Wang Zhijun, Jin Li, Wegrzyn Grzegorz, Wegrzyn Alicja
CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031, Shanghai, PR China.
BMC Biochem. 2009 Mar 16;10:6. doi: 10.1186/1471-2091-10-6.
Glutathione transferases (GSTs) belong to the family of Phase II detoxification enzymes. GSTs catalyze the conjugation of glutathione to different endogenous and exogenous electrophilic compounds. Over-expression of GSTs was demonstrated in a number of different human cancer cells. It has been found that the resistance to many anticancer chemotherapeutics is directly correlated with the over-expression of GSTs. Therefore, it appears to be important to find new GST inhibitors to prevent the resistance of cells to anticancer drugs. In order to search for glutathione transferase (GST) inhibitors, a novel method was designed.
Our results showed that two fragments of GST, named F1 peptide (GYWKIKGLV) and F2 peptide (KWRNKKFELGLEFPNL), can significantly inhibit the GST activity. When these two fragments were compared with several known potent GST inhibitors, the order of inhibition efficiency (measured in reactions with 2,4-dinitrochlorobenzene (CDNB) and glutathione as substrates) was determined as follows: tannic acid > cibacron blue > F2 peptide > hematin > F1 peptide > ethacrynic acid. Moreover, the F1 peptide appeared to be a noncompetitive inhibitor of the GST-catalyzed reaction, while the F2 peptide was determined as a competitive inhibitor of this reaction.
It appears that the F2 peptide can be used as a new potent specific GST inhibitor. It is proposed that the novel method, described in this report, might be useful for screening the inhibitors of not only GST but also other enzymes.
谷胱甘肽转移酶（GSTs）属于Ⅱ相解毒酶家族。GSTs催化谷胱甘肽与不同的内源性和外源性亲电化合物结合。在许多不同的人类癌细胞中都证实了GSTs的过表达。已经发现对许多抗癌化疗药物的耐药性与GSTs的过表达直接相关。因此，寻找新的GST抑制剂以防止细胞对抗癌药物产生耐药性似乎很重要。为了寻找谷胱甘肽转移酶（GST）抑制剂，设计了一种新方法。
我们的结果表明，GST的两个片段，名为F1肽（GYWKIKGLV）和F2肽（KWRNKKFELGLEFPNL），可以显著抑制GST活性。当将这两个片段与几种已知的强效GST抑制剂进行比较时，抑制效率顺序（以2,4-二硝基氯苯（CDNB）和谷胱甘肽为底物的反应中测定）如下：单宁酸＞汽巴蓝＞F2肽＞血红素＞F1肽＞依他尼酸。此外，F1肽似乎是GST催化反应的非竞争性抑制剂，而F2肽被确定为该反应的竞争性抑制剂。
似乎F2肽可以用作一种新的强效特异性GST抑制剂。有人提出，本报告中描述的新方法可能不仅对筛选GST抑制剂有用，而且对筛选其他酶的抑制剂也有用。
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