Han Bing, Luo Guoyang, Shi Zheng-Zheng, Barrios Roberto, Atwood Donna, Liu Weili, Habib Geetha M, Sifers Richard N, Corry David B, Lieberman Michael W
Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
Am J Pathol. 2002 Aug;161(2):481-90. doi: 10.1016/s0002-9440(10)64204-6.
The metabolism of cysteinyl leukotrienes in vivo and the pathophysiological effects of individual cysteinyl leukotrienes are primarily unknown. Recently we identified an additional member of the gamma-glutamyl transpeptidase (GGT) family, gamma-glutamyl leukotrienase (GGL), and developed mice deficient in this enzyme. Here we show that in vivo GGL, and not GGT as previously believed, is primarily responsible for conversion of leukotriene C(4) to leukotriene D(4), the most potent of the cysteinyl leukotrienes and the immediate precursor of leukotriene E(4). GGL is a glycoprotein consisting of two polypeptide chains encoded by one gene and is attached at the amino terminus of the heavy chain to endothelial cell membranes. In mice it localizes to capillaries and sinusoids in most organs and in lung to larger vessels as well. In contrast to wild-type and GGT-deficient mice, GGL-deficient mice do not form leukotriene D(4) in vivo either in blood when exogenous leukotriene C(4) is administered intravenously or in bronchoalveolar lavage fluid of Aspergillus fumigatus extract-induced experimental asthma. Further, GGL-deficient mice show leukotriene C(4) accumulation and significantly more airway hyperreponsiveness than wild-type mice in the experimental asthma, and induction of asthma results in increased GGL protein levels and enzymatic activity. Thus GGL plays an important role in leukotriene D(4) synthesis in vivo and in inflammatory processes.
半胱氨酰白三烯在体内的代谢以及单个半胱氨酰白三烯的病理生理作用目前主要尚不清楚。最近我们鉴定出γ-谷氨酰转肽酶（GGT）家族的另一个成员，γ-谷氨酰白三烯酶（GGL），并培育出该酶缺陷型小鼠。在此我们表明，在体内主要负责将白三烯C4转化为白三烯D4的是GGL，而非先前认为的GGT，白三烯D4是最有效的半胱氨酰白三烯，也是白三烯E4的直接前体。GGL是一种糖蛋白，由一个基因编码的两条多肽链组成，重链的氨基末端附着于内皮细胞膜。在小鼠中，它定位于大多数器官的毛细血管和血窦，在肺中也定位于较大血管。与野生型和GGT缺陷型小鼠不同，无论是静脉注射外源性白三烯C4时血液中的白三烯D4形成，还是烟曲霉提取物诱导的实验性哮喘的支气管肺泡灌洗液中的白三烯D4形成，GGL缺陷型小鼠在体内均无法形成白三烯D4。此外，在实验性哮喘中，GGL缺陷型小鼠表现出白三烯C4蓄积，且气道高反应性显著高于野生型小鼠，哮喘诱导会导致GGL蛋白水平和酶活性增加。因此，GGL在体内白三烯D4合成及炎症过程中发挥重要作用。
