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Gene Review

LTC4S  -  leukotriene C4 synthase

Homo sapiens

Synonyms: LTC4 synthase, Leukotriene C4 synthase, Leukotriene-C(4) synthase, MGC33147
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Disease relevance of LTC4S

  • Immunohistochemical studies of mucosal biopsies from the bronchi of aspirin-intolerant asthmatics show that LTC4S is overrepresented in individuals with this phenotype, and this finding correlates with overproduction of cysteinyl leukotrienes and lysine-aspirin bronchial hyperreactivity [1].
  • In the mucosa of polyps from aspirin-intolerant asthmatic patients, cells immunopositive for LTC4 synthase were four-fold more numerous than in aspirin-tolerant asthmatic patients (p=0.04) [2].
  • BACKGROUND: We have reported that in patients with chronic idiopathic urticaria (CIU) who reacted adversely to aspirin, the frequency of the (-444)C allele of the leukotriene C(4) synthase gene (LTC4S) was higher than in patients who tolerated aspirin well [3].
  • Fluorescent in situ hybridization mapped LTC4 synthase to chromosomal location 5q35, which is in close proximity to the cluster of genes for cytokines and receptors involved in the regulation of cells central to allergic inflammation and implicated in bronchial asthma [4].
  • Inverse relationship between myeloid maturation and leukotriene C4 synthase expression in normal and leukemic myelopoiesis-consistent overexpression of the enzyme in myeloid cells from patients with chronic myeloid leukemia [5].

High impact information on LTC4S


Chemical compound and disease context of LTC4S


Biological context of LTC4S

  • Once the lineage is established by morphologic criteria, the eosinophilopoietic cytokines mediate upregulation of FLAP and LTC4S, members of a newly recognized gene family, and of 5-LO, during ongoing cell maturation [12].
  • BACKGROUND: The A to C transversion in the promoter region of the gene encoding leukotriene C4 synthase (LTC4S) is proposed to be associated with the development of aspirin-induced asthma (AIA) [13].
  • CONCLUSION: Our findings reveal the lack of functionality of the polymorphism in the LTC4S gene, whereas this polymorphism might have some effect on the development of AIA, probably in linkage disequilibrium with another causatively important mutation [13].
  • The gene for LTC4S is 2.5 kb in length and is localized on chromosome 5q35, distal to that of the genes for cytokines and receptors important in the development and perpetuation of allergic inflammation [1].
  • Treated individuals with asthma with more than 12% reversibility had significantly higher density of LTC4S-positive mast cells than those with less reversibility, and it correlated significantly with reduction in lung function (FEV1-predicted), both before and after salbutamol inhalation [14].

Anatomical context of LTC4S

  • At 14 days, 94% of the cells were of eosinophil lineage, both LTC4S mRNA transcript and protein were present, and ionophore stimulation resulted in the generation of 23.9 +/- 6.0 pmol cysteinyl leukotrienes/10(6) eosinophil-lineage cells (mean +/- SEM, n = 6) [12].
  • The expression of leukotriene C4 synthase (LTC4S) was examined during the development of eosinophils in vitro from cord blood mononuclear cells [12].
  • The density of LTC4S-positive mast cells correlated, moreover, with both the reduction in lung function and the degree of reversibility in treated asthma [14].
  • LTC4 synthase (LTC4S) protein is present in the perinuclear membranes of a limited number of hematopoietic cells involved in allergic inflammation, including mast cells, eosinophils, basophils, and macrophages [1].
  • Multiple constructs encoding fusion proteins of green fluorescent protein (GFP) as the N-terminal part and various truncated variants of human LTC4S as C-terminal part were prepared and transfected into HEK 293/T or COS-7 cells [15].

Associations of LTC4S with chemical compounds


Physical interactions of LTC4S


Regulatory relationships of LTC4S

  • The deletion of the third hydrophobic domain with the carboxyl terminus abolishes the enzyme activity, and function is restored by the substitution of the third hydrophobic domain and carboxyl terminus of 5-lipoxygenase-activating protein for that of LTC4S [18].
  • TGF-beta conditioning of cells resulted in a time- and dose-dependent increase in stimulated LTC4 synthase activity [19].

