title: Leukotriene C4 synthase: a pivotal enzyme in cellular biosynthesis of the cysteinyl leukotrienes.
abstract: Leukotriene C4 synthase (LTC4S) conjugates LTA4 with glutathione (GSH) to form LTC4, the parent compound of the cysteinyl LTs. LTC4S is an 18 kDa membrane protein and functions as a noncovalent homodimer. The enzyme activity of LTC4S is augmented by Mg2+ and inhibited by Co2+ and the function of 5-lipoxygenase (LO) activating protein (FLAP) inhibitor MK-886. The Km and Vmax values are 3.6 microM and 1.3 micromol/mg/min for LTA4 and 1.6 mM and 2.7 micromol/mg/min for GSH, respectively. The deduced amino acid sequence and the predicted secondary of LTC4S shares significant homology to FLAP, mGST-2 and mGST-3 which are all members of MAPEG protein superfamily. LTC4S and FLAP exhibited identical genomic organization of five exons and four introns. Site-directed mutagenesis suggests that Arg-51 is involved in opening the epoxide ring of LTA4 and Tyr-93 in GSH thiolate anion formation during catalytic conjugation. LTC4S is a TATA-less gene whose transcription assessed in a reporter construct involved both cell-specific and nonspecific regulatory elements. LTC4S-/- mice grow normally, and are attenuated for innate and adaptive immune inflammatory permeability responses.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. blam@rics.bwh.harvard.edu
authors.forename: Bing K
authors.initials: BK
authors.lastname: Lam
authors.forename: K Frank
authors.initials: KF
authors.lastname: Austen
mesh_terms: D000818:Animals; D001249:Asthma / Q000378:metabolism; D020134:Catalytic Domain; D003545:Cysteine / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D018390:Gene Targeting; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015289:Leukotrienes / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure
chemical_list: D015289:Leukotrienes; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase; D003545:Cysteine