Leukotriene C4 synthase

Abstract

LTC₄ synthase conjugates LTA₄ with glutathione (GSH) to form LTC₄, the parent compound of the cysteinyl leukotrienes. LTC₄ synthase is a membrane protein that functions as a non-covalent homodimer of two 18-kDa polypeptides. The enzymatic activity of LTC₄ synthase is augmented by Mg²⁺ and inhibited by Co²⁺ and the FLAP inhibitor MK-886. The K_m and V_max values of human LTC₄ synthase are 3.6 μM and 1.3 μmol/mg/min for LTA₄ and 1.6 mM and 2.7 μmol/mg/min for GSH, respectively. The deduced amino acid sequence and the predicted secondary structure of LTC₄ synthase share significant homology to FLAP, mGST-2, and mGST-3. Site-directed mutagenesis of LTC₄ synthase suggests that Arg-51 is involved in opening the epoxide ring of LTA₄ and Tyr-93 in GSH thiolate anion formation during catalytic conjugation. LTC₄ synthase is a TATA-less gene whose transcription involved both cell- and non-specific regulatory elements. LTC₄ synthase gene disrupted mice grow normally, and are attenuated for innate and adaptive immune inflammatory permeability responses.