Bunik Victoria I, Artiukhov Artem V, Kazantsev Alexey V, Aleshin Vasily A, Boyko Alexandra I, Ksenofontov Alexander L, Lukashev Nikolay V, Graf Anastasia V
Department of Biokinetics, A. N. Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, Moscow, Russia.
Department of Biochemistry, Sechenov University, Moscow, Russia.
Front Chem. 2022 Jun 20;10:892284. doi: 10.3389/fchem.2022.892284. eCollection 2022.
and in cell cultures, succinyl phosphonate (SP) and adipoyl phosphonate (AP) selectively target dehydrogenases of 2-oxoglutarate (OGDH, encoded by ) and 2-oxoadipate (OADH, encoded by ), 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 . 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.
在细胞培养中，琥珀酰膦酸酯（SP）和己二酰膦酸酯（AP）分别选择性地作用于2-氧代戊二酸脱氢酶（由 编码的OGDH）和2-氧代己二酸脱氢酶（由 编码的OADH）。为了评估在动物体内的选择性，比较了SP、AP及其膜穿透性三乙酯（TESP和TEAP）对大鼠脑代谢和动物生理的影响。结果表明，OGDH和OADH抑制剂对OGDH、苹果酸脱氢酶、谷氨酰胺合成酶的活性以及谷氨酸、赖氨酸、瓜氨酸和肌肽水平的相反作用导致了不同的生理反应。AP/TEAP会改变心电图，而SP/TESP会增加焦虑。评估了酯部分在2-氧代酸脱氢酶抑制剂不带电荷前体中的潜在作用。结果表明，TMAP的效率低于TEAP，这与TMAP较低的亲脂性一致。TEAP。揭示了增加OADH抑制作用的非单调代谢和生理影响。与未处理的动物相比，强烈抑制OADH会降低色氨酸和β-氨基异丁酸的水平以及苹果酸脱氢酶和丙酮酸脱氢酶的活性，增加心电图的R-R间期。因此，OADH定向抑制剂AP/TEAP的代谢和生理作用与OGDH定向抑制剂SP/TESP的不同，乙酯比甲酯更有效。
