PMID- 28358347
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201001
IS  - 2079-7737 (Print)
IS  - 2079-7737 (Electronic)
IS  - 2079-7737 (Linking)
VI  - 6
IP  - 2
DP  - 2017 Mar 30
TI  - The Enzymology of 2-Hydroxyglutarate, 2-Hydroxyglutaramate and 
      2-Hydroxysuccinamate and Their Relationship to Oncometabolites.
LID - 10.3390/biology6020024 [doi]
LID - 24
AB  - 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.
FAU - Hariharan, Vivek A
AU  - Hariharan VA
AD  - Department of Biochemistry and Molecular Biology, New York Medical College, 
      Valhalla, NY 10590, USA. hariharanviv@gmail.com.
FAU - Denton, Travis T
AU  - Denton TT
AD  - Department of Pharmaceutical Sciences, Washington State University, College of 
      Pharmacy, Spokane, WA 99210-1495, USA. travis.denton@wsu.edu.
FAU - Paraszcszak, Sarah
AU  - Paraszcszak S
AD  - Department of Biochemistry and Molecular Biology, New York Medical College, 
      Valhalla, NY 10590, USA. sparaszczak@umass.edu.
FAU - McEvoy, Kyle
AU  - McEvoy K
AD  - Department of Biochemistry and Molecular Biology, New York Medical College, 
      Valhalla, NY 10590, USA. kyle_mcevoy@nymc.edu.
FAU - Jeitner, Thomas M
AU  - Jeitner TM
AD  - Department of Biochemistry and Molecular Biology, New York Medical College, 
      Valhalla, NY 10590, USA. thomas_jeitner@nymc.edu.
FAU - Krasnikov, Boris F
AU  - Krasnikov BF
AD  - Department of Biochemistry and Molecular Biology, New York Medical College, 
      Valhalla, NY 10590, USA. boris_krasnikov@nymc.edu.
FAU - Cooper, Arthur J L
AU  - Cooper AJ
AD  - Department of Biochemistry and Molecular Biology, New York Medical College, 
      Valhalla, NY 10590, USA. arthur_cooper@nymc.edu.
LA  - eng
PT  - Journal Article
DEP - 20170330
PL  - Switzerland
TA  - Biology (Basel)
JT  - Biology
JID - 101587988
PMC - PMC5485471
OTO - NOTNLM
OT  - 2-hydroxyglutaramate
OT  - 2-hydroxyglutarate
OT  - 2-hydroxysuccinamate
OT  - 2-oxoglutaramate
OT  - 2-oxoglutarate
OT  - asparagine transaminase
OT  - glutamine synthetase
OT  - glutamine transaminases
OT  - omega-Amidase
COIS- The authors declare no conflict of interest.
EDAT- 2017/03/31 06:00
MHDA- 2017/03/31 06:01
PMCR- 2017/06/01
CRDT- 2017/03/31 06:00
PHST- 2016/12/01 00:00 [received]
PHST- 2017/03/10 00:00 [revised]
PHST- 2017/03/13 00:00 [accepted]
PHST- 2017/03/31 06:00 [entrez]
PHST- 2017/03/31 06:00 [pubmed]
PHST- 2017/03/31 06:01 [medline]
PHST- 2017/06/01 00:00 [pmc-release]
AID - biology6020024 [pii]
AID - biology-06-00024 [pii]
AID - 10.3390/biology6020024 [doi]
PST - epublish
SO  - Biology (Basel). 2017 Mar 30;6(2):24. doi: 10.3390/biology6020024.