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Hariharan VA, Denton TT, Paraszcszak S, et al. The Enzymology of 2-Hydroxyglutarate, 2-Hydroxyglutaramate and 2-Hydroxysuccinamate and Their Relationship to Oncometabolites. Biology (Basel). 2017;6(2)doi: 10.3390/biology6020024.
Hariharan, V. A., Denton, T. T., Paraszcszak, S., McEvoy, K., Jeitner, T. M., Krasnikov, B. F., & Cooper, A. J. (2017). The Enzymology of 2-Hydroxyglutarate, 2-Hydroxyglutaramate and 2-Hydroxysuccinamate and Their Relationship to Oncometabolites. Biology, 6(2), . https://doi.org/10.3390/biology6020024
Hariharan, Vivek A, et al. "The Enzymology of 2-Hydroxyglutarate, 2-Hydroxyglutaramate and 2-Hydroxysuccinamate and Their Relationship to Oncometabolites." Biology vol. 6,2 (2017). doi: https://doi.org/10.3390/biology6020024
Hariharan VA, Denton TT, Paraszcszak S, McEvoy K, Jeitner TM, Krasnikov BF, Cooper AJ. The Enzymology of 2-Hydroxyglutarate, 2-Hydroxyglutaramate and 2-Hydroxysuccinamate and Their Relationship to Oncometabolites. Biology (Basel). 2017 Mar 30;6(2). doi: 10.3390/biology6020024. PMID: 28358347; PMCID: PMC5485471.
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Biology (Basel). 2017 Mar 30;6(2). doi: 10.3390/biology6020024.

The Enzymology of 2-Hydroxyglutarate, 2-Hydroxyglutaramate and 2-Hydroxysuccinamate and Their Relationship to Oncometabolites.

Biology

Vivek A Hariharan, Travis T Denton, Sarah Paraszcszak, Kyle McEvoy, Thomas M Jeitner, Boris F Krasnikov, Arthur J L Cooper

Affiliations

  1. Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10590, USA. [email protected].
  2. Department of Pharmaceutical Sciences, Washington State University, College of Pharmacy, Spokane, WA 99210-1495, USA. [email protected].
  3. Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10590, USA. [email protected].
  4. Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10590, USA. [email protected].
  5. Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10590, USA. [email protected].
  6. Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10590, USA. [email protected].
  7. Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10590, USA. [email protected].

PMID: 28358347 PMCID: PMC5485471 DOI: 10.3390/biology6020024

Abstract

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.

Keywords: 2-hydroxyglutaramate; 2-hydroxyglutarate; 2-hydroxysuccinamate; 2-oxoglutaramate; 2-oxoglutarate; asparagine transaminase; glutamine synthetase; glutamine transaminases; ω-Amidase

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