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

Niegowski D, Kleinschmidt T, Olsson U, Ahmad S, Rinaldo-Matthis A, Haeggström JZ

J. Biol. Chem. 289 (8) 5199-5207 [2014-02-21; online 2013-12-25]

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 Trp-116 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, identify a new conformation of the GSH moiety at the active site, and suggest a route for product release, aided by Trp-116.

Protein Science Facility (PSF)

PubMed 24366866

DOI 10.1074/jbc.M113.534628

Crossref 10.1074/jbc.M113.534628

pii: M113.534628
pmc: PMC3931076
PDB: 4J7T
PDB: 4J7Y
PDB: 4JC7
PDB: 4JCZ
PDB: 4JRZ