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Information on EC 2.1.1.20 - glycine N-methyltransferase and Organism(s) Mus musculus and UniProt Accession Q9QXF8
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2.1.1.20 glycine N-methyltransferaseIUBMB Comments
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 . Sarcosine, which has no physiological role, is converted back into glycine by the action of EC 1.5.8.3, sarcosine dehydrogenase.
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Word Map
- 2.1.1.20
- s-adenosylmethionine
- s-adenosylhomocysteine
- homocysteine
- folate
- sarcosine
-
adenosyltransferase
- cystathionine
-
transmethylation
- adomet
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betaine-homocysteine
-
remethylation
- beta-synthase
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one-carbon
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transsