Bora P S, Spilburg C A, Lange L G
Department of Medicine, Jewish Hospital, Washington University Medical Center, Saint Louis, MO 63110.
Proc Natl Acad Sci U S A. 1989 Jun;86(12):4470-3. doi: 10.1073/pnas.86.12.4470.
Nonoxidative alcohol metabolism to form fatty acid ethyl esters contributes to alcohol-related end-organ damage, and these products are formed by two synthase enzymes. We recently purified the major (pI 4.9) synthase from human myocardium. The N-terminal sequence (A P Y T V V Y F P V R G R X K A L R M L X A D) is greater than 73% identical with that of a neutral (pI 6.7) detoxification enzyme, glutathione transferase P from rat hepatocellular carcinoma (P P Y T I V Y F P V R G R C E A T R M L L A D). Moreover, both the major human fatty acid ethyl ester synthase and bovine liver glutathione transferase catalyze the formation of fatty acid ethyl esters (Vmax 105 and 98 nmol per hr per mg, respectively). In addition, both enzymes catalyze the formation of glutathione-xenobiotic conjugates (Vmax 67 and 335 mol per hr per mol of enzyme, respectively). Physiological concentrations of glutathione increase the rate of formation of fatty acid ethyl esters up to 5-fold, and the glutathione transferase substrate 1-chloro-2,4-dinitrobenzene is a potent inhibitor of human myocardial fatty acid ethyl ester synthase. Thus, the identification of the major form of human myocardial fatty acid ethyl ester synthase as an acidic glutathione transferase links alcohol and xenobiotic metabolism and may relate the enhancement of tumorigenesis by alcohol abuse with carcinogen-conjugation reactions.
非氧化酒精代谢形成脂肪酸乙酯会导致与酒精相关的终末器官损伤，这些产物由两种合成酶形成。我们最近从人心脏中纯化了主要的（pI 4.9）合成酶。其N端序列（APYTVVYFPVRGRXKALRMLXAD）与大鼠肝细胞癌中的一种中性（pI 6.7）解毒酶——谷胱甘肽转移酶P（PPYTIVYFPVRGRCEATRML LAD）的序列一致性超过73%。此外，主要的人脂肪酸乙酯合成酶和牛肝谷胱甘肽转移酶都催化脂肪酸乙酯的形成（最大反应速度分别为每小时每毫克105和98纳摩尔）。另外，这两种酶都催化谷胱甘肽 - 异生物结合物的形成（最大反应速度分别为每小时每摩尔酶67和335微摩尔）。生理浓度的谷胱甘肽可使脂肪酸乙酯的形成速度提高至5倍，且谷胱甘肽转移酶底物1 - 氯 - 2,4 - 二硝基苯是人心肌脂肪酸乙酯合成酶的有效抑制剂。因此，将人心肌脂肪酸乙酯合成酶的主要形式鉴定为酸性谷胱甘肽转移酶，这将酒精和异生物代谢联系起来，并且可能将酒精滥用导致的肿瘤发生增强与致癌物结合反应联系起来。
