Design, Synthesis, and Evaluation of Inhibitors of Pyruvate Phosphate Dikinase
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- 作者：Chun Wu ; Debra Dunaway-Mariano ; Patrick S. Mariano
- 刊名：The Journal of Organic Chemistry
- 出版年：2013
- 出版时间：March 1, 2013
- 年：2013
- 卷：78
- 期：5
- 页码：1910-1922
- 全文大小：571K
- 年卷期：v.78,no.5(March 1, 2013)
- ISSN：1520-6904
文摘
Pyruvate phosphate dikinase (PPDK) catalyzes the phosphorylation reaction of pyruvate that forms phosphoenolpyruvate (PEP) via two partial reactions: PPDK + ATP + Pi 鈫?PPDK-P + AMP + PPi and PPDK-P + pyruvate 鈫?PEP + PPDK. Based on its role in the metabolism of microbial human pathogens, PPDK is a potential drug target. A screen of substances that bind to the PPDK ATP-grasp domain active site revealed that flavone analogues are potent inhibitors of the Clostridium symbiosum PPDK. In silico modeling studies suggested that placement of a 3鈥? carbon-tethered ammonium substituent at the 3鈥? or 4鈥?positions of 5,7-dihydroxyflavones would result in favorable electrostatic interactions with the PPDK Mg-ATP binding site. As a result, polymethylene-tethered amine derivatives of 5,7-dihydroxyflavones were prepared. Steady-state kinetic analysis of these substances demonstrates that the 4鈥?aminohexyl-5,7-dyhydroxyflavone 10 is a potent competitive PPDK inhibitor (Ki = 1.6 卤 0.1 渭M). Single turnover experiments were conducted using 4鈥?aminopropyl-5,7-dihydroxyflavone 7 to show that this flavone specifically targets the ATP binding site and inhibits catalysis of only the PPDK + ATP + Pi 鈫?PPDK-P + AMP PPi partial reaction. Finally, the 4鈥?aminopbutyl-5,7-dihydroxyflavone 8 displays selectivity for inhibition of PPDK versus other enzymes that utilize ATP and NAD.