title: The catalytic architecture of leukotriene C4 synthase with two arginine residues.
abstract: Leukotriene (LT) C(4) and its metabolites, LTD(4) and LTE(4), are involved in the pathobiology of bronchial asthma. LTC(4) synthase is the nuclear membrane-embedded enzyme responsible for LTC(4) biosynthesis, catalyzing the conjugation of two substrates that have considerably different water solubility; that amphipathic LTA(4) as a derivative of arachidonic acid and a water-soluble glutathione (GSH). A previous crystal structure revealed important details of GSH binding and implied a GSH activating function for Arg-104. In addition, Arg-31 was also proposed to participate in the catalysis based on the putative LTA(4) binding model. In this study enzymatic assay with mutant enzymes demonstrates that Arg-104 is required for the binding and activation of GSH and that Arg-31 is needed for catalysis probably by activating the epoxide group of LTA(4).
authors: Structural Biophysics Laboratory, RIKEN SPring-8 Center, Harima Institute, Sayo, Hyogo, Japan.
authors: Hiromichi
authors: H
authors: Saino
authors: Yoko
authors: Y
authors: Ukita
authors: Hideo
authors: H
authors: Ago
authors: Daisuke
authors: D
authors: Irikura
authors: Atsushi
authors: A
authors: Nisawa
authors: Go
authors: G
authors: Ueno
authors: Masaki
authors: M
authors: Yamamoto
authors: Yoshihide
authors: Y
authors: Kanaoka
authors: Bing K
authors: BK
authors: Lam
authors: K Frank
authors: KF
authors: Austen
authors: Masashi
authors: M
authors: Miyano
mesh_terms: D001120:Arginine / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001249:Asthma / Q000201:enzymology / Q000235:genetics; D001665:Binding Sites; D018360:Crystallography, X-Ray; D005978:Glutathione / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D005982:Glutathione Transferase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017997:Leukotriene C4 / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics; D009154:Mutation; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D017997:Leukotriene C4; D001120:Arginine; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase; D005978:Glutathione