NYMC Faculty Publications
DOI
10.3390/biology6020024
Journal Title
Biology
First Page
24
Document Type
Article
Publication Date
3-1-2017
Department
Biochemistry and Molecular Biology
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 omega-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 omega-amidase converts the product of this reaction (i.e., l-2-hydroxysuccinamate; l-2-HSM) to l-malate. Thus, omega-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 omega-amidase/4- and 5-C compounds in photorespiration in plants.
Recommended Citation
Hariharan, V., Denton, T., Paraszcszak, S., McEvoy, K., Jeitner, T., Krasnikov, B., & Cooper, A. (2017). The Enzymology of 2-hydroxyglutarate, 2-hydroxyglutaramate and 2-hydroxysuccinamate and Their Relationship to Oncometabolites. Biology, 6 (2), 24. https://doi.org/10.3390/biology6020024
Publisher's Statement
Originally published in Biology, 6(2), 24. The original material can be found here.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
