:1417–1427

    Article  CAS  PubMed  Google Scholar 

  44. Ahmad S, Niegowski D, Wetterholm A, Haeggstrom JZ, Morgenstern R, Rinaldo-Matthis A (2013) Catalytic characterization of human microsomal glutathione S-transferase 2: identification of rate-limiting steps. Biochemistry 52:1755–1764

    Article  CAS  PubMed  Google Scholar 

  45. Bresell A, Weinander R, Lundqvist G, Raza H, Shimoji M, Sun TH, Balk L, Wiklund R, Eriksson J, Jansson C, Persson B, Jakobsson PJ, Morgenstern R (2005) Bioinformatic and enzymatic characterization of the MAPEG superfamily. FEBS J 272:1688–1703

    Article  CAS  PubMed  Google Scholar 

  46. Holm P, Morgenstern R, Fujiyoshi Y, Hebert H (2001) The 3-D structure of microsomal glutathione transferase 1 at 6 angstrom resolution as determined by electron crystallography of p22(1)2(1) crystals. Chem-Biol Interact 133:68–70

    CAS  Google Scholar 

  47. Ferguson AD, McKeever BM, Xu S, Wisniewski D, Miller DK, Yamin TT, Spencer RH, Chu L, Ujjainwalla F, Cunningham BR, Evans JF, Becker JW (2007) Crystal structure of inhibitor-bound human 5-lipoxygenase-activating protein. Science 317:510–512

    Article  CAS  PubMed  Google Scholar 

  48. Sjogren T, Nord J, Ek M, Johansson P, Liu G, Geschwindner S (2013) Crystal structure of microsomal prostaglandin E2 synthase provides insight into diversity in the MAPEG superfamily. Proc Natl Acad Sci USA 110:3806–3811

    Article  PubMed  PubMed Central  Google Scholar 

  49. Rinaldo-Matthis A, Wetterholm A, Molina DM, Holm J, Niegowski D, Ohlson E, Nordlund P, Morgenstern R, Haeggstrom JZ (2010) Arginine 104 is a key catalytic residue in leukotriene C4 synthase. J Biol Chem 285:40771–40776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Saino H, Ago H, Ukita Y, Miyano M (2011) Seleno-detergent MAD phasing of leukotriene C4 synthase in complex with dodecyl-beta-D-selenomaltoside. Acta Crystallogr Sect F Struct Biol Cryst Commun 67:1666–1673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Niegowski D, Kleinschmidt T, Olsson U, Ahmad S, Rinaldo-Matthis A, Haeggstrom JZ (2014) Crystal structures of leukotriene C4 synthase in complex with product analogs, implications for the enzyme mechanism. J Biol Chem 289:5199–5207

    Google Scholar 

  52. Rinaldo-Matthis A, Ahmad S, Wetterholm A, Lachmann P, Morgenstern R, Haeggstrom JZ (2012) Pre-steady-state kinetic characterization of thiolate anion formation in human leukotriene C4 synthase. Biochemistry 51:848–856

    Article  CAS  PubMed  Google Scholar 

  53. Saino H, Ukita Y, Ago H, Irikura D, Nisawa A, Ueno G, Yamamoto M, Kanaoka Y, Lam BK, Austen KF, Miyano M (2011) The catalytic architecture of leukotriene C4 synthase with two arginine residues. J Biol Chem 286:16392–16401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Niegowski D, Kleinschmidt T, Ahmad S, Qureshi AA, Marback M, Rinaldo-Matthis A, Haeggstrom JZ (2014) Structure and inhibition of mouse leukotriene C4 synthase. PLoS One 9:e96763

    Article  PubMed  PubMed Central  Google Scholar 

  55. Hay DW, Torphy TJ, Undem BJ (1995) Cysteinyl leukotrienes in asthma: old mediators up to new tricks. Trends Pharmacol Sci 16:304–309

    Article  CAS  PubMed  Google Scholar 

  56. Amat M, Barcons M, Mancebo J, Mateo J, Oliver A, Mayoral JF, Fontcuberta J, Vila L (2000) Evolution of leukotriene B4, peptide leukotrienes, and interleukin-8 plasma concentrations in patients at risk of acute respiratory distress syndrome and with acute respiratory distress syndrome: mortality prognostic study. Crit Care Med 28:57–62

    Article  CAS  PubMed  Google Scholar 

  57. Matthay MA, Eschenbacher WL, Goetzl EJ (1984) Elevated concentrations of leukotriene D4 in pulmonary edema fluid of patients with the adult respiratory distress syndrome. J Clin Immunol 4:479–483

