REVIEW: Directed Regulation of Multienzyme Complexes of 2-Oxo Acid Dehydrogenases Using Phosphonate and Phosphinate Analogs of 2-Oxo Acids

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A. V. Artiukhov¹, A. V. Graf^2,3, and V. I. Bunik^1,4*

¹Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, 119991 Moscow, Russia

²Lomonosov Moscow State University, Faculty of Biology, 119991 Moscow, Russia

³Moscow Institute of Physics and Technology, Faculty of Nano-, Bio-, Informational and Cognitive Technologies, 123098 Moscow, Russia

⁴Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, 119991 Moscow, Russia; E-mail: bunik@belozersky.msu.ru

^* To whom correspondence should be addressed.

Received July 8, 2016; Revision received September 4, 2016

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2-Oxo acid dehydrogenase complexes are important metabolic checkpoints functioning at the intercept of sugar and amino acid degradation. This review presents a short summary of architectural, catalytic, and regulatory principles of the complexes structure and function, based on recent advances in studies of well-characterized family members. Special attention is given to use of synthetic phosphonate and phosphinate analogs of 2-oxo acids as selective and efficient inhibitors of the cognate complexes in biological systems of bacterial, plant, and animal origin. We summarize our own results concerning the application of synthetic analogs of 2-oxo acids in situ and in vivo to reveal functional interactions between 2-oxo acid dehydrogenase complexes and other components of metabolic networks specific to different cells and tissues. Based on our study of glutamate excitotoxicity in cultured neurons, we show how a modulation of metabolism by specific inhibition of its key reaction may be employed to correct pathologies. This approach is further developed in our study on the action of the phosphonate analog of 2-oxoglutarate in animals. The study revealed that upregulation of 2-oxoglutarate dehydrogenase complex is involved in animal stress response and may provide increased resistance to damaging effects, underlying so-called preconditioning. The presented analysis of published data suggests synthetic inhibitors of metabolic checkpoints as promising tools to solve modern challenges of systems biology, metabolic engineering, and medicine.

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KEY WORDS: directed metabolic regulation, 2-oxo acid dehydrogenase complex, phosphonate or phosphinate analog of 2-oxo acids, stress resistance, tricarboxylic acid cycle, amino acid metabolism

DOI: 10.1134/S0006297916120129

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