The Enzymology of 2-Hydroxyglutarate, 2-Hydroxyglutaramate and 2-Hydroxysuccinamate and Their Relationship to OncometabolitesReport as inadecuate


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


The Enzymology of 2-Hydroxyglutarate, 2-Hydroxyglutaramate and 2-Hydroxysuccinamate and Their Relationship to Oncometabolites - Download this document for free, or read online. Document in PDF available to download.

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

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





Author: Vivek A. Hariharan 1, Travis T. Denton 2, Sarah Paraszcszak 1, Kyle McEvoy 1, Thomas M. Jeitner 1, Boris F. Krasnikov 1 and Arthur J. L. Cooper 1,*

Source: http://mdpi.com/



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