Information on EC 2.1.1.20 - glycine N-methyltransferase

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The expected taxonomic range for this enzyme is: Euteleostomi

EC NUMBER
COMMENTARY
2.1.1.20
-
RECOMMENDED NAME
GeneOntology No.
glycine N-methyltransferase
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
S-adenosyl-L-methionine + glycine = S-adenosyl-L-homocysteine + sarcosine
show the reaction diagram
mechanism
-
S-adenosyl-L-methionine + glycine = S-adenosyl-L-homocysteine + sarcosine
show the reaction diagram
enzyme is also a polycyclic aromatic hydrocarbon binding protein
-
S-adenosyl-L-methionine + glycine = S-adenosyl-L-homocysteine + sarcosine
show the reaction diagram
N-terminal acetylation or deprotonation is required for cooperative reaction mechanism
-
S-adenosyl-L-methionine + glycine = S-adenosyl-L-homocysteine + sarcosine
show the reaction diagram
homodimer of enzyme acts as polycyclic aromatic hydrocarbon binding protein involved in cytochrome P-450IA1 expression
-
S-adenosyl-L-methionine + glycine = S-adenosyl-L-homocysteine + sarcosine
show the reaction diagram
overview mechanism
-
S-adenosyl-L-methionine + glycine = S-adenosyl-L-homocysteine + sarcosine
show the reaction diagram
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
methyl group transfer
-
-
-
-
PATHWAY
KEGG Link
MetaCyc Link
glycine betaine biosynthesis IV (from glycine)
-
glycine betaine biosynthesis V (from glycine)
-
Glycine, serine and threonine metabolism
-
SYSTEMATIC NAME
IUBMB Comments
S-adenosyl-L-methionine:glycine N-methyltransferase
This enzyme is thought to play an important role in the regulation of methyl group metabolism in the liver and pancreas by regulating the ratio between S-adenosyl-L-methionine and S-adenosyl-L-homocysteine. It is inhibited by 5-methyltetrahydrofolate pentaglutamate [4]. Sarcosine, which has no physiological role, is converted back into glycine by the action of EC 1.5.8.3, sarcosine dehydrogenase.
SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
4S polycyclic aromatic hydrocarbon binding protein
-
-
glycine methyltransferase
-
-
-
-
glycine methyltransferase
-
-
glycine methyltransferase
-
-
glycine methyltransferase
-
-
glycine N-methyltransferase
-
-
glycine-N methyltransferase
-
-
GNMT
-
-
-
-
GNMT
-
-
GNMT
Q14749
-
GNMT
Q9QXF8
-
GNMT
-
-
GNMT
Q9QXF8
-
Gnmt gene product
-
-
methyltransferase, glycine
-
-
-
-
S-adenosyl-L-methionine:glycine methyltransferase
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY
37228-72-1
-
ORGANISM
COMMENTARY
LITERATURE
SEQUENCE CODE
SEQUENCE DB
SOURCE
; prostate cancer patients and normal control individuals
-
-
Manually annotated by BRENDA team
cholangiocarcinoma patients
-
-
Manually annotated by BRENDA team
normal enzyme and naturally occurring H176N mutation which is found in humans with hypermethioninaemia
UniProt
Manually annotated by BRENDA team
recombinant enzyme
-
-
Manually annotated by BRENDA team
three cases of GNMT mutations known, all suffering from mild liver disease and display elevated methionine levels
-
-
Manually annotated by BRENDA team
women
-
-
Manually annotated by BRENDA team
-
SwissProt
Manually annotated by BRENDA team
construction of -/- and +/- knockout mutants
-
-
Manually annotated by BRENDA team
construction of GNMT knockout mice, loss of enzyme results in highly elevated levels of free methionine and S-adenosyl-L-methionine
SwissProt
Manually annotated by BRENDA team
male, construction of GNMT knockout mice
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
malfunction
-
Gnmt knockout mice develop hepatocellular carcinoma, hemangioma, dysplastic nodules, fatty nodules and lung metastasis, DNA methyltransferase activity is decreased in 11 weeks old Gnmt knockout mice, the MAPK pathway is activated in female Gnmt knockout mice
malfunction
-
Gnmt knockout mice develop fatty livers when they have increased S-adenosyl-L-methionine
malfunction
-
siRNA mediated GNMT knockdown results in an inhibition of proliferation, and induces G1 arrest and apoptosis in prostate cancer cell lines. Patients with high GNMT cytoplasmic expression showed significantly lower disease-free survival rates than patients with low expression
malfunction
-
overexpression of GNMT causes activation of mTOR/raptor downstream signaling and delays G2/M cell cycle progression, which altogether results in cellular senescence
metabolism
-
GNMT is involved in both hepatic methyl group and one-carbon metabolism
physiological function
-
GNMT plays a major role in maintaining normal S-adenosyl-L-methionine levels
physiological function
-
GNMT is a tumor suppressor for hepatocellular carcinoma cells and it exerts protective effects in hepatocytes via direct interaction with aflatoxin B1, resulting in reduced aflatoxin B1-DNA adducts formation and cell death
physiological function
-
using HepG2 -/- cells and HepG2 cells overexpressing GNMT it is shown that GNMT in is involved in methyl group homeostasis by regulating transmethylation kinetics and DNA methylation
physiological function
-
GNMT regulates hepatocellular growth in part through interacting with DEPDC6/DEPTOR and modulating mTOR/raptor signaling pathway
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + sarcosine
show the reaction diagram
-
-
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + sarcosine
show the reaction diagram
-
-
-
-
-
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + sarcosine
show the reaction diagram
-
-
