Wang Xuan, Song Ke-Sheng, Guo Qing-Xiang, Tian Wei-Xi
Department of Biology, Graduate School of Chinese Academy of Sciences, Beijing 100039, PR China.
Biochem Pharmacol. 2003 Nov 15;66(10):2039-47. doi: 10.1016/s0006-2952(03)00585-9.
It has been reported that inhibition of fatty-acid synthase (FAS) is selectively cytotoxic to human cancer cells. Considerable interest has developed in identifying novel inhibitors of this enzyme complex. Our previous work showed that green tea (-)-epigallocatechin gallate can inhibit FAS in vitro. To elucidate the structure-activity relationship of the inhibitory effects of tea polyphenols, we investigated the inhibition kinetics of the major catechins and analogues. Ungallated catechins from green tea do not show obvious inhibition compared with gallated catechins. Another gallated catechin, (-)-epicatechin gallate, was also found as a potent inhibitor of FAS and its inhibition characteristics are similar to (-)-epigallocatechin gallate. Furthermore, the analogues of galloyl moiety without the catechin skeleton such as propyl gallate also showed obvious slow-binding inhibition, whereas the green tea ungallated catechin not. Atomic orbital energy analyses suggest that the positive charge is more distinctly distributed on the carbon atom of ester bond of galloyl moiety of gallate catechins, and that gallated forms are more susceptible for a nucleophilic attack than other catechins. Here we identify the galloyl moiety of green tea catechins as critical in the inactivation of the ketoacyl reductase activity of FAS for the first time.
据报道，脂肪酸合酶（FAS）的抑制对人类癌细胞具有选择性细胞毒性。在鉴定这种酶复合物的新型抑制剂方面已产生了相当大的兴趣。我们之前的工作表明，绿茶（-）-表没食子儿茶素没食子酸酯在体外可抑制FAS。为阐明茶多酚抑制作用的构效关系，我们研究了主要儿茶素及其类似物的抑制动力学。与没食子酸化儿茶素相比，来自绿茶的非没食子酸化儿茶素未表现出明显抑制作用。另一种没食子酸化儿茶素，（-）-表儿茶素没食子酸酯，也被发现是FAS的有效抑制剂，其抑制特性与（-）-表没食子儿茶素没食子酸酯相似。此外，没有儿茶素骨架的没食子酰部分类似物，如没食子酸丙酯，也表现出明显的慢结合抑制作用，而绿茶非没食子酸化儿茶素则没有。原子轨道能量分析表明，正电荷在没食子酸儿茶素没食子酰部分酯键的碳原子上分布更明显，并且没食子酸化形式比其他儿茶素更容易受到亲核攻击。在此，我们首次确定绿茶儿茶素的没食子酰部分在FAS酮酰还原酶活性失活中起关键作用。
