PMID- 37995940
OWN - NLM
STAT- MEDLINE
DCOM- 20240207
LR  - 20240207
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 300
IP  - 1
DP  - 2024 Jan
TI  - Structure and biochemical characterization of l-2-hydroxyglutarate dehydrogenase 
      and its role in the pathogenesis of l-2-hydroxyglutaric aciduria.
PG  - 105491
LID - S0021-9258(23)02519-X [pii]
LID - 10.1016/j.jbc.2023.105491 [doi]
LID - 105491
AB  - l-2-hydroxyglutarate dehydrogenase (L2HGDH) is a mitochondrial 
      membrane-associated metabolic enzyme, which catalyzes the oxidation of 
      l-2-hydroxyglutarate (l-2-HG) to 2-oxoglutarate (2-OG). Mutations in human L2HGDH 
      lead to abnormal accumulation of l-2-HG, which causes a neurometabolic disorder 
      named l-2-hydroxyglutaric aciduria (l-2-HGA). Here, we report the crystal 
      structures of Drosophila melanogaster L2HGDH (dmL2HGDH) in FAD-bound form and in 
      complex with FAD and 2-OG and show that dmL2HGDH exhibits high activity and 
      substrate specificity for l-2-HG. dmL2HGDH consists of an FAD-binding domain and 
      a substrate-binding domain, and the active site is located at the interface of 
      the two domains with 2-OG binding to the re-face of the isoalloxazine moiety of 
      FAD. Mutagenesis and activity assay confirmed the functional roles of key 
      residues involved in the substrate binding and catalytic reaction and showed that 
      most of the mutations of dmL2HGDH equivalent to l-2-HGA-associated mutations of 
      human L2HGDH led to complete loss of the activity. The structural and biochemical 
      data together reveal the molecular basis for the substrate specificity and 
      catalytic mechanism of L2HGDH and provide insights into the functional roles of 
      human L2HGDH mutations in the pathogeneses of l-2-HGA.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Yang, Jun
AU  - Yang J
AD  - State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and 
      Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of 
      Sciences, University of Chinese Academy of Sciences, Shanghai, China.
FAU - Chen, Xingchen
AU  - Chen X
AD  - State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and 
      Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of 
      Sciences, University of Chinese Academy of Sciences, Shanghai, China.
FAU - Jin, Shan
AU  - Jin S
AD  - State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and 
      Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of 
      Sciences, University of Chinese Academy of Sciences, Shanghai, China.
FAU - Ding, Jianping
AU  - Ding J
AD  - State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and 
      Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of 
      Sciences, University of Chinese Academy of Sciences, Shanghai, China; School of 
      Life Science and Technology, ShanghaiTech University, Shanghai, China. Electronic 
      address: jpding@sibcb.ac.cn.
LA  - eng
PT  - Journal Article
DEP - 20231122
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - EC 1.1.99.2 (2-hydroxyglutarate dehydrogenase)
RN  - EC 1.1.- (Alcohol Oxidoreductases)
RN  - 0 (Glutarates)
RN  - 0 (Recombinant Proteins)
RN  - 2-Hydroxyglutaricaciduria
SB  - IM
MH  - Animals
MH  - Humans
MH  - *Alcohol Oxidoreductases/chemistry/metabolism
MH  - *Brain Diseases, Metabolic, Inborn/enzymology/genetics/physiopathology
MH  - *Drosophila melanogaster/enzymology
MH  - Glutarates/metabolism
MH  - Mutation
MH  - Catalytic Domain/genetics
MH  - Substrate Specificity/genetics
MH  - *Models, Molecular
MH  - Protein Structure, Tertiary
MH  - Recombinant Proteins/chemistry/genetics/metabolism
PMC - PMC10726252
OTO - NOTNLM
OT  - 2-hydroxyglutaric aciduria
OT  - catalytic mechanism
OT  - l-2-hydroxyglutarate dehydrogenase
OT  - protein crystallography
OT  - substrate specificity
COIS- Conflict of interest The authors declare that they have no conflicts of interest 
      with the contents of this article.
EDAT- 2023/11/24 00:42
MHDA- 2024/02/05 06:42
PMCR- 2023/11/22
CRDT- 2023/11/23 19:30
PHST- 2023/09/11 00:00 [received]
PHST- 2023/11/06 00:00 [revised]
PHST- 2023/11/09 00:00 [accepted]
PHST- 2024/02/05 06:42 [medline]
PHST- 2023/11/24 00:42 [pubmed]
PHST- 2023/11/23 19:30 [entrez]
PHST- 2023/11/22 00:00 [pmc-release]
AID - S0021-9258(23)02519-X [pii]
AID - 105491 [pii]
AID - 10.1016/j.jbc.2023.105491 [doi]
PST - ppublish
SO  - J Biol Chem. 2024 Jan;300(1):105491. doi: 10.1016/j.jbc.2023.105491. Epub 2023 
      Nov 22.