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + sarcosine
show the reaction diagram
-
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + sarcosine
show the reaction diagram
-
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + sarcosine
show the reaction diagram
-
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + sarcosine
show the reaction diagram
-
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + sarcosine
show the reaction diagram
-
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + sarcosine
show the reaction diagram
-
-
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + sarcosine
show the reaction diagram
-
-
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + sarcosine
show the reaction diagram
-
strict specificity for glycine as methyl acceptor
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + sarcosine
show the reaction diagram
-
strict specificity for glycine as methyl acceptor
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + sarcosine
show the reaction diagram
-
regulates the ratio of S-adenosylmethionine to S-adenosylhomocysteine
-
-
-
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + sarcosine
show the reaction diagram
-
the enzyme regulates the methyl group supply for S-adenosylmethionine-dependent transmethylation reactions. All-trans-retinoic acid rapidly induces glycine N-methyltransferase in a dose-dependent manner and reduces circulating methionine and homocysteine levels in rats
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + sarcosine
show the reaction diagram
-
mechanism: the bound S-adenosyl-L-methionine is firmly connected to protein and a Gly pocket" is created near the bound S-adenosyl-L-methionine. The second substrate Gly binds to Arg175 and is brought into the Gly pocket. Five hydrogen bonds connect the Gly in the proximity of the bound S-adenosyl-L-methionine and orient the lone pair orbital on the amino nitrogen of Gly towards the donor methyl group of S-adenosyl-L-methionine. Thermal motion of the enzyme leads to a collision of the N and C(E) so that a SN2 methyltransfer reaction occurs
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + sarcosine
show the reaction diagram
-
mechanism: the bound S-adenosyl-L-methionine is firmly connected to protein and a Gly pocket" is created near the bound S-adenosyl-L-methionine. The second substrate Gly binds to Arg175 and is brought into the Gly pocket. Five hydrogen bonds connect the Gly in the proximity of the bound S-adenosyl-L-methionine and orient the lone pair orbital on the amino nitrogen of Gly towards the donor methyl group of S-adenosyl-L-methionine. Thermal motion of the enzyme leads to a collision of the N and C(E) so that a SN2 methyltransfer reaction occurs
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
-
-
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
-
-
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
-
-
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
-
-
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
-
-
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
-
-
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
Q9QXF8
-
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
Q9QXF8
-
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
-
-
N-methylglycine = sarcosine
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
Q14749
-
N-methylglycine = sarcosine
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
-
key regulatory enzyme for methyl group metabolism by regulating the S-adenosyl-L-methionine/S-adenosyl-L-homocysteine ratio
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
-
key regulatory enzyme for methyl group metabolism by regulating the S-adenosyl-L-methionine/S-adenosyl-L-homocysteine ratio
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
Q9QXF8
key regulatory enzyme for methyl group metabolism by regulating the S-adenosyl-L-methionine/S-adenosyl-L-homocysteine ratio
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
-
key enzyme for the regulation of the ratio of S-adenosylmethionine to S-adenosylhomocysteine
N-methylglycine = sarcosine
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
-
key enzyme for the regulation of the ratio of S-adenosylmethionine to S-adenosylhomocysteine
N-methylglycine = sarcosine
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
-
key enzyme for the regulation of the ratio of S-adenosylmethionine to S-adenosylhomocysteine
N-methylglycine = sarcosine
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
Q14749
key enzyme for the regulation of the ratio of S-adenosylmethionine to S-adenosylhomocysteine
N-methylglycine = sarcosine
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
-
key enzyme for the regulation of the ratio of S-adenosylmethionine to S-adenosylhomocysteine, affects genetic stability by regulating DNA methylation and interacting with environmental carcinogens
N-methylglycine = sarcosine
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
-
key enzyme for the regulation of the ratio of S-adenosylmethionine to S-adenosylhomocysteine, affects genetic stability by regulating DNA-methylation, key role in the one-carbon metabolism pathway
N-methylglycine = sarcosine
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
-
key enzyme for the regulation of the ratio of S-adenosylmethionine to S-adenosylhomocysteine, control of the methylating potential of the cell
N-methylglycine = sarcosine
-
?
additional information
?
