The Enzymology of 2-Hydroxyglutarate, 2-Hydroxyglutaramate and 2-Hydroxysuccinamate and Their Relationship to Oncometabolites
Many enzymes make “mistakes”. Consequently, repair enzymes have evolved to correct these mistakes. For example, lactate dehydrogenase (LDH) and mitochondrial malate dehydrogenase (mMDH) slowly catalyze the reduction of 2-oxoglutarate (2-OG) to the oncometabolite l-2-hydroxyglutarate (l-2-HG). l-2-HG...
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2017-03-01
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| Online Access: | http://www.mdpi.com/2079-7737/6/2/24 |
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| author | Vivek A. Hariharan Travis T. Denton Sarah Paraszcszak Kyle McEvoy Thomas M. Jeitner Boris F. Krasnikov Arthur J. L. Cooper |
| author_facet | Vivek A. Hariharan Travis T. Denton Sarah Paraszcszak Kyle McEvoy Thomas M. Jeitner Boris F. Krasnikov Arthur J. L. Cooper |
| author_sort | Vivek A. Hariharan |
| collection | DOAJ |
| description | Many enzymes make “mistakes”. Consequently, repair enzymes have evolved to correct these mistakes. For example, lactate dehydrogenase (LDH) and mitochondrial malate dehydrogenase (mMDH) slowly catalyze the reduction of 2-oxoglutarate (2-OG) to the oncometabolite l-2-hydroxyglutarate (l-2-HG). l-2-HG dehydrogenase corrects this error by converting l-2-HG to 2-OG. LDH also catalyzes the reduction of the oxo group of 2-oxoglutaramate (2-OGM; transamination product of l-glutamine). We show here that human glutamine synthetase (GS) catalyzes the amidation of the terminal carboxyl of both the l- and d- isomers of 2-HG. The reaction of 2-OGM with LDH and the reaction of l-2-HG with GS generate l-2-hydroxyglutaramate (l-2-HGM). We also show that l-2-HGM is a substrate of human ω-amidase. The product (l-2-HG) can then be converted to 2-OG by l-2-HG dehydrogenase. Previous work showed that 2-oxosuccinamate (2-OSM; transamination product of l-asparagine) is an excellent substrate of LDH. Finally, we also show that human ω-amidase converts the product of this reaction (i.e., l-2-hydroxysuccinamate; l-2-HSM) to l-malate. Thus, ω-amidase may act together with hydroxyglutarate dehydrogenases to repair certain “mistakes” of GS and LDH. The present findings suggest that non-productive pathways for nitrogen metabolism occur in mammalian tissues in vivo. Perturbations of these pathways may contribute to symptoms associated with hydroxyglutaric acidurias and to tumor progression. Finally, methods for the synthesis of l-2-HGM and l-2-HSM are described that should be useful in determining the roles of ω-amidase/4- and 5-C compounds in photorespiration in plants. |
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| issn | 2079-7737 |
| language | English |
| last_indexed | 2024-03-12T19:16:52Z |
| publishDate | 2017-03-01 |
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| spelling | doaj.art-53e26ddf90384bac9b83029b4ccc6e232023-08-02T05:27:23ZengMDPI AGBiology2079-77372017-03-01622410.3390/biology6020024biology6020024The Enzymology of 2-Hydroxyglutarate, 2-Hydroxyglutaramate and 2-Hydroxysuccinamate and Their Relationship to OncometabolitesVivek A. Hariharan0Travis T. Denton1Sarah Paraszcszak2Kyle McEvoy3Thomas M. Jeitner4Boris F. Krasnikov5Arthur J. L. Cooper6Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10590, USADepartment of Pharmaceutical Sciences, Washington State University, College of Pharmacy, Spokane, WA 99210-1495, USADepartment of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10590, USADepartment of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10590, USADepartment