Hariharan Vivek A, Denton Travis T, Paraszcszak Sarah, McEvoy Kyle, Jeitner Thomas M, Krasnikov Boris F, Cooper Arthur J L
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10590, USA.
Department of Pharmaceutical Sciences, Washington State University, College of Pharmacy, Spokane, WA 99210-1495, USA.
Biology (Basel). 2017 Mar 30;6(2):24. doi: 10.3390/biology6020024.
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.
许多酶会出现“错误”。因此，修复酶逐渐进化以纠正这些错误。例如，乳酸脱氢酶（LDH）和线粒体苹果酸脱氢酶（mMDH）会缓慢催化将2-氧代戊二酸（2-OG）还原为致癌代谢物L-2-羟基戊二酸（L-2-HG）。L-2-HG脱氢酶通过将L-2-HG转化为2-OG来纠正这一错误。LDH还催化2-氧代谷氨酰胺（2-OGM；L-谷氨酰胺的转氨产物）的氧代基团的还原。我们在此表明，人谷氨酰胺合成酶（GS）催化L-和D-异构体的2-HG的末端羧基的酰胺化。2-OGM与LDH的反应以及L-2-HG与GS的反应生成L-2-羟基谷氨酰胺（L-2-HGM）。我们还表明，L-2-HGM是人ω-酰胺酶的底物。然后产物（L-2-HG）可被L-2-HG脱氢酶转化为2-OG。先前的研究表明，2-氧代琥珀酸酰胺（2-OSM；L-天冬酰胺的转氨产物）是LDH的优良底物。最后，我们还表明，人ω-酰胺酶将该反应的产物（即L-2-羟基琥珀酸酰胺；L-2-HSM）转化为L-苹果酸。因此，ω-酰胺酶可能与羟基戊二酸脱氢酶共同作用以修复GS和LDH的某些“错误”。目前的研究结果表明，氮代谢的非生产性途径在哺乳动物组织的体内发生。这些途径的扰动可能导致与羟基戊二酸尿症相关的症状以及肿瘤进展。最后，描述了L-2-HGM和L-2-HSM的合成方法，这些方法在确定ω-酰胺酶/4-和5-C化合物在植物光呼吸中的作用方面应该是有用的。