-
-
all-trans-retinoic acid and dexamethasone independently induce GNMT in liver, no effect on enzyme from pancreas
-
-
-
additional information
?
-
-
interaction of benzo(a)pyrene with the enzyme may contribute to carcinogenesis
-
-
-
additional information
?
-
-
major folate binding protein
-
-
-
additional information
?
-
-
major folate binding protein
-
-
-
additional information
?
-
-
major folate binding protein
-
-
-
additional information
?
-
Q14749
major folate binding protein
-
-
-
additional information
?
-
-
major folate binding protein, interacts with environmental carcinogens such as benzo(a)pyrene
-
-
-
additional information
?
-
-
major folate binding protein, involved in the regulation of the expression of S-adenosylhomocysteine hydrolase and formiminotransferase cyclodeaminase, binds benzo(a)pyrene and prevents DNA-adduct formation
-
-
-
additional information
?
-
Q9QXF8
GNMT is phosphorylated by cAMP-dependent protein kinase at Ser9, Ser71, Ser139, Ser182, and Ser241
-
-
-
additional information
?
-
-
a mammalian target of rapamycin (mTOR) inhibitor (DEP domain containing MTOR-interacting protein [DEPDC6/DEPTOR]) is identified as a GNMT-binding protein by using yeast two-hybrid screening. The C-terminal half of GNMT interacts with the PSD-95/Dlg1/ZO-1 (PDZ) domain of DEPDC6/DEPTOR
-
-
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + sarcosine
show the reaction diagram
-
regulates the ratio of S-adenosylmethionine to S-adenosylhomocysteine
-
-
-
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + sarcosine
show the reaction diagram
-
the enzyme regulates the methyl group supply for S-adenosylmethionine-dependent transmethylation reactions. All-trans-retinoic acid rapidly induces glycine N-methyltransferase in a dose-dependent manner and reduces circulating methionine and homocysteine levels in rats
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
-
key regulatory enzyme for methyl group metabolism by regulating the S-adenosyl-L-methionine/S-adenosyl-L-homocysteine ratio
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
-
key regulatory enzyme for methyl group metabolism by regulating the S-adenosyl-L-methionine/S-adenosyl-L-homocysteine ratio
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
Q9QXF8
key regulatory enzyme for methyl group metabolism by regulating the S-adenosyl-L-methionine/S-adenosyl-L-homocysteine ratio
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
-
key enzyme for the regulation of the ratio of S-adenosylmethionine to S-adenosylhomocysteine
N-methylglycine = sarcosine
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
-
key enzyme for the regulation of the ratio of S-adenosylmethionine to S-adenosylhomocysteine
N-methylglycine = sarcosine
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
-
key enzyme for the regulation of the ratio of S-adenosylmethionine to S-adenosylhomocysteine
N-methylglycine = sarcosine
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
Q14749
key enzyme for the regulation of the ratio of S-adenosylmethionine to S-adenosylhomocysteine
N-methylglycine = sarcosine
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
-
key enzyme for the regulation of the ratio of S-adenosylmethionine to S-adenosylhomocysteine, affects genetic stability by regulating DNA methylation and interacting with environmental carcinogens
N-methylglycine = sarcosine
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
-
key enzyme for the regulation of the ratio of S-adenosylmethionine to S-adenosylhomocysteine, affects genetic stability by regulating DNA-methylation, key role in the one-carbon metabolism pathway
N-methylglycine = sarcosine
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
show the reaction diagram
-
key enzyme for the regulation of the ratio of S-adenosylmethionine to S-adenosylhomocysteine, control of the methylating potential of the cell
N-methylglycine = sarcosine
-
?
additional information
?
-
-
all-trans-retinoic acid and dexamethasone independently induce GNMT in liver, no effect on enzyme from pancreas
-
-
-
additional information
?
-
-
interaction of benzo(a)pyrene with the enzyme may contribute to carcinogenesis
-
-
-
additional information
?
-
-
major folate binding protein
-
-
-
additional information
?
-
-
major folate binding protein
-
-
-
additional information
?
-
-
major folate binding protein
-
-
-
additional information
?
-
Q14749
major folate binding protein
-
-
-
additional information
?
-
-
major folate binding protein, interacts with environmental carcinogens such as benzo(a)pyrene
-
-
-
additional information
?
-
-
major folate binding protein, involved in the regulation of the expression of S-adenosylhomocysteine hydrolase and formiminotransferase cyclodeaminase, binds benzo(a)pyrene and prevents DNA-adduct formation
-
-
-
additional information
?
-
-
a mammalian target of rapamycin (mTOR) inhibitor (DEP domain containing MTOR-interacting protein [DEPDC6/DEPTOR]) is identified as a GNMT-binding protein by using yeast two-hybrid screening. The C-terminal half of GNMT interacts with the PSD-95/Dlg1/ZO-1 (PDZ) domain of DEPDC6/DEPTOR
-
-
-
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
2'-deoxyadenosine
-
-
3-deazaadenosine
-
-
5'-N-ethylcarboxamidoadenosine
-
-
5'-S-isobutylthio-5'-deoxyadenosine
-
-
5'-[p-(fluorosulfonyl)benzoyl]adenosine
-
-
5,5'-dithiobis(2-nitrobenzoate)
-
-
5-methyl-tetrahydrofolate
-
-
5-methyl-tetrahydrofolate
Q9QXF8
-
5-methyl-tetrahydrofolate
-
-
5-methyl-tetrahydrofolate
Q9QXF8
-
5-methyltetrahydrofolate
-
-
5-Methyltetrahydrofolate hexaglutamate
-
-
5-methyltetrahydrofolate monoglutamate
-
native N-acetylated form of the enzyme shows 50% inhibition at 0.05 mM while the recombinant non-acetylated form shows 50% inhibition at 1.89 mM
5-Methyltetrahydrofolate pentaglutamate
-
native N-acetylated form of the enzyme shows 50% inhibition at 0.0013 mM while the recombinant non-acetylated form shows 50% inhibition at 0.59 mM
5-Methyltetrahydrofolate pentaglutamate
-
-
5-Methyltetrahydrofolate pentaglutamate
-
-
5-Methyltetrahydrofolate pentaglutamate
-
-
5-Methyltetrahydrofolate pentaglutamate
-
noncompetitive inhibitor with respect to substrates S-adenosyl-L-methionine and glycine
5-Methyltetrahydrofolate pentaglutamate
Q9QXF8
noncompetitive inhibitor regarding substrates S-adenosyl-L-methionine and glycine
5-Methyltetrahydrofolate pentaglutamate
-
noncompetitive inhibitor with respect to substrates S-adenosyl-L-methionine and glycine
5-Methyltetrahydrofolate pentaglutamate
Q9QXF8
noncompetitive inhibitor with respect to substrates S-adenosyl-L-methionine and glycine
5-Methyltetrahydrofolate triglutamate
-
-
5-methyltetrahydrofolic acid
-
-
5-Methyltetrahydropteroylpentaglutamate
-
-
5-Methyltetrahydropteroylpentaglutamate
-
-
5-Methyltetrahydropteroylpentaglutamate
-
-
folinic acid
-
-
Gly
-
at very high concentrations
p-chloromercuribenzoate
-
-
S-adenosyl-L-homocysteine
-
-
S-adenosyl-L-homocysteine
-
weak
thioglycolic acid
-
weak
methotrexate
-
-
additional information
-
folate-containing diets attenuate GNMT activity in diabetic rats but are without effect on abundance
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
Glucagon
-
elevates GNMT activity
phosphate
-
in vitro phosphorylation increases activity, about 0.55 mol of phosphate present per mol of N-methyltransferase subunit
KM VALUE [mM]
KM VALUE [mM] Maximum
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.0122
-
Gly
-
pH 7.5, 25C, wild-type enzyme
0.02
-
Gly
-
pH 7.5, 25C, mutant enzyme H176N
0.0721
-
Gly
-
pH 7.5, 25C, mutant enzyme L49P
0.24
-
Gly
-
pH 7.2, mutant enzyme Y21F
0.43
-
Gly
-
pH 7.2, wild-type enzyme
0.44
-
Gly
-
pH 7.2, mutant enzyme Y242F
2.8
-
Gly
-
pH 7.2, mutant enzyme Y194F
25
-
Gly
-
pH 7.2, mutant enzyme Y33F
30
-
Gly
-
pH 7.2, mutant enzyme Y220F
0.13
-
glycine
-
-
1.2
-
glycine
-
pH 7.5, 25C, recombinant enzyme
1.9
-
glycine
-
pH 7.5, 25C, native enzyme
0.014
-
S-adenosyl-L-methionine
-
pH 7.2, mutant enzyme Y220F
0.017
-
S-adenosyl-L-methionine
-
pH 7.2, mutant enzyme Y33F
0.032
-
S-adenosyl-L-methionine
-
pH 7.2, mutant enzyme Y242F
0.035
-
S-adenosyl-L-methionine
-
pH 7.2, mutant enzyme Y194F
0.036
-
S-adenosyl-L-methionine
-
pH 7.2, wild-type enzyme
0.042
-
S-adenosyl-L-methionine
-
pH 7.2, mutant enzyme Y21F
0.12
-
S-adenosyl-L-methionine
-
pH 7.5, 25C, mutant enzyme L49P
0.2
-
S-adenosyl-L-methionine
-
pH 8.6
0.242
-
S-adenosyl-L-methionine
-
pH 7.5, 25C, mutant enzyme H176N
0.281
-
S-adenosyl-L-methionine
-
pH 7.5, 25C, wild-type enzyme
0.03
-
S-adenosylmethionine
-
-
0.1
-
S-adenosylmethionine
-
-
TURNOVER NUMBER [1/s]
TURNOVER NUMBER MAXIMUM[1/s]
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.105
-
Gly
-
pH 7.2, mutant enzyme Y21F
0.18
-
Gly
-
pH 7.2, mutant enzyme Y194F; pH 7.2, mutant enzyme Y220F
0.21
-
Gly
-
pH 7.2, mutant enzyme Y33F
0.35
-
Gly
-
pH 7.5, 25C, mutant enzyme L49P
0.45
-
Gly
-
pH 7.2, wild-type enzyme
0.47
-
Gly
-
pH 7.2, mutant enzyme Y242F
1.19
-
Gly
-
pH 7.5, 25C, mutant enzyme H176N
1.6
-
Gly
-
pH 7.5, 25C, wild-type enzyme
0.7
-
glycine
-
pH 7.5, 25C, native enzyme
51.9
-
glycine
-
pH 7.5, 25C, recombinant enzyme
0.105
-
S-adenosyl-L-methionine
-
pH 7.2, mutant enzyme Y21F
0.18
-
S-adenosyl-L-methionine
-
pH 7.2, mutant enzyme Y194F; pH 7.2, mutant enzyme Y220F
0.21
-
S-adenosyl-L-methionine
-
pH 7.2, mutant enzyme Y33F
0.35
-
S-adenosyl-L-methionine
-
pH 7.5, 25C, mutant enzyme L49P
0.45
-
S-adenosyl-L-methionine
-
pH 7.2, wild-type enzyme
0.47
-
S-adenosyl-L-methionine
-
pH 7.2, mutant enzyme Y242F
1.19
-
S-adenosyl-L-methionine
-
pH 7.5, 25C, mutant enzyme H176N
1.6
-
S-adenosyl-L-methionine
-
pH 7.5, 25C, wild-type enzyme
Ki VALUE [mM]
Ki VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.38
-
2'-deoxyadenosine
-
pH 8.6
0.9
-
3-deazaadenosine
-
pH 8.6
0.51
-
5'-N-ethylcarboxamidoadenosine
-
pH 8.6
0.056
-
5'-S-isobutylthio-5'-deoxyadenosine
-
pH 8.6
0.28
-
aciclovir
-
pH 8.6
0.21
-
adenosine
-
pH 8.6
0.03
-
S-adenosyl-L-homocysteine
-
pH 8.6
IC50 VALUE [mM]
IC50 VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.001
-
5-Methyltetrahydrofolate pentaglutamate
-
at pH 9.0
0.0013
-
5-Methyltetrahydrofolate pentaglutamate
-
native enzyme
0.002
-
5-Methyltetrahydrofolate pentaglutamate
-
at pH 7.5
0.59
-
5-Methyltetrahydrofolate pentaglutamate
-
recombinant enzyme
SPECIFIC ACTIVITY [µmol/min/mg]
SPECIFIC ACTIVITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
additional information
-
-
-
pH OPTIMUM
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
7.5
-
-
assay pH
8
-
Q14749
assay pH
pH RANGE
pH RANGE MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
7.5
9.5
-
pH 7.5: about 40% of maximal activity, pH 9.5: about 45% of maximal activity
TEMPERATURE OPTIMUM
TEMPERATURE OPTIMUM MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
25
-
-
assay temperature
25
-
Q14749
assay temperature
37
-
-
assay at
pI VALUE
pI VALUE MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
6.6
-
-
calculation from nucleotide sequence
7.1
-
-
calculation from nucleotide sequence
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
-
high expression in normal tissue, reduced expression in tumorous tissue, some tumor samples show no enzyme expression
Manually annotated by BRENDA team
D3GAN3, -
in unfertilized, 2 days postfertilization, and 3 days postfertilization embryos GNMT is constitutively higher than in 4, 7, 10 or 14 days postfertilization embryos
Manually annotated by BRENDA team
-
expresses very low levels of GNMT
Manually annotated by BRENDA team
-
higher expression level in female than in male mice
Manually annotated by BRENDA team
-
kidney cDNA library is used
Manually annotated by BRENDA team
-
activity of GNMT is increased about 2fold in diabetic liver
Manually annotated by BRENDA team
-
normal liver, not present in hepatocellular carcinoma
Manually annotated by BRENDA team
-
high expression in normal tissue, only 4% of hepatocellular carcinoma show GNMT expression
Manually annotated by BRENDA team
-
abundant GNMT expression; high GNMT-expression in normal prostatic and benign prostatic hyperplasia tissues, whereas it was diminished in 82% of the prostate cancer tissues
Manually annotated by BRENDA team
-
36.4% of tissues show loss of heterozygosity of the GNMT gene, GNMT expression diminished in 82.2% of tissues
Manually annotated by BRENDA team
-
LNCaP cells and PC-3 cells
Manually annotated by BRENDA team
-
DNA extracted from peripherial blood cells
Manually annotated by BRENDA team
additional information
-
overview on tissue distribution
Manually annotated by BRENDA team
additional information
-
tissue distribution
Manually annotated by BRENDA team
additional information
-
abundant GNMT expression in benign prostatic hyperplasia tissue
Manually annotated by BRENDA team
additional information
-
SCG2-1-1 cell, expresses high levels of GNMT
Manually annotated by BRENDA team
additional information
-
not detected in brain
Manually annotated by BRENDA team
additional information
-
no GNMT activity is detected in fetal liver, Novikoff hepatoma cells, Morris hepatoma cells, and Ehrlich ascites cells
Manually annotated by BRENDA team
additional information
Q9QXF8
no GNMT activity is detected in fetal liver, Novikoff hepatoma cells, Morris hepatoma cells, and Ehrlich ascites cells
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
GNMT is expressed in cytoplasm before treatment with benzo(a)pyrene and translocated to cell nuclei after treatment with benzo(a)pyrene
Manually annotated by BRENDA team
-
concentrated in the paranuclear region near the bile duct lumen
Manually annotated by BRENDA team
-
GNMT is expressed in cytoplasm before treatment with benzo(a)pyrene and translocated to cell nuclei after treatment with benzo(a)pyrene
Manually annotated by BRENDA team
-
GNMT is translocated into nuclei after aflatoxin B1 treatment
Manually annotated by BRENDA team
additional information
-
overview on subcellular localization
-
Manually annotated by BRENDA team
MOLECULAR WEIGHT
MOLECULAR WEIGHT MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
32420
79000
-
mass spectrometry, mass spectra of the proteins greatly depend on the method of sample preparation and storage
123500
-
-
sedimentation equilibrium centrifugation
130000
132000
-
sedimenation equilibrium centrifugation, gel filtration
130000
-
-
gel filtration
130000
-
-
gel filtration
130000
-
-
gel filtration
130000
-
-
gel filtration
130000
-
-
-
130000
-
Q9QXF8
-
130000
-
Q9QXF8
-
135000
-
-
gel filtration
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
?
-
x * 34000, rat, SDS-PAGE
homotetramer
-
4 * 32500
tetramer
-
4 * 31500, identical subunits, SDS-PAGE
tetramer
-
4 * 32500, deduced from cDNA, crystal structure
tetramer
-
crystallographic studies; crystal structure analysis
tetramer
Q14749
crystal structure analysis, in the presence of moderate (2-4 M) urea concentrations the tetrameric enzyme dissociates into compact monomers, higher concentrations of urea (7-8 M) promote complete denaturation of enzyme
trimer or tetramer
-
3 or 4 * 27000-33000, nonidentical subunits, SDS-PAGE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
phosphoprotein
-
GNMT is phosphorylated by cAMP-dependent protein kinase at Ser9, Ser71, Ser139, Ser182, and Ser241
glycoprotein
-
4 residues of sialic acid and 2 residues of hexose per mol of protein
phosphoprotein
-
GNMT is phosphorylated by cAMP-dependent protein kinase at Ser9, Ser71, Ser139, Ser182, and Ser241
acetylated protein
-
N-terminal valine of native GNMT is N-acetylated while in the recombinant enzyme it is not
phosphoprotein
-
GNMT is phosphorylated by cAMP-dependent protein kinase at Ser9, Ser71, Ser139, Ser182, and Ser241
phosphoprotein
Q9QXF8
GNMT is phosphorylated by cAMP-dependent protein kinase at Ser9, Ser71, Ser139, Ser182, and Ser241
Crystallization/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
crystals are grown at 4C by hanging drop vapor diffusion method
-
wild type and H176N mutant enzyme as cocrystals with a citrate molecule bound in the active site
Q14749
crystals are grown at 22C by hanging drop vapor diffusion method, crystallized in two crystal forms, a monoclinic form and a tetragonal form, P2(1) and P4(1)2(1)2
-
crystallized by the sitting drop method in complex with (6S)-5-methyltetrahydrofolat monoglutamate; GNMT complexed with 5-methyltetrahydrofolate, by the sitting drop method at room temperature, two folate binding sites in the intersubunit areas of the tetramer, each folate binding site is formed primarily by two 1-7 N-terminal regions of one pair of subunits and two 205-218 regions of the other pair of subunits. Both the pteridine and p-aminobenzoyl rings are located in the hydrophobic cavities formed by Tyr5, Leu207, and Met215 residues of all subunits; sitting-drop vapor diffusion method in complex with 5-methyltetrahydrofolate pentaglutamate, two molecules of inhibitor bound to a tetramer
-
hanging drop method of vapor diffusion, crystal structure of the enzyme complexed with S-adenosyl-L-methionine and acetate (a potent competitive inhibitor of Gly) and the R175K mutated enzyme complexed with S-adenosyl-L-methionine are determined at 2.8 A and 3.0 A resolution, respectively
-
including R175K mutant
-
GENERAL STABILITY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
urea unfolding of GNMT is a two-step process. The first transition is a reversible dissociation of the GNMT tetramer to compact monomers in 1.0-3.5 M urea with enzyme inactivation. The second step of GNMT unfolding is a reversible transition of monomers from compact to a fully unfolded state with R(S) of 50 A, exposed tryptophan residues, and disrupted secondary structure in 8 M urea
-
ORGANIC SOLVENT
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
urea
Q14749
H176N mutant completely inactive at 2 M urea compared with 60% remaining activity of the wild type enzyme
STORAGE STABILITY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
4C, 5.0 mM DTT, 2.0 mM EDTA, 0.02% NaN3, stable for at least 2 weeks
-
Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
recombinant enzymes
Q14749
by ammonium sulfate precipitation and gel filtration; recombinant protein
-
from liver by anion and cation exchange chromatography and from isolated hepatocytes and liver tissue by immunoprecipitation
-
native enzyme from rat liver and recombinant enzyme from Escherichia coli
-
-
Q9QXF8
Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
from adult liver
D3GAN3, -
expressed in Mus musculus liver and kidney
-
expression in Escherichia coli
-
full-length human GNMT is used as the bait in a yeast two-hybrid screen system with a human kidney cDNA library
-
overexpression of GNMT in SCG2-1-1 cells
-
overview
-
PC-3 cells, LNCaP cells, HA22T/VGH cells and HEK-293A cells transfected with plasmid containing haplotype C
-
when expressed in pTYB vector as a fusion protein with intein and the chitin binding domain, a cleavage of intein is found. The cleavage takes place at two sites near the N-terminus of intein and results in the appearance of an abnormal GNMT protein after one-column cleavage of the fusion protein, which can not be separated from normal GNMT. For this reason expression is done in the vector pET-17b. Expression of soluble protein in Escherichia coli at about 20-40 mg/L
-
wild type and H176N mutant enzyme
Q14749
wild-type and mutant enzymes H176N, L49P and N140S, expressed in Escherichia coli
-
cloning of the gene and construction of enzyme deficient mice
Q9QXF8
overview
-
when expressed in pTYB vector as a fusion protein with intein and the chitin binding domain, a cleavage of intein is found. The cleavage takes place at two sites near the N-terminus of intein and results in the appearance of an abnormal GNMT protein after one-column cleavage of the fusion protein, which can not be separated from normal GNMT. For this reason expression is done in the vector pET-17b. Expression of soluble protein in Escherichia coli at about 20-40 mg/L
-
expressed in Escherichia coli
-
expressed in Escherichia coli BL21(DE3); expressed in Escherichia coli BL21(GE3); into pET-17b vector and expressed in Escherichia coli BL21(GE3)
-
when expressed in pTYB vector as a fusion protein with intein and the chitin binding domain, a cleavage of intein is found. The cleavage takes place at two sites near the N-terminus of intein and results in the appearance of an abnormal GNMT protein after one-column cleavage of the fusion protein, which can not be separated from normal GNMT. For this reason expression is done in the vector pET-17b. Expression of soluble protein in Escherichia coli at about 20-40 mg/L
-
-
Q9QXF8
EXPRESSION
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
GNMT expression is down-regulated or even completely blocked in liver and prostate tumor tissue
-
benzo[a]pyrene treatment of HepG2 cells (0.001 or 0.01 mM) induces GNMT expression
-
GNMT expression is down-regulated or even completely blocked in liver and prostate tumor tissue
-
ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
DELTA171-295
-
to map the interactive domain of GNMT plasmids containing different domains GNMT are constructed: The C-terminal 171-295 amino acid fragment of GNMT is identified as interactive domain
H176N
-
mutant enzyme possesses 75% activity of the wild-type enzyme
H176N
Q14749
naturally occurring mutation, 25% less activity and highly reduced stability compared with the native enzyme, completely inactive at 2 M urea compared with 60% remaining activity of the wild type enzyme
H176N
-
the mutant activity decreases 25% regarding Vmax
L149P
-
the mutant is inactivated by 90%
N140S
-
mutant enzyme possesses less than 5% activity of the wild-type enzyme
R175K
-
crystal structure: N-terminal domains of subunits have moved out of the active sites of adjacent subunits
Y194F
-
the ratio of turnover-number to KM-value for S-adenosyl-L-methionine is 2.4fold lower than the wild-type value, the ratio of turnover-number to KM-value for Gly is 16.4fold lower than the wild-type value
Y21F
-
the ratio of turnover-number to KM-value for S-adenosyl-L-methionine is 5fold lower than the wild-type value, the ratio of turnover-number to KM-value for Gly is 2.4fold lower than the wild-type value
Y220F
-
the ratio of turnover-number to KM-value for S-adenosyl-L-methionine is nearly identical to the wild-type value, the ratio of turnover-number to KM-value for Gly is 179fold lower than the wild-type value
Y242F
-
the ratio of turnover-number to KM-value for S-adenosyl-L-methionine is 1.14fold higher than the wild-type value, the ratio of turnover-number to KM-value for Gly is 2325fold lower than the wild-type value
