Administration of Phosphonate Inhibitors of Dehydrogenases of 2-Oxoglutarate and 2-Oxoadipate to Rats Elicits Target-Specific Metabolic and Physiological Responses

Victoria I Bunik; Artem V Artiukhov; Alexey V Kazantsev; Vasily A Aleshin; Alexandra I Boyko; Alexander L Ksenofontov; Nikolay V Lukashev; Anastasia V Graf

doi:10.3389/fchem.2022.892284

Administration of Phosphonate Inhibitors of Dehydrogenases of 2-Oxoglutarate and 2-Oxoadipate to Rats Elicits Target-Specific Metabolic and Physiological Responses

Front Chem. 2022 Jun 20:10:892284. doi: 10.3389/fchem.2022.892284. eCollection 2022.

Authors

Victoria I Bunik^{1

2

3}, Artem V Artiukhov^{1

2}, Alexey V Kazantsev^{1

4}, Vasily A Aleshin^{1

2}, Alexandra I Boyko³, Alexander L Ksenofontov¹, Nikolay V Lukashev⁴, Anastasia V Graf^{1

5}

Affiliations

¹ Department of Biokinetics, A. N. Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, Moscow, Russia.
² Department of Biochemistry, Sechenov University, Moscow, Russia.
³ Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia.
⁴ Faculty of Chemistry, Lomonosov Moscow State University, Moscow, Russia.
⁵ Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia.

Abstract

In vitro and in cell cultures, succinyl phosphonate (SP) and adipoyl phosphonate (AP) selectively target dehydrogenases of 2-oxoglutarate (OGDH, encoded by OGDH/OGDHL) and 2-oxoadipate (OADH, encoded by DHTKD1), respectively. To assess the selectivity in animals, the effects of SP, AP, and their membrane-penetrating triethyl esters (TESP and TEAP) on the rat brain metabolism and animal physiology are compared. Opposite effects of the OGDH and OADH inhibitors on activities of OGDH, malate dehydrogenase, glutamine synthetase, and levels of glutamate, lysine, citrulline, and carnosine are shown to result in distinct physiological responses. ECG is changed by AP/TEAP, whereas anxiety is increased by SP/TESP. The potential role of the ester moiety in the uncharged precursors of the 2-oxo acid dehydrogenase inhibitors is estimated. TMAP is shown to be less efficient than TEAP, in agreement with lower lipophilicity of TMAP vs. TEAP. Non-monotonous metabolic and physiological impacts of increasing OADH inhibition are revealed. Compared to the non-treated animals, strong inhibition of OADH decreases levels of tryptophan and beta-aminoisobutyrate and activities of malate dehydrogenase and pyruvate dehydrogenase, increasing the R-R interval of ECG. Thus, both metabolic and physiological actions of the OADH-directed inhibitors AP/TEAP are different from those of the OGDH-directed inhibitors SP/TESP, with the ethyl ester being more efficient than methyl ester.

Keywords: 2-oxoadipate dehydrogenase; 2-oxoglutarate dehydrogenase; DHTKD1; phosphonate analog of 2-oxo acid; regulation of brain metabolism.