Synthesis and Evaluation of Substrate Analogues as Mechanism-Based Inhibitors of Type II Isopentenyl Diphosphate Isomerase

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• 作者：Joel R. Walker ; Steven C. Rothman ; C. Dale Poulter
• 刊名：Journal of Organic Chemistry
• 出版年：2008
• 出版时间：January 18, 2008
• 年：2008
• 卷：73
• 期：2
• 页码：726 - 729
• 全文大小：96K
• 年卷期：v.73,no.2(January 18, 2008)
• ISSN：1520-6904

文摘

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Type 2 isopentenyl diphosphate isomerase (IDI-2), whichcatalyzes the interconversion of isopentenyl diphosphate anddimethylallyl diphosphate, contains a tightly bound moleculeof FMN. To probe the mechanism of the reaction, cyclopropyl and epoxy substrate analogues, designed to bemechanism-based irreversible inhibitors, were synthesizedand evaluated with IDI-2 from Thermus thermophilus. Thecyclopropyl analogues were alternative substrates. The epoxyanalogue was an irreversible inhibitor, with k_I = 0.37 ± 0.07min^-1 and K_I = 1.4 ± 0.3 M. LC-MS studies revealedformation of an epoxide-FMN adduct.