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Information on EC 1.1.99.39 - D-2-hydroxyglutarate dehydrogenase
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EC Tree
1.1.99.39 D-2-hydroxyglutarate dehydrogenaseIUBMB Comments
Contains FAD. The enzyme has no activity with NAD+ or NADP+, and was assayed in vitro using artificial electron acceptors. It has lower activity with (R)-lactate, (R)-2-hydroxybutyrate and meso-tartrate, and no activity with the (S) isomers. The mammalian enzyme is stimulated by Zn2+, Co2+ and Mn2+.
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Word Map
- 1.1.99.39
-
acidurias
-
neurometabolic
- isocitrate
- 2-ketoglutarate
- l2hgdh
-
l-2-hga
- d-lactate
- d-malate
- chondromatosis
-
metaphyseal
-
oncometabolite
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
Synonyms
d2hgdh, d-2-hga, d-2-hydroxyglutarate dehydrogenase, d2hdh, atd-2hgdh, d-2-hg dehydrogenase, d2-hydroxyglutarate dehydrogenase, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
D-2-HG dehydrogenase
D2HGDH
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
(R)-2-hydroxyglutarate + acceptor = 2-oxoglutarate + reduced acceptor
-
-
-
-
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PATHWAY SOURCE
PATHWAYS
-
-
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SYSTEMATIC NAME
IUBMB Comments
(R)-2-hydroxyglutarate:acceptor 2-oxidoreductase
Contains FAD. The enzyme has no activity with NAD+ or NADP+, and was assayed in vitro using artificial electron acceptors. It has lower activity with (R)-lactate, (R)-2-hydroxybutyrate and meso-tartrate, and no activity with the (S) isomers. The mammalian enzyme is stimulated by Zn2+, Co2+ and Mn2+.
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
(R)-2-hydroxyglutarate + electron transfer flavoprotein
2-oxoglutarate + reduced electron transfer flavoprotein
(R)-2-hydroxyglutarate + oxidized 2,6-dichlorophenolindophenol
2-oxoglutarate + reduced 2,6-dichlorophenolindophenol
-
-
-
?
(R)-2-hydroxyglutarate + phenazine methosulfate
2-oxoglutarate + reduced phenazine methosulfate
(R)-2-hydroxyglutarate + phenazinemethosulfate
2-oxoglutarate + reduced phenazinemethosulfate
(S)-2-hydroxyglutarate + acceptor
2-oxoglutarate + reduced acceptor
necessary step in the serine biosynthetic pathway
-
-
?
D-malate + phenazine methosulfate
? + reduced phenazine methosulfate
-
-
-
?
(R)-2-hydroxyglutarate + acceptor
2-oxoglutarate + reduced acceptor
-
-
-
-
?
(R)-2-hydroxyglutarate + acceptor
2-oxoglutarate + reduced acceptor
-
-
-
?
(R)-2-hydroxyglutarate + acceptor
2-oxoglutarate + reduced acceptor
-
-
-
?
(R)-2-hydroxyglutarate + acceptor
2-oxoglutarate + reduced acceptor
-
-
-
-
?
(R)-2-hydroxyglutarate + acceptor
2-oxoglutarate + reduced acceptor
-
-
-
-
?
(R)-2-hydroxyglutarate + cytochrome c
2-oxoglutarate + reduced cytochrome c
-
-
-
-
?
(R)-2-hydroxyglutarate + cytochrome c
2-oxoglutarate + reduced cytochrome c
-
-
-
-
?
(R)-2-hydroxyglutarate + electron transfer flavoprotein
2-oxoglutarate + reduced electron transfer flavoprotein
-
-
-
?
(R)-2-hydroxyglutarate + electron transfer flavoprotein
2-oxoglutarate + reduced electron transfer flavoprotein
-
-
-
-
?
(R)-2-hydroxyglutarate + electron transfer flavoprotein
2-oxoglutarate + reduced electron transfer flavoprotein
-
-
-
-
?
(R)-2-hydroxyglutarate + phenazine methosulfate
2-oxoglutarate + reduced phenazine methosulfate
-
-
-
?
(R)-2-hydroxyglutarate + phenazine methosulfate
2-oxoglutarate + reduced phenazine methosulfate
-
-
-
?
(R)-2-hydroxyglutarate + phenazinemethosulfate
2-oxoglutarate + reduced phenazinemethosulfate
-
-
-
-
?
(R)-2-hydroxyglutarate + phenazinemethosulfate
2-oxoglutarate + reduced phenazinemethosulfate
-
-
-
-
?
additional information
?
-
low activity with D-lactate, D-2-hydroxybutyrate, meso-tartrate
-
-
?
additional information
?
-
-
low activity with D-lactate, D-2-hydroxybutyrate, meso-tartrate
-
-
?
additional information
?
-
-
description of two pathogenic mutations in the D-2-hydroxyglutarate dehydrogenase gene causing D-2-HGA with a very mild clinical presentation: a splice error (IVS4-2A->G) and a missense mutation (c.1315A->G, p.Asn439Asp). Mutations in the D-2-hydroxyglutarate dehydrogenase gene cause bith the severe and mild phenotypes of D-2-HGA
-
-
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
(R)-2-hydroxyglutarate + electron transfer flavoprotein
2-oxoglutarate + reduced electron transfer flavoprotein
(S)-2-hydroxyglutarate + acceptor
2-oxoglutarate + reduced acceptor
necessary step in the serine biosynthetic pathway
-
-
?
additional information
?
-
-
description of two pathogenic mutations in the D-2-hydroxyglutarate dehydrogenase gene causing D-2-HGA with a very mild clinical presentation: a splice error (IVS4-2A->G) and a missense mutation (c.1315A->G, p.Asn439Asp). Mutations in the D-2-hydroxyglutarate dehydrogenase gene cause bith the severe and mild phenotypes of D-2-HGA
-
-
?
(R)-2-hydroxyglutarate + acceptor
2-oxoglutarate + reduced acceptor
-
-
-
-
?
(R)-2-hydroxyglutarate + acceptor
2-oxoglutarate + reduced acceptor
-
-
-
?
(R)-2-hydroxyglutarate + acceptor
2-oxoglutarate + reduced acceptor
-
-
-
?
(R)-2-hydroxyglutarate + acceptor
2-oxoglutarate + reduced acceptor
-
-
-
-
?
(R)-2-hydroxyglutarate + acceptor
2-oxoglutarate + reduced acceptor
-
-
-
-
?
(R)-2-hydroxyglutarate + electron transfer flavoprotein
2-oxoglutarate + reduced electron transfer flavoprotein
-
-
-
?
(R)-2-hydroxyglutarate + electron transfer flavoprotein
2-oxoglutarate + reduced electron transfer flavoprotein
-
-
-
-
?
(R)-2-hydroxyglutarate + electron transfer flavoprotein
2-oxoglutarate + reduced electron transfer flavoprotein
-
-
-
-
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
no reaction with NAD+, NADP+ or cytochrome c
-
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
alcohol dehydrogenase deficiency
D-2-hydroxyglutaric aciduria in three patients with proven SSADH deficiency: genetic coincidence or a related biochemical epiphenomenon?
Brain Diseases
Phenotypic heterogeneity in the presentation of D-2-hydroxyglutaric aciduria in monozygotic twins.
Brain Neoplasms
Mutational analysis of D2HGDH and L2HGDH in brain tumours without IDH1 or IDH2 mutations.
Breast Neoplasms
D-2-hydroxyglutarate dehydrogenase in breast carcinoma as a potent prognostic marker associated with proliferation.
Chondromatosis
IDH1 mutated acute myeloid leukemia in a child with metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria.
Colitis
Elevated d-2-hydroxyglutarate during colitis drives progression to colorectal cancer.
Colitis, Ulcerative
Elevated d-2-hydroxyglutarate during colitis drives progression to colorectal cancer.
Enchondromatosis
Widespread and debilitating hemangiomas in a patient with enchondromatosis and D-2-hydroxyglutaric aciduria.
Glioma
Adult Diffuse Glioma GWAS by Molecular Subtype Identifies Variants in D2HGDH and FAM20C.
Hemangioma
Widespread and debilitating hemangiomas in a patient with enchondromatosis and D-2-hydroxyglutaric aciduria.
Language Development Disorders
D-2-hydroxyglutaric aciduria in a patient with speech delay due to a novel homozygous deletion in the D2HGDH gene.
Lymphoma, B-Cell
D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2.
Lymphoma, B-Cell
Structure, substrate specificity, and catalytic mechanism of human D-2-HGDH and insights into pathogenicity of disease-associated mutations.
Lymphoma, Large B-Cell, Diffuse
D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2.
Lymphoma, Large B-Cell, Diffuse
Structure, substrate specificity, and catalytic mechanism of human D-2-HGDH and insights into pathogenicity of disease-associated mutations.
Muscle Hypotonia
IDH1 mutated acute myeloid leukemia in a child with metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria.
Neoplasms
D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2.
