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Biology 2017, 6(2), 24; doi:10.3390/biology6020024

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

1
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10590, USA
2
Department of Pharmaceutical Sciences, Washington State University, College of Pharmacy, Spokane, WA 99210-1495, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Chris O’Callaghan
Received: 1 December 2016 / Revised: 10 March 2017 / Accepted: 13 March 2017 / Published: 30 March 2017
(This article belongs to the Special Issue Enzymes of Glutamate Metabolism in Health and Disease)
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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. View Full-Text
Keywords: ω-Amidase; asparagine transaminase; 2-hydroxyglutarate; 2-hydroxyglutaramate; 2-hydroxysuccinamate; glutamine synthetase; glutamine transaminases; 2-oxoglutaramate; 2-oxoglutarate ω-Amidase; asparagine transaminase; 2-hydroxyglutarate; 2-hydroxyglutaramate; 2-hydroxysuccinamate; glutamine synthetase; glutamine transaminases; 2-oxoglutaramate; 2-oxoglutarate
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Hariharan, V.A.; Denton, T.T.; Paraszcszak, S.; McEvoy, K.; Jeitner, T.M.; Krasnikov, B.F.; Cooper, A.J.L. The Enzymology of 2-Hydroxyglutarate, 2-Hydroxyglutaramate and 2-Hydroxysuccinamate and Their Relationship to Oncometabolites. Biology 2017, 6, 24.

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