4j7y
From Proteopedia
Human LTC4 synthase in complex with product analogs - implications for enzyme catalysis
Structural highlights
DiseaseLTC4S_HUMAN Defects in LTC4S are the cause of leukotriene C4 synthase deficiency (LTC4 synthase deficiency) [MIM:246530. LTC4 synthase deficiency is a fatal neurometabolic developmental disorder. It is associated with muscular hypotonia, psychomotor retardation, failure to thrive, and microcephaly. FunctionLTC4S_HUMAN Catalyzes the conjugation of leukotriene A4 with reduced glutathione to form leukotriene C4. Publication Abstract from PubMedLeukotriene (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. 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, Haeggstrom JZ J Biol Chem. 2013 Dec 23. PMID:24366866[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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