Discovery of a Novel Class of Covalent Inhibitor for Aldehyde Dehydrogenases
Discovery of a Novel Class of Covalent Inhibitor for Aldehyde Dehydrogenases
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DOI：
10.1074/jbc.m111.293597
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发表时间：
2011-12-16
影响因子：
4.8
通讯作者：
Hurley, Thomas D.
中科院分区：
文献类型：
--
作者：
Khanna, May;Chen, Che-Hong;Hurley, Thomas D.
人醛脱氢酶(ALDHs)由17种同源酶组成，代谢不同的生物和外源醛。到目前为止，可以用来探索这类酶对特定代谢途径的贡献的通用ALDH抑制剂相对较少。在这里，我们报告了一类具有共同作用机制的ALDH抑制剂的发现。动力学研究、质谱学测量和结晶学分析的综合数据表明，这些抑制剂经历了酶介导的β-消除反应，生成了乙烯基酮中间体，该中间体共价修饰存在于这些酶中的活性部位半胱氨酸残基。这里描述的研究可以为合理设计ALDH同工酶特异性抑制剂作为研究工具和药物提供基础，以应对ALDH活性增加与细胞表型相关的疾病，如癌症。
Human aldehyde dehydrogenases (ALDHs) comprise a family of 17 homologous enzymes that metabolize different biogenic and exogenic aldehydes. To date, there are relatively few general ALDH inhibitors that can be used to probe the contribution of this class of enzymes to particular metabolic pathways. Here, we report the discovery of a general class of ALDH inhibitors with a common mechanism of action. The combined data from kinetic studies, mass spectrometric measurements, and crystallographic analyses demonstrate that these inhibitors undergo an enzyme-mediated beta-elimination reaction generating a vinyl ketone intermediate that covalently modifies the active site cysteine residue present in these enzymes. The studies described here can provide the basis for rational approach to design ALDH isoenzyme-specific inhibitors as research tools and perhaps as drugs, to address diseases such as cancer where increased ALDH activity is associated with a cellular phenotype.