Leukotriene C4 synthase: a pivotal enzyme in cellular biosynthesis of the cysteinyl leukotrienes.
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.
Lam
Bing K
BK
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. blam@rics.bwh.harvard.edu
Austen
K Frank
KF
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
D015289:Leukotrienes; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase; D003545:Cysteine