Leukotriene C 4 synthase

Abstract

LTC 4 synthase conjugates LTA 4 with glutathione (GSH) to form LTC 4, the parent compound of the cysteinyl leukotrienes. LTC 4 synthase is a membrane protein that functions as a non-covalent homodimer of two 18-kDa polypeptides. The enzymatic activity of LTC 4 synthase is augmented by Mg 2+ and inhibited by Co 2+ and the FLAP inhibitor MK-886. The K m and V max values of human LTC 4 synthase are 3.6 μM and 1.3 μmol/mg/min for LTA 4 and 1.6 mM and 2.7 μmol/mg/min for GSH, respectively. The deduced amino acid sequence and the predicted secondary structure of LTC 4 synthase share significant homology to FLAP, mGST-2, and mGST-3. Site-directed mutagenesis of LTC 4 synthase suggests that Arg-51 is involved in opening the epoxide ring of LTA 4 and Tyr-93 in GSH thiolate anion formation during catalytic conjugation. LTC 4 synthase is a TATA-less gene whose transcription involved both cell- and non-specific regulatory elements. LTC 4 synthase gene disrupted mice grow normally, and are attenuated for innate and adaptive immune inflammatory permeability responses.