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.
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DOI：
10.3390/biology6020024
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发表时间：
2017-03-30
期刊：
影响因子：
4.2
通讯作者：
Cooper AJ
中科院分区：
文献类型：
--
作者：
Hariharan VA;Denton TT;Paraszcszak S;McEvoy K;Jeitner TM;Krasnikov BF;Cooper AJ
许多酶会“出错”。因此，修复酶进化来纠正这些错误。例如，乳酸脱氢酶（LDH）和线粒体苹果酸脱氢酶（mMDH）缓慢催化2-氧戊二酸（2-OG）还原为肿瘤代谢物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来纠正这个错误。LDH还能催化2-氧谷酰胺酸酯（2-OGM； l-谷氨酰胺的转氨化产物）的氧基还原。我们在这里表明，人类谷氨酰胺合成酶（GS）催化2-HG的l-和d-异构体的末端羧基的酰胺化。2-OGM与LDH和l-2-HG与GS反应生成l-2-羟基谷氨酰胺（l-2-HGM）。我们还发现l-2-HGM是人ω-氨基酶的底物。产物（l-2-HG）可以通过l-2-HG脱氢酶转化为2-OG。先前的研究表明，2-氧琥珀酸酯（2-OSM； l-天冬酰胺转氨化产物）是LDH的优良底物。最后，我们还表明，人类ω-氨基酶将该反应的产物（即，l-2-羟基琥珀酸酯；l-2-HSM）转化为l-苹果酸盐。因此，ω-酰胺酶可能与羟戊二酸脱氢酶共同作用，修复GS和LDH的某些“错误”。目前的研究结果表明，哺乳动物体内组织中存在非生产性氮代谢途径。这些通路的扰动可能导致与羟基戊二酸尿症相关的症状和肿瘤进展。最后，描述了l-2-HGM和l-2-HSM的合成方法，这些方法将有助于确定ω-氨基酶/4-和5-C化合物在植物光呼吸中的作用。
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.