Crystal structures of leukotriene C4 synthase in complex with product analogs: Implications for the enzyme mechanism

Leukotriene (LT) C4 synthase (LTC4S) catalyzes the conjugation of the fatty acid LTA4 with the tripeptide GSH to produce LTC4, the parent compound of the cysteinyl-leukotrienes, important mediators of asthma. Here we mutated Trp116 in human LTC4S, a residue proposed to play a key role in substrate binding, into an Ala or Phe. Biochemical and structural characterization of these mutants along with crystal structures of the wild type and mutated enzymes in complex with three product analogs, viz. S-hexyl-, 4- phenyl-butyl-, and 2-hydroxy-4-phenyl-butyl-glutathione, provide new insights to binding of substrates and product, identifies a new conformation of the GSH moiety at the active site, and suggests a route for product release, aided by Trp116.