Lam Bing K, Austen K Frank
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Prostaglandins Other Lipid Mediat. 2002 Aug;68-69:511-20. doi: 10.1016/s0090-6980(02)00052-7.
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.
白三烯C4合成酶(LTC4S)将白三烯A4(LTA4)与谷胱甘肽(GSH)结合形成LTC4,即半胱氨酰白三烯的母体化合物。LTC4S是一种18 kDa的膜蛋白,以非共价同源二聚体形式发挥作用。LTC4S的酶活性受Mg2+增强,受Co2+和5-脂氧合酶(LO)激活蛋白(FLAP)抑制剂MK-886抑制。LTA4的Km和Vmax值分别为3.6 μM和1.3 μmol/mg/min,GSH的Km和Vmax值分别为1.6 mM和2.7 μmol/mg/min。推导的LTC4S氨基酸序列和预测的二级结构与FLAP、mGST-2和mGST-3具有显著同源性,它们均为MAPEG蛋白超家族成员。LTC4S和FLAP表现出相同的由五个外显子和四个内含子组成的基因组结构。定点诱变表明,Arg-51参与LTA4环氧环的打开,Tyr-93参与催化结合过程中GSH硫醇盐阴离子的形成。LTC4S是一个无TATA盒的基因,其在报告基因构建体中的转录涉及细胞特异性和非特异性调控元件。LTC4S基因敲除小鼠生长正常,其先天性和适应性免疫炎症通透性反应减弱。