    Article  CAS  PubMed  Google Scholar 

  58. Petric R, Ford-Hutchinson A (1995) Inhibition of leukotriene biosynthesis improves renal function in experimental glomerulonephritis. J Lipid Mediat Cell Signal 11:231–240

    Article  CAS  PubMed  Google Scholar 

  59. Al-Amran FG, Hadi NR, Hashim AM (2011) Leukotriene biosynthesis inhibition ameliorates acute lung injury following hemorrhagic shock in rats. J Cardiothorac Surg 6:81

    Article  PubMed  PubMed Central  Google Scholar 

  60. Sun LH, Chen AH, Yang ZF, Chen JJ, Guan WD, Wu JL, Qin S, Zhong NS (2013) Respiratory syncytial virus induces leukotriene C4 synthase expression in bronchial epithelial cells. Respirology 18 Suppl 3:40–46

    Article  PubMed  Google Scholar 

  61. Szczeklik A, Stevenson DD (1999) Aspirin-induced asthma: advances in pathogenesis and management. J Allergy Clin Immunol 104:5–13

    Article  CAS  PubMed  Google Scholar 

  62. Lam BK, Austen KF (2002) Leukotriene C4 synthase: a pivotal enzyme in cellular biosynthesis of the cysteinyl leukotrienes. Prostaglandins Other Lipid Mediat 68–69:511–520

    Article  PubMed  Google Scholar 

  63. Devi NS, Doble M (2012) Leukotriene C4 synthase: upcoming drug target for inflammation. Curr Drug Targets 13:1107–1118

    Article  CAS  PubMed  Google Scholar 

  64. Tornhamre S, Schmidt TJ, Nasman-Glaser B, Ericsson I, Lindgren JA (2001) Inhibitory effects of helenalin and related compounds on 5-lipoxygenase and leukotriene C4 synthase in human blood cells. Biochem Pharmacol 62:903–911

    Article  CAS  PubMed  Google Scholar 

  65. Mansour M, Tornhamre S (2004) Inhibition of 5-lipoxygenase and leukotriene C4 synthase in human blood cells by thymoquinone. J Enzyme Inhib Med Chem 19:431–436

    Article  CAS  PubMed  Google Scholar 

  66. El Gazzar M, El Mezayen R, Nicolls MR, Marecki JC, Dreskin SC (2006) Downregulation of leukotriene biosynthesis by thymoquinone attenuates airway inflammation in a mouse model of allergic asthma. Biochim Biophys Acta 1760:1088–1095

    Article  PubMed  Google Scholar 

  67. Lam BK, Penrose JF, Freeman GJ, Austen KF (1994) Expression cloning of a cDNA for human leukotriene C4 synthase, an integral membrane protein conjugating reduced glutathione to leukotriene A4. Proc Natl Acad Sci USA 91:7663–7667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gugliucci A, Ranzato L, Scorrano L, Colonna R, Petronilli V, Cusan C, Prato M, Mancini M, Pagano F, Bernardi P (2002) Mitochondria are direct targets of the lipoxygenase inhibitor MK886. A strategy for cell killing by combined treatment with MK886 and cyclooxygenase inhibitors. J Biol Chem 277:31789–31795

    Article  CAS  PubMed  Google Scholar 

  69. Lyss G, Knorre A, Schmidt TJ, Pahl HL, Merfort I (1998) The anti-inflammatory sesquiterpene lactone helenalin inhibits the transcription factor NF-kappaB by directly targeting p65. J Biol Chem 273:33508–33516

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheelesväg 2, 17177, Stockholm, Sweden

    Agnes Rinaldo-Matthis & Jesper Z. Haeggström

Authors
  1. Agnes Rinaldo-Matthis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jesper Z. Haeggström
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jesper Z. Haeggström .

Editor information

Editors and Affiliations

  1. Goethe University Frankfurt, Institute of Pharmaceutical Chemistry, Frankfurt, Germany

    Dieter Steinhilber

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Rinaldo-Matthis, A., Haeggström, J.Z. (2016). Leukotriene A4 Hydrolase and Leukotriene C4 Synthase. In: Steinhilber, D. (eds) Lipoxygenases in Inflammation. Progress in Inflammation Research. Springer, Cham. https://doi.org/10.1007/978-3-319-27766-0_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-27766-0_3

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-27764-6

  • Online ISBN: 978-3-319-27766-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation