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Information on EC 1.5.8.4 - dimethylglycine dehydrogenase and Organism(s) Homo sapiens and UniProt Accession Q9UI17
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1.5.8.4 dimethylglycine dehydrogenaseIUBMB Comments
A flavoprotein, containing a histidyl(Npi)-(8alpha)FAD linkage at position 91 in the human protein. An imine intermediate is channeled from the FAD binding site to the 5,6,7,8-tetrahydrofolate binding site through a 40 A tunnel [5,8,9]. In the absence of 5,6,7,8-tetrahydrofolate the enzyme forms formaldehyde [5,9].
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The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Reaction Schemes
Synonyms
dimethylglycine dehydrogenase, dmgdh, me2glydh, csal_0990, n,n-dimethylglycine oxidase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
Me2GlyDH
-
-
-
-
N,N-dimethylglycine oxidase
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
-
-
-
-
oxidation
-
-
-
-
reduction
-
-
-
-
oxidative deamination
-
-
-
-
PATHWAY SOURCE
PATHWAYS
BRENDA
-
-
SYSTEMATIC NAME
IUBMB Comments
N,N-dimethylglycine,5,6,7,8-tetrahydrofolate:electron-transferflavoprotein oxidoreductase (demethylating,5,10-methylenetetrahydrofolate-forming)
A flavoprotein, containing a histidyl(Npi)-(8alpha)FAD linkage at position 91 in the human protein. An imine intermediate is channeled from the FAD binding site to the 5,6,7,8-tetrahydrofolate binding site through a 40 A tunnel [5,8,9]. In the absence of 5,6,7,8-tetrahydrofolate the enzyme forms formaldehyde [5,9].
CAS REGISTRY NUMBER
COMMENTARY
37256-30-7
-
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
N,N-dimethylglycine + 5,6,7,8-tetrahydrofolate + electron-transfer flavoprotein
sarcosine + 5,10-methylenetetrahydrofolate + reduced electron-transfer flavoprotein
N,N-dimethylglycine + ferricenium + H2O
sarcosine + formaldehyde + ferrocene
-
-
-
?
N,N-dimethylglycine + H2O + ferrocene
sarcosine + formaldehyde + ?
-
-
-
?
N,N-dimethylglycine + H2O + oxidized 2,6-dichlorophenolindophenol
sarcosine + formaldehyde + reduced 2,6-dichlorophenolindophenol
-
-
-
?
N,N-dimethylglycine + electron-transfer flavoprotein + H2O
sarcosine + formaldehyde + reduced electron-transfer flavoprotein
-
-
-
?
N,N-dimethylglycine + ferricenium hexafluorophosphate + H2O
sarcosine + formaldehyde + reduced ferricenium hexafluorophosphate
-
-
-
-
?
N,N-dimethylglycine + 5,6,7,8-tetrahydrofolate + electron-transfer flavoprotein
sarcosine + 5,10-methylenetetrahydrofolate + reduced electron-transfer flavoprotein
the enzyme takes part in choline degradation, one-carbon metabolism and electron transfer to the respiratory chain
-
-
?
N,N-dimethylglycine + 5,6,7,8-tetrahydrofolate + electron-transfer flavoprotein
sarcosine + 5,10-methylenetetrahydrofolate + reduced electron-transfer flavoprotein
ferrocene or 2,6-dichlorophenolindophenol are used as artificial electron acceptor
-
-
?
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
N,N-dimethylglycine + 5,6,7,8-tetrahydrofolate + electron-transfer flavoprotein
sarcosine + 5,10-methylenetetrahydrofolate + reduced electron-transfer flavoprotein
the enzyme takes part in choline degradation, one-carbon metabolism and electron transfer to the respiratory chain
-
-
?
N,N-dimethylglycine + electron-transfer flavoprotein + H2O
sarcosine + formaldehyde + reduced electron-transfer flavoprotein
-
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
FAD
A280/A450 ratios of the highly pure protein fractions are between 14-16 and 20-25 for wild-type and mutant H109R, respectively. The redox potential for the reduction of FAD is -93 mV
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.3
N,N-dimethylglycine
25°C, pH 7.8, artificial electron acceptor: 2,6-dichlorophenolindophenol, wild-type enzyme
0.3
N,N-dimethylglycine
wild type enzyme, with 2,6-dichlorophenolindophenol as cosubstrate, at 25°C and pH 7.8 in 50 mM HEPES/NaOH with 150 mM NaCl
1.4
N,N-dimethylglycine
25°C, pH 7.8, artificial electron acceptor: ferrocene, wild-type enzyme
1.4
N,N-dimethylglycine
wild type enzyme, with ferrocene as cosubstrate, at 25°C and pH 7.8 in 50 mM HEPES/NaOH with 150 mM NaCl
4.7
N,N-dimethylglycine
25°C, pH 7.8, artificial electron acceptor: 2,6-dichlorophenolindophenol, mutant enzyme H109R
4.7
N,N-dimethylglycine
mutant enzyme H109R, with 2,6-dichlorophenolindophenol as cosubstrate, at 25°C and pH 7.8 in 50 mM HEPES/NaOH with 150 mM NaCl
32.2
N,N-dimethylglycine
25°C, pH 7.8, artificial electron acceptor: ferrocene, mutant enzyme H109R
32.2
N,N-dimethylglycine
mutant enzyme H109R, with ferrocene as cosubstrate, at 25°C and pH 7.8 in 50 mM HEPES/NaOH with 150 mM NaCl
0.045
N,N-dimethylglycine
-
and second value 1.10 mM, wild-type, presence of tetrahydrofolate, pH 7.5, 25°C
1.1
N,N-dimethylglycine
-
and first value 0.045 mM, wild-type, presence of tetrahydrofolate, pH 7.5, 25°C
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.73
N,N-dimethylglycine
wild type enzyme, with 2,6-dichlorophenolindophenol as cosubstrate, at 25°C and pH 7.8 in 50 mM HEPES/NaOH with 150 mM NaCl
0.733
N,N-dimethylglycine
25°C, pH 7.8, artificial electron acceptor: 2,6-dichlorophenolindophenol, wild-type enzyme
1.5
N,N-dimethylglycine
25°C, pH 7.8, artificial electron acceptor: 2,6-dichlorophenolindophenol, mutant enzyme H109R
1.52
N,N-dimethylglycine
mutant enzyme H109R, with 2,6-dichlorophenolindophenol as cosubstrate, at 25°C and pH 7.8 in 50 mM HEPES/NaOH with 150 mM NaCl
3.55
N,N-dimethylglycine
25°C, pH 7.8, artificial electron acceptor: ferrocene, wild-type enzyme
3.55
N,N-dimethylglycine
wild type enzyme, with ferrocene as cosubstrate, at 25°C and pH 7.8 in 50 mM HEPES/NaOH with 150 mM NaCl
9.07
N,N-dimethylglycine
mutant enzyme H109R, with ferrocene as cosubstrate, at 25°C and pH 7.8 in 50 mM HEPES/NaOH with 150 mM NaCl
9.1
N,N-dimethylglycine
25°C, pH 7.8, artificial electron acceptor: ferrocene, mutant enzyme H109R
0.225
N,N-dimethylglycine
-
wild-type, presence of tetrahydrofolate, pH 7.5, 25°C
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.18
N,N-dimethylglycine
mutant enzyme H109R, with ferrocene as cosubstrate, at 25°C and pH 7.8 in 50 mM HEPES/NaOH with 150 mM NaCl
0.28
N,N-dimethylglycine
25°C, pH 7.8, artificial electron acceptor: ferrocene, mutant enzyme H109R
0.32
N,N-dimethylglycine
25°C, pH 7.8, artificial electron acceptor: 2,6-dichlorophenolindophenol, mutant enzyme H109R
0.33
N,N-dimethylglycine
mutant enzyme H109R, with 2,6-dichlorophenolindophenol as cosubstrate, at 25°C and pH 7.8 in 50 mM HEPES/NaOH with 150 mM NaCl
2.28
N,N-dimethylglycine
wild type enzyme, with ferrocene as cosubstrate, at 25°C and pH 7.8 in 50 mM HEPES/NaOH with 150 mM NaCl
2.43
N,N-dimethylglycine
wild type enzyme, with 2,6-dichlorophenolindophenol as cosubstrate, at 25°C and pH 7.8 in 50 mM HEPES/NaOH with 150 mM NaCl
2.44
N,N-dimethylglycine
25°C, pH 7.8, artificial electron acceptor: 2,6-dichlorophenolindophenol, wild-type enzyme
2.54
N,N-dimethylglycine
25°C, pH 7.8, artificial electron acceptor: ferrocene, wild-type enzyme
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
rare natural mutation H109R, causes dimethylglycine dehydrogenase deficiency leading to increased blood and urinary dimethylglycine concentrations
metabolism
physiological function
the enzyme suppresses metastasis in hepatocellular carcinoma
physiological function
metabolism
the enzyme takes part in choline degradation, one-carbon metabolism and electron transfer to the respiratory chain
metabolism
the phosphorylation of Akt-308/473 is significantly suppressed when the enzyme is overexpressed
physiological function
dimethylglycine dehydrogenase expression suppresses metastasis through the Akt signaling pathway
physiological function
DMGDH suppresses migration, invasion and metastasis both in vitro and in vivo. In a DMGDH over-expressing cell line, the phosphorylation of Akt-308/473 is significantly suppressed
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). M2GD_HUMAN
866
0
96811
Swiss-Prot
Mitochondrion (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystallization of the wild-type enzyme and determination of the structure to 3.1A resolution, microbatch method using different commercial crystallization screens
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
H109R
H109R
-
natural polymorphism identified in a dimethylglycine dehydrogenase-deficient patient. Mutant shows only 47% of the wild-type level of bound flavin, a 27fold decrease in specific activity and a 65fold increase in Km value
H109R
rare natural variant, mutation leads to decreased protein stability, cofactor saturation, and substrate affinity
H109R
rare natural variant, suffers from decreased protein stability, cofactor saturation, and substrate affinity and causes dimethylglycine dehydrogenase deficiency leading to increased blood and urinary dimethylglycine concentrations
H109R
the mutation causes dimethylglycine dehydrogenase deficiency leading to increased blood and urinary dimethylglycine concentrations
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
47
52
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
development of an intracellular, heterologous expression system in Komagataella phaffii (formerly known as Pichia pastoris). Initial attempts to express the gene in Escherichia coli (BL21 DE3) yielded largely insoluble protein. The H109R variant is expressed in lower amounts compared to the wild-type enzyme
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
diagnostics
the enzyme may be a valuable biomarker of hepatocellular carcinoma diagnosis
medicine
the enzyme may be a valuable biomarker of hepatocellular carcinoma diagnosis
medicine
medicine
expression of DMGDH is decreased in hepatocellular carcinoma. the enzyme can be applied as valuable biomarker for both diagnosis and prognosis
medicine
the enzyme is biomarker for both diagnosis and prognosis for hepatocellular carcinoma
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
McAndrew, R.P.; Vockley, J.; Kim, J.J.
Molecular basis of dimethylglycine dehydrogenase deficiency associated with pathogenic variant H109R
J. Inherit. Metab. Dis.
31
761-768
2008
Homo sapiens
Augustin, P.; Hromic, A.; Pavkov-Keller, T.; Gruber, K.; Macheroux, P.
Structure and biochemical properties of recombinant human dimethylglycine dehydrogenase and comparison to the disease-related H109R variant
FEBS J.
283
3587-3603
2016
Homo sapiens (Q9UI17), Homo sapiens
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