Neoplasms
Elevated d-2-hydroxyglutarate during colitis drives progression to colorectal cancer.
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.584
(R)-2-hydroxyglutarate
25°C, pH 8.75, cofactor oxidized 2,6-dichlorophenolindophenol
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.8
(R)-2-hydroxyglutarate
25°C, pH 8.75, cofactor oxidized 2,6-dichlorophenolindophenol
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1.37
(R)-2-hydroxyglutarate
25°C, pH 8.75, cofactor oxidized 2,6-dichlorophenolindophenol
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug target
the dependence of Pseudomonas aeruginosa on PaD2HGDH makes the enzyme a potential therapeutic target against Pseudomonas aeruginosa
evolution
a phylogenetic tree analysis of D-2-hydroxyglutarate dehydrogenase from Pseudomonas aeruginosa, vanillyl alcohol oxidase, and human D-2-hydroxyglutarate dehydrogenase establishes genetic diversity among these enzymes
malfunction
metabolism
the enzyme elevates 2-oxoglutarate levels, influencing histone and DNA methylation, and HIF1alpha hydroxylation, and induces mitochondrial isocitrate dehydrogenase activity
physiological function
malfunction
-
deletion mutant displays decreased growth. The defect is rescued by adding L-serine
malfunction
-
deletion mutant displays decreased growth. The defect is rescued by adding L-serine
-
physiological function
the enzyme catalyzes a necessary step in the serine biosynthetic pathway
physiological function
the enzyme directly reduces recombinant human electron transferring flavoprotein (ETF), thus establishing a metabolic link between the oxidation of D-2-hydroxyglutarate and the mitochondrial electron transport chain
physiological function
-
the enzyme is functionally tied to L-serine synthesis. D-2-Hydroxyglutarate-mediated coupling between D-3-phosphoglycerate dehydrogenase (SerA) and D-2-hydroxyglutarate dehydrogenase drives bacterial L-serine synthesis
physiological function
-
the enzyme plays a dual role in L-serine biosynthesis and D-malate utilization
physiological function
-
the enzyme plays a dual role in L-serine biosynthesis and D-malate utilization
-
physiological function
-
the enzyme is functionally tied to L-serine synthesis. D-2-Hydroxyglutarate-mediated coupling between D-3-phosphoglycerate dehydrogenase (SerA) and D-2-hydroxyglutarate dehydrogenase drives bacterial L-serine synthesis
-
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UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). D2HDH_ARATH
559
0
61445
Swiss-Prot
Mitochondrion (Reliability: 2)
D2HDH_BOVIN
544
0
59056
Swiss-Prot
Secretory Pathway (Reliability: 5)
D2HDH_DANRE
533
0
58714
Swiss-Prot
Mitochondrion (Reliability: 2)
D2HDH_HUMAN
521
0
56416
Swiss-Prot
Mitochondrion (Reliability: 2)
D2HDH_MOUSE
535
0
58576
Swiss-Prot
Mitochondrion (Reliability: 1)
D2HDH_ORYSI
559
0
61129
Swiss-Prot
Mitochondrion (Reliability: 1)
D2HDH_ORYSJ
559
0
61097
Swiss-Prot
Mitochondrion (Reliability: 1)
D2HDH_PSEU5
Pseudomonas stutzeri (strain A1501)
464
0
51086
Swiss-Prot
-
D2HDH_RAT
535
0
58805
Swiss-Prot
Mitochondrion (Reliability: 1)
D2HDH_XANCL
Xanthomonas citri pv. viticola (strain LMG 965 / NCPPB 2475 / ICMP 3867 / CFBP 7660)
472
0
51032
Swiss-Prot
-
A0A812B3T4_SEPPH
1020
0
113540
TrEMBL
other Location (Reliability: 1)
A0A369QBB9_9SPHN
482
0
50899
TrEMBL
-
A0A7R8D0I4_LEPSM
376
0
41764
TrEMBL
other Location (Reliability: 5)
A0A6J8EE57_MYTCO
513
0
56567
TrEMBL
Mitochondrion (Reliability: 2)
A0A2G9HE49_9LAMI
497
0
54501
TrEMBL
Mitochondrion (Reliability: 1)
Q7K511_DROME
533
0
58364
TrEMBL
Mitochondrion (Reliability: 1)
A0A8B6E6B9_MYTGA
126
0
13900
TrEMBL
other Location (Reliability: 5)
A0A1J0LJ95_9FLAO
467
0
53435
TrEMBL
-
Q9I6H4_PSEAE
Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1)
464
0
51287
TrEMBL
-
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
homodimer
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
I147S
D-2-hydroxyglutaric aciduria disease-related variant. The cofactor binding site is compromised by the single amino acid replacement. The variant forms aggregates that are unable to bind the FAD cofactor
V444A
D-2-hydroxyglutaric aciduria disease-related variant. The cofactor binding site is compromised by the single amino acid replacement. The variant forms aggregates that are unable to bind the FAD cofactor
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression in Escherichia coli
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
expression of the enzyme is upregulated in the presence of high endogenous concentrations of (S)-2-hydroxyglutarate
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Struys, E.A.; Korman, S.H.; Salomons, G.S.; Darmin, P.S.; Achouri, Y.; van Schaftingen, E.; Verhoeven, N.M.; Jakobs, C.
Mutations in phenotypically mild D-2-hydroxyglutaric aciduria
Ann. Neurol.
58
626-630
2005
Homo sapiens
brenda
Engqvist, M.; Drincovich, M.F.; Fluegge, U.I.; Maurino, V.G.
Two D-2-hydroxy-acid dehydrogenases in Arabidopsis thaliana with catalytic capacities to participate in the last reactions of the methylglyoxal and beta-oxidation pathways
J. Biol. Chem.
284
25026-25037
2009
Arabidopsis thaliana (O23240), Arabidopsis thaliana
brenda
Araujo, W.L.; Ishizaki, K.; Nunes-Nesi, A.; Larson, T.R.; Tohge, T.; Krahnert, I.; Witt, S.; Obata, T.; Schauer, N.; Graham, I.A.; Leaver, C.J.; Fernie, A.R.
Identification of the 2-hydroxyglutarate and isovaleryl-CoA dehydrogenases as alternative electron donors linking lysine catabolism to the electron transport chain of Arabidopsis mitochondria
Plant Cell
22
1549-1563
2010
Arabidopsis thaliana
brenda
Lin, A.P.; Abbas, S.; Kim, S.W.; Ortega, M.; Bouamar, H.; Escobedo, Y.; Varadarajan, P.; Qin, Y.; Sudderth, J.; Schulz, E.; Deutsch, A.; Mohan, S.; Ulz, P.; Neumeister, P.; Rakheja, D.; Gao, X.; Hinck, A.; Weintraub, S.T.; DeBerardinis, R.J.; Sill, H.; Dahia, P.L.; Aguiar, R.C.
D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2
Nat. Commun.
6
7768
2015
Homo sapiens (Q8N465)
brenda
Quaye, J.A.; Gadda, G.
Kinetic and bioinformatic characterization of D-2-hydroxyglutarate dehydrogenase from Pseudomonas aeruginosa PAO1
Biochemistry
59
4833-4844
2020
Pseudomonas aeruginosa (Q9I6H4), Pseudomonas aeruginosa
brenda
Toplak, M.; Brunner, J.; Schmidt, J.; Macheroux, P.
Biochemical characterization of human D-2-hydroxyglutarate dehydrogenase and two disease related variants reveals the molecular cause of D-2-hydroxyglutaric aciduria
Biochim. Biophys. Acta
1867
140255
2019
Homo sapiens (Q8N465), Homo sapiens
brenda
Guo, X.; Zhang, M.; Cao, M.; Zhang, W.; Kang, Z.; Xu, P.; Ma, C.; Gao, C.
D-2-Hydroxyglutarate dehydrogenase plays a dual role in L-serine biosynthesis and D-malate utilization in the bacterium Pseudomonas stutzeri
J. Biol. Chem.
293
15513-15523
2018
Pseudomonas stutzeri, Pseudomonas stutzeri A1501
brenda
Zhang, W.; Zhang, M.; Gao, C.; Zhang, Y.; Ge, Y.; Guo, S.; Guo, X.; Zhou, Z.; Liu, Q.; Zhang, Y.; Ma, C.; Tao, F.; Xu, P.
Coupling between D-3-phosphoglycerate dehydrogenase and D-2-hydroxyglutarate dehydrogenase drives bacterial L-serine synthesis
Proc. Natl. Acad. Sci. USA
114
E7574-E7582
2017
Pseudomonas stutzeri, Pseudomonas stutzeri A1501
brenda
Berger, R.S.; Ellmann, L.; Reinders, J.; Kreutz, M.; Stempfl, T.; Oefner, P.J.; Dettmer, K.
Degradation of D-2-hydroxyglutarate in the presence of isocitrate dehydrogenase mutations
Sci. Rep.
9
7436
2019
Homo sapiens (Q8N465)
brenda
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Release 2023.1 (January 2023)
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