The biochemical, molecular, and genomic aspects of leukotriene C4 synthase.

Abstract

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.