of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10590, USADepartment of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10590, USADepartment of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10590, USAMany enzymes make “mistakes”. Consequently, repair enzymes have evolved to correct these mistakes. For example, lactate dehydrogenase (LDH) and mitochondrial malate dehydrogenase (mMDH) slowly catalyze the reduction of 2-oxoglutarate (2-OG) to the oncometabolite l-2-hydroxyglutarate (l-2-HG). l-2-HG dehydrogenase corrects this error by converting l-2-HG to 2-OG. LDH also catalyzes the reduction of the oxo group of 2-oxoglutaramate (2-OGM; transamination product of l-glutamine). We show here that human glutamine synthetase (GS) catalyzes the amidation of the terminal carboxyl of both the l- and d- isomers of 2-HG. The reaction of 2-OGM with LDH and the reaction of l-2-HG with GS generate l-2-hydroxyglutaramate (l-2-HGM). We also show that l-2-HGM is a substrate of human ω-amidase. The product (l-2-HG) can then be converted to 2-OG by l-2-HG dehydrogenase. Previous work showed that 2-oxosuccinamate (2-OSM; transamination product of l-asparagine) is an excellent substrate of LDH. Finally, we also show that human ω-amidase converts the product of this reaction (i.e., l-2-hydroxysuccinamate; l-2-HSM) to l-malate. Thus, ω-amidase may act together with hydroxyglutarate dehydrogenases to repair certain “mistakes” of GS and LDH. The present findings suggest that non-productive pathways for nitrogen metabolism occur in mammalian tissues in vivo. Perturbations of these pathways may contribute to symptoms associated with hydroxyglutaric acidurias and to tumor progression. Finally, methods for the synthesis of l-2-HGM and l-2-HSM are described that should be useful in determining the roles of ω-amidase/4- and 5-C compounds in photorespiration in plants.http://www.mdpi.com/2079-7737/6/2/24ω-Amidaseasparagine transaminase2-hydroxyglutarate2-hydroxyglutaramate2-hydroxysuccinamateglutamine synthetaseglutamine transaminases2-oxoglutaramate2-oxoglutarate |
| spellingShingle | Vivek A. Hariharan Travis T. Denton Sarah Paraszcszak Kyle McEvoy Thomas M. Jeitner Boris F. Krasnikov Arthur J. L. Cooper The Enzymology of 2-Hydroxyglutarate, 2-Hydroxyglutaramate and 2-Hydroxysuccinamate and Their Relationship to Oncometabolites Biology ω-Amidase asparagine transaminase 2-hydroxyglutarate 2-hydroxyglutaramate 2-hydroxysuccinamate glutamine synthetase glutamine transaminases 2-oxoglutaramate 2-oxoglutarate |
| title | The Enzymology of 2-Hydroxyglutarate, 2-Hydroxyglutaramate and 2-Hydroxysuccinamate and Their Relationship to Oncometabolites |
| title_full | The Enzymology of 2-Hydroxyglutarate, 2-Hydroxyglutaramate and 2-Hydroxysuccinamate and Their Relationship to Oncometabolites |
| title_fullStr | The Enzymology of 2-Hydroxyglutarate, 2-Hydroxyglutaramate and 2-Hydroxysuccinamate and Their Relationship to Oncometabolites |
| title_full_unstemmed | The Enzymology of 2-Hydroxyglutarate, 2-Hydroxyglutaramate and 2-Hydroxysuccinamate and Their Relationship to Oncometabolites |
| title_short | The Enzymology of 2-Hydroxyglutarate, 2-Hydroxyglutaramate and 2-Hydroxysuccinamate and Their Relationship to Oncometabolites |
| title_sort | enzymology of 2 hydroxyglutarate 2 hydroxyglutaramate and 2 hydroxysuccinamate and their relationship to oncometabolites |
| topic | ω-Amidase asparagine transaminase 2-hydroxyglutarate 2-hydroxyglutaramate 2-hydroxysuccinamate glutamine synthetase glutamine transaminases 2-oxoglutaramate 2-oxoglutarate |
| url | http://www.mdpi.com/2079-7737/6/2/24 |
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