Administration of Phosphonate Inhibitors of Dehydrogenases of 2-Oxoglutarate and 2-Oxoadipate to Rats Elicits Target-Specific Metabolic and Physiological Responses
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 mem...
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| Format: | Article |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fchem.2022.892284/full |
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| author | Victoria I. Bunik Victoria I. Bunik Victoria I. Bunik Artem V. Artiukhov Artem V. Artiukhov Alexey V. Kazantsev Alexey V. Kazantsev Vasily A. Aleshin Vasily A. Aleshin Alexandra I. Boyko Alexander L. Ksenofontov Nikolay V. Lukashev Anastasia V. Graf Anastasia V. Graf |
| author_facet | Victoria I. Bunik Victoria I. Bunik Victoria I. Bunik Artem V. Artiukhov Artem V. Artiukhov Alexey V. Kazantsev Alexey V. Kazantsev Vasily A. Aleshin Vasily A. Aleshin Alexandra I. Boyko Alexander L. Ksenofontov Nikolay V. Lukashev Anastasia V. Graf Anastasia V. Graf |
| author_sort | Victoria I. Bunik |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T13:22:04Z |
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| id | doaj.art-ae420945964148f7aeda0e9e80f8ae1c |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-04-12T13:22:04Z |
| publishDate | 2022-06-01 |
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| series | Frontiers in Chemistry |
| spelling | doaj.art-ae420945964148f7aeda0e9e80f8ae1c2022-12-22T03:31:27ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462022-06-011010.3389/fchem.2022.892284892284Administration of Phosphonate Inhibitors of Dehydrogenases of 2-Oxoglutarate and 2-Oxoadipate to Rats Elicits Target-Specific Metabolic and Physiological ResponsesVictoria I. Bunik0Victoria I. Bunik1Victoria I. Bunik2Artem V. Artiukhov3Artem V. Artiukhov4Alexey V. Kazantsev5Alexey V. Kazantsev6Vasily A. Aleshin7Vasily A. Aleshin8Alexandra I. Boyko9Alexander L. Ksenofontov10Nikolay V. Lukashev11Anastasia V. Graf12Anastasia V. Graf13Department of Biokinetics, A. N. Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, Moscow, RussiaDepartment of Biochemistry, Sechenov University, Moscow, RussiaFaculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, RussiaDepartment of Biokinetics, A. N. Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, Moscow, RussiaDepartment of Biochemistry, Sechenov University, Moscow, RussiaDepartment of Biokinetics, A. N. Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, Moscow, RussiaFaculty of Chemistry, Lomonosov Moscow State University, Moscow, RussiaDepartment of Biokinetics, A. N. Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, Moscow, RussiaDepartment of Biochemistry, Sechenov University, Moscow, RussiaFaculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, RussiaDepartment of Biokinetics, A. N. Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, Moscow, RussiaFaculty of Chemistry, Lomonosov Moscow State University, Moscow, RussiaDepartment of Biokinetics, A. N. Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, Moscow, RussiaFaculty of Biology, Lomonosov Moscow State University, Moscow, RussiaIn 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.https://www.frontiersin.org/articles/10.3389/fchem.2022.892284/full2-oxoglutarate dehydrogenase2-oxoadipate dehydrogenaseDHTKD1phosphonate analog of 2-oxo acidregulation of brain metabolism |
| spellingShingle | Victoria I. Bunik Victoria I. Bunik Victoria I. Bunik Artem V. Artiukhov Artem V. Artiukhov Alexey V. Kazantsev Alexey V. Kazantsev Vasily A. Aleshin Vasily A. Aleshin Alexandra I. Boyko Alexander L. Ksenofontov Nikolay V. Lukashev Anastasia V. Graf Anastasia V. Graf Administration of Phosphonate Inhibitors of Dehydrogenases of 2-Oxoglutarate and 2-Oxoadipate to Rats Elicits Target-Specific Metabolic and Physiological Responses Frontiers in Chemistry 2-oxoglutarate dehydrogenase 2-oxoadipate dehydrogenase DHTKD1 phosphonate analog of 2-oxo acid regulation of brain metabolism |
| title | Administration of Phosphonate Inhibitors of Dehydrogenases of 2-Oxoglutarate and 2-Oxoadipate to Rats Elicits Target-Specific Metabolic and Physiological Responses |
| title_full | Administration of Phosphonate Inhibitors of Dehydrogenases of 2-Oxoglutarate and 2-Oxoadipate to Rats Elicits Target-Specific Metabolic and Physiological Responses |
| title_fullStr | Administration of Phosphonate Inhibitors of Dehydrogenases of 2-Oxoglutarate and 2-Oxoadipate to Rats Elicits Target-Specific Metabolic and Physiological Responses |
| title_full_unstemmed | Administration of Phosphonate Inhibitors of Dehydrogenases of 2-Oxoglutarate and 2-Oxoadipate to Rats Elicits Target-Specific Metabolic and Physiological Responses |
| title_short | Administration of Phosphonate Inhibitors of Dehydrogenases of 2-Oxoglutarate and 2-Oxoadipate to Rats Elicits Target-Specific Metabolic and Physiological Responses |
| title_sort | administration of phosphonate inhibitors of dehydrogenases of 2 oxoglutarate and 2 oxoadipate to rats elicits target specific metabolic and physiological responses |
| topic | 2-oxoglutarate dehydrogenase 2-oxoadipate dehydrogenase DHTKD1 phosphonate analog of 2-oxo acid regulation of brain metabolism |
| url | https://www.frontiersin.org/articles/10.3389/fchem.2022.892284/full |
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