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

• Aspirin may remove PGE2-dependent suppression in all subjects, but only in AIA patients does increased bronchial expression of LTC4 synthase allow marked overproduction of cys-LTs leading to bronchoconstriction [6].
• Enzymatic activity in cell-free BALF was assessed by specific assays for leukotriene (LT) A4 hydrolase, 5-lipoxygenase, and LTC4 synthase using HPLC [7].
• The synthesis of LTD4 likely occurs directly from macrophages or from macrophage-derived LTA4, through LTC4 synthase in glomerular cells [8].
• INTERPRETATION: In this patient, inability to synthesise LTC4 suggests a deficiency of LTC4 synthase [9].
• The amino acid sequence for human LTC4S is unique and shows no homology to other glutathione S-transferases [10].

Chemical compound and disease context of LTC4S

• These results also suggest that human melanoma cells can generate LTB4 and LTC4 from LTA4, and that this process is catalyzed by two enzymes: LTA4 hydrolase and LTC4 synthase [11].
• Considerable activity of LTC4 synthase, which catalyzes the conversion of LTA4 to LTC4, was detected in the microsomal fraction of both MeWo and melanoma cells [11].

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

• Inosine-containing oligonucleotides based on the partial protein sequence were used to isolate a 679-bp cDNA for LTC4S from THP-1 cells [10].
• We assessed the basal levels of urinary LTE4, the increment of urinary LTE4 on venous aspirin challenge, and LTC4S activity in peripheral blood eosinophils [13].
• The increased bronchial production of leukotriene C4 (LTC4) in asthma is assumed to derive from infiltrating eosinophils expressing LTC4-synthase (LTC4S) [14].
• LTA4 is further converted to LTC4 by conjugation with glutathione, a reaction catalyzed by the integral membrane protein LTC4 synthase (LTC4S), which is localized on the NE and endoplasmic reticulum (ER) [15].
• LTC4S conjugates reduce glutathione to LTA4 and is positioned as the pivotal and only committed enzyme involved in the formation of cysteinyl LTs [16].

Physical interactions of LTC4S

• These results implicate that compounds that bind competitively to arachidonic acid binding sites on FLAP and 5-LO recognize motifs that are also weakly conserved on the binding site of LTC4 synthase [17].

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

• Microsomal GST-II also catalyzed the formation of another product, displaying a conjugated triene UV absorption spectra with a maximum at 283 nm, suggesting less catalytic stereospecificity compared with LTC4 synthase [20].
• Therefore, it is proposed that this novel membrane protein is a member of the microsomal glutathione S-transferase family, also including LTC4 synthase, with significant sequence identities to both LTC4 synthase and FLAP [20].
• RESULTS: 5-LO, FLAP and LTC4S, and the CysLT1 and CysLT2 receptors were expressed in the majority of eosinophils and in subsets of mast cells and mononuclear cells [21].
• DNA was analyzed for the LTC4S and the PAI-1 promoter polymorphisms using standard PCR techniques [22].
• Furthermore, there is genetic linkage of this region of human chromosome 5 to atopy and asthma, whereas no linkage exists for the chromosomal localization of the other family members, FLAP and mGST II, distinguishing LTC4S as a unique member of the novel gene family [16].

Analytical, diagnostic and therapeutic context of LTC4S

• This differs from FLAP mRNA, which was detected in lung, various organs of the immune system, and peripheral blood leukocytes, and LTC4 synthase mRNA, which could not be detected in any tissues by Northern blot analysis [20].
• Fluorescent in situ hybridization mapped the mouse LTC4S gene to mouse chromosome 11, in a region containing the genes for interleukin 13 and granulocyte/macrophage-colony-stimulating factor, and orthologous to the chromosomal location of 5q35 for the human LTC4S gene [23].
• Molecular cloning and expression of human leukotriene-C4 synthase [10].
• Protein-protein interaction affinity chromatography of leukotriene C4 synthase [24].
• The frequency of positive nickel patch-test results and the A38G and A444C frequency in CC16 and LTC4S genes were not significantly different (p > 0.05) [25].

References