Other interactions of LTC4S


Analytical, diagnostic and therapeutic context of LTC4S


  1. The biochemical, molecular, and genomic aspects of leukotriene C4 synthase. Penrose, J.F., Austen, K.F. Proc. Assoc. Am. Physicians (1999) [Pubmed]
  2. Expression of 5-lipoxygenase and cyclooxygenase pathway enzymes in nasal polyps of patients with aspirin-intolerant asthma. Adamjee, J., Suh, Y.J., Park, H.S., Choi, J.H., Penrose, J.F., Lam, B.K., Austen, K.F., Cazaly, A.M., Wilson, S.J., Sampson, A.P. J. Pathol. (2006) [Pubmed]
  3. Familial aggregation of aspirin-induced urticaria and leukotriene C synthase allelic variant. Mastalerz, L., Setkowicz, M., Sanak, M., Rybarczyk, H., Szczeklik, A. Br. J. Dermatol. (2006) [Pubmed]
  4. Molecular cloning of the gene for human leukotriene C4 synthase. Organization, nucleotide sequence, and chromosomal localization to 5q35. Penrose, J.F., Spector, J., Baldasaro, M., Xu, K., Boyce, J., Arm, J.P., Austen, K.F., Lam, B.K. J. Biol. Chem. (1996) [Pubmed]
  5. Inverse relationship between myeloid maturation and leukotriene C4 synthase expression in normal and leukemic myelopoiesis-consistent overexpression of the enzyme in myeloid cells from patients with chronic myeloid leukemia. Tornhamre, S., Stenke, L., Granzelius, A., Sjölinder, M., Näsman-Glaser, B., Roos, C., Widell, S., Lindgren, J.A. Exp. Hematol. (2003) [Pubmed]
  6. Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma. Cowburn, A.S., Sladek, K., Soja, J., Adamek, L., Nizankowska, E., Szczeklik, A., Lam, B.K., Penrose, J.F., Austen, F.K., Holgate, S.T., Sampson, A.P. J. Clin. Invest. (1998) [Pubmed]
  7. Leukotriene A4 hydrolase in human bronchoalveolar lavage fluid. Munafo, D.A., Shindo, K., Baker, J.R., Bigby, T.D. J. Clin. Invest. (1994) [Pubmed]
  8. Leukotriene D4 is a mediator of proteinuria and glomerular hemodynamic abnormalities in passive Heymann nephritis. Katoh, T., Lianos, E.A., Fukunaga, M., Takahashi, K., Badr, K.F. J. Clin. Invest. (1993) [Pubmed]
  9. Leukotriene C4-synthesis deficiency: a new inborn error of metabolism linked to a fatal developmental syndrome. Mayatepek, E., Flock, B. Lancet (1998) [Pubmed]
  10. Molecular cloning and expression of human leukotriene-C4 synthase. Welsch, D.J., Creely, D.P., Hauser, S.D., Mathis, K.J., Krivi, G.G., Isakson, P.C. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  11. Human melanoma cells generate leukotrienes B4 and C4 from leukotriene A4. Okano-Mitani, H., Ikai, K., Imamura, S. Arch. Dermatol. Res. (1997) [Pubmed]
  12. Expression of LTC4 synthase during the development of eosinophils in vitro from cord blood progenitors. Boyce, J.A., Lam, B.K., Penrose, J.F., Friend, D.S., Parsons, S., Owen, W.F., Austen, K.F. Blood (1996) [Pubmed]
  13. Leukotriene C4 synthase promoter polymorphism in Japanese patients with aspirin-induced asthma. Kawagishi, Y., Mita, H., Taniguchi, M., Maruyama, M., Oosaki, R., Higashi, N., Kashii, T., Kobayashi, M., Akiyama, K. J. Allergy Clin. Immunol. (2002) [Pubmed]
  14. Bronchial mast cells are the dominating LTC4S-expressing cells in aspirin-tolerant asthma. Cai, Y., Bjermer, L., Halstensen, T.S. Am. J. Respir. Cell Mol. Biol. (2003) [Pubmed]
  15. Identification of regions of leukotriene C4 synthase which direct the enzyme to its nuclear envelope localization. Svartz, J., Hallin, E., Shi, Y., Söderström, M., Hammarström, S. J. Cell. Biochem. (2006) [Pubmed]
  16. LTC4 synthase. Enzymology, biochemistry, and molecular characterization. Penrose, J.F. Clinical reviews in allergy & immunology. (1999) [Pubmed]
  17. Pharmacological cross-reactivity between 5-lipoxygenase-activating protein, 5-lipoxygenase, and leukotriene C4 synthase. Gupta, N., Nicholson, D.W., Ford-Hutchinson, A.W. Can. J. Physiol. Pharmacol. (1997) [Pubmed]
  18. Site-directed mutagenesis of human leukotriene C4 synthase. Lam, B.K., Penrose, J.F., Xu, K., Baldasaro, M.H., Austen, K.F. J. Biol. Chem. (1997) [Pubmed]
  19. TGF-beta increases leukotriene C4 synthase expression in the monocyte-like cell line, THP-1. Riddick, C.A., Serio, K.J., Hodulik, C.R., Ring, W.L., Regan, M.S., Bigby, T.D. J. Immunol. (1999) [Pubmed]
  20. 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]
  21. Expression of cysteinyl leukotriene synthetic and signalling proteins in inflammatory cells in active seasonal allergic rhinitis. Figueroa, D.J., Borish, L., Baramki, D., Philip, G., Austin, C.P., Evans, J.F. Clin. Exp. Allergy (2003) [Pubmed]
  22. Expression of leukotriene C4 synthase and plasminogen activator inhibitor 1 gene promoter polymorphisms in sinusitis. de Alarc??n, A., Steinke, J.W., Caughey, R., Barekzi, E., Hise, K., Gross, C.W., Han, J.K., Borish, L. American journal of rhinology. (2006) [Pubmed]
  23. Molecular cloning of the gene for mouse leukotriene-C4 synthase. Penrose, J.F., Baldasaro, M.H., Webster, M., Xu, K., Austen, K.F., Lam, B.K. Eur. J. Biochem. (1997) [Pubmed]
  24. Protein-protein interaction affinity chromatography of leukotriene C4 synthase. Söderström, M., Morgenstern, R., Hammarström, S. Protein Expr. Purif. (1995) [Pubmed]
  25. Analgesic intolerance with or without bronchial asthma: is there a marker? Kalyoncu, A.F., Karakaya, G., Yilmaz, E., Balci, B., Karaduman, A., Yasavul, U. Journal of investigational allergology & clinical immunology : official organ of the International Association of Asthmology (INTERASMA) and Sociedad Latinoamericana de Alergia e Inmunología. (2003) [Pubmed]
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