Leukotriene C4 (
LTC4) synthase is an 18 kD integral membrane
enzyme of the
5-lipoxygenase/
LTC4 synthase pathway and is positioned as the pivotal and only committed
enzyme for the formation of the cysteinyl
leukotrienes. Although its function is to conjugate catalytically
LTA4 to
reduced glutathione,
LTC4 synthase is differentiated from other
glutathione S-transferase family members by its lack of
amino acid homology, substrate specificity, and kinetics.
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. The
cDNA encodes a monomeric
protein of 150
amino acids with three hydrophobic domains interspersed with two hydrophilic loops. Site-directed mutagenic studies reveal that the
enzyme functions as a homodimer and that arginine-51 in the first hydrophilic loop, and tyrosine-93 in the second hydrophilic loop, are involved in the
acid and base catalysis of
LTA4 and
glutathione, respectively. Homology and secondary structural predictions indicate that LTC4S is a novel member of a new gene superfamily of
integral membrane proteins, each with the capacity to participate in
leukotriene biosynthesis. 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. 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.