白三烯C4合成酶的生化、分子和基因组方面。

J F Penrose, K F Austen
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引用次数: 31

摘要

白三烯C4 (LTC4)合成酶是5-脂氧合酶/LTC4合成酶途径的18 kD完整膜酶,被定位为半胱氨酸白三烯形成的关键和唯一的承诺酶。虽然其功能是催化LTA4与还原性谷胱甘肽结合,但LTC4合成酶与其他谷胱甘肽s -转移酶家族成员的区别在于其缺乏氨基酸同源性、底物特异性和动力学。LTC4合成酶(LTC4S)蛋白存在于少数参与过敏性炎症的造血细胞的核周膜中,包括肥大细胞、嗜酸性粒细胞、嗜碱性粒细胞和巨噬细胞。cDNA编码一个由150个氨基酸组成的单体蛋白,具有三个疏水结构域和两个亲水性环。位点定向诱变研究表明,该酶作为一种同型二聚体起作用,第一个亲水性环上的精氨酸-51和第二个亲水性环上的酪氨酸-93分别参与LTA4和谷胱甘肽的酸催化和谷胱甘肽的碱催化。同源性和二级结构预测表明,LTC4S是一个新的完整膜蛋白基因超家族的新成员,每个都具有参与白三烯生物合成的能力。LTC4S基因长度为2.5 kb,位于染色体5q35上,远低于在过敏性炎症发生和延续中重要的细胞因子和受体基因。对阿司匹林不耐受哮喘患者支气管粘膜活检的免疫组织化学研究表明,LTC4S在这种表型的个体中过度存在,这一发现与半胱氨酸白三烯过量产生和赖氨酸-阿司匹林支气管高反应性有关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The biochemical, molecular, and genomic aspects of leukotriene C4 synthase.
Leukotriene C4 (LTC4) synthase is an 18 kD integral membrane enzyme of the 5-lipoxygenase/LTC4 synthase pathway and is positioned as the pivotal and only committed enzyme for the formation of the cysteinyl leukotrienes. Although its function is to conjugate catalytically LTA4 to reduced glutathione, LTC4 synthase is differentiated from other glutathione S-transferase family members by its lack of amino acid homology, substrate specificity, and kinetics. LTC4 synthase (LTC4S) protein is present in the perinuclear membranes of a limited number of hematopoietic cells involved in allergic inflammation, including mast cells, eosinophils, basophils, and macrophages. The cDNA encodes a monomeric protein of 150 amino acids with three hydrophobic domains interspersed with two hydrophilic loops. Site-directed mutagenic studies reveal that the enzyme functions as a homodimer and that arginine-51 in the first hydrophilic loop, and tyrosine-93 in the second hydrophilic loop, are involved in the acid and base catalysis of LTA4 and glutathione, respectively. Homology and secondary structural predictions indicate that LTC4S is a novel member of a new gene superfamily of integral membrane proteins, each with the capacity to participate in leukotriene biosynthesis. The gene for LTC4S is 2.5 kb in length and is localized on chromosome 5q35, distal to that of the genes for cytokines and receptors important in the development and perpetuation of allergic inflammation. Immunohistochemical studies of mucosal biopsies from the bronchi of aspirin-intolerant asthmatics show that LTC4S is overrepresented in individuals with this phenotype, and this finding correlates with overproduction of cysteinyl leukotrienes and lysine-aspirin bronchial hyperreactivity.
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