Y33F
-
the ratio of turnover-number to KM-value for S-adenosyl-L-methionine is nearly identical to the wild-type value, the ratio of turnover-number to KM-value for Gly is 123fold lower than the wild-type value
L49P
-
mutant enzyme possesses 10% activity of the wild-type enzyme
additional information
-
patients with mutations Leu49Pro and His176Asn suffer from mild liver disease
N140S
-
the mutant possesses only traces of wild type activity
additional information
-
construction of GNMT knockout mice, knockout mice have elevated serum aminotransferase, methionine, and S-adenosyl-L-methionine levels and develop liver steatosis, fibrosis, and hepatocellular carcinoma, loss of GNMT induces aberrant methylation of DNA and histones, resulting in epigenetic modulation of critical carcinogenic pathways, several Ras and JAK/STAT inhibitors are reduced in liver tumors of enzyme knockout mice
additional information
-
construction of -/- and +/- knockout mutants, Gnmt -/- mice show hepatomegaly, hypermethioninemia, and significantly higher levels of serum alanine aminotransferase and hepatic S-adenosylmethionine, down regulation of S-adenosylhomocysteine hydrolase and formiminotransferase cyclodeaminase, abnormally high glycogen accumulation in liver, hypoglycemia, increased serum cholesterol, and significantly lower numbers of white blood cells, neutrophils, and monocytes, some genes of gluconeogenesis enzyme significantly down regulated in Gnmt -/- mice
APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
diagnostics
-
partially suitable to distinguish between benign and malign tumor forms
diagnostics
-
enzyme level suitable as prognostic marker for human cholangiocarcinoma and hepatocellular carcinoma
medicine
-
patients with mutations Leu49Pro and His176Asn suffer from mild liver disease
medicine
-
GNMT is a tumor susceptibility gene for prostate cancer, three major GNMT haplotypes in our populations, haplotype C conferred protection from the development of prostate cancer and exhibits the highest promoter activity
medicine
-
GNMT 1289 C->T polymorphism influences plasma homocysteine and is responsive to folate intake, plasma homocysteine concentrations do not differ among the GNMT C1289T genotypes at baseline. After folate restriction, women with the GNMT 1289 TT genotype have higher homocysteine concentrations than women with the CT or CC genotype. The influence of the GNMT 1289 C->T variant on homocysteine is dependent on the MTHFR C677T genotype. In subjects with the MTHFR 677 CC genotype, homocysteine is greater for GNMT 1289 TT subjects relative to 1289 CT or CC subjects. In subjects with the MTHFR 677 TT genotype, plasma homocysteine concentrations do not differ among the GNMT C1289T genotypes
medicine
-
GNMT sequesters benzo[a]pyrene, diminishes benzo[a]pyrene's effects to the liver detoxification pathway and prevents subsequent cytotoxicity
medicine
-
glycine N-methyltransferase is a tumor susceptibility gene for both hepatocellular carcinoma and prostate cancer
medicine
-
GNMT may represent a novel marker of malignant progression and poor prognosis in prostate cancer
medicine
-
GNMT is a tumor suppressor gene for liver cancer, and is associated with gender disparity in liver cancer susceptibility
medicine
-
vitamin A may induce enzyme, induction by all-trans-retinoic acid can lead to impairment of essential transmethylation processes
medicine
-
feeding with excess methionine leads to upregulation of hepatic enzyme
medicine
-
activation and induction of enzyme by retinoids are tissue- and gender-specific
medicine
-
all-trans-retinoic acid and dexamethasone independently induce GNMT in liver, thereby having substantial implications for the potential interaction of retinoic administration with diabetes
medicine
-
diabetes increases the activity and abundance of GNMT, lack of dietary folate results in the highest activity of GNMT in diabetic rats without the abundance of the protein being altered
additional information
-
phosphorylated serine residues 71, 182, and 241, in GNMT prepared from liver tissue and hepatocytes an S9 additional residue is phosphorylated, in hepatocytes and in recombinant GNMT S139 is detected, serine 9 is also identified as a target for cAMP-dependent protein kinase in vitro, positions of these phosphorylated residues in the tertiary structure of GNMT indicate their possible effect on enzyme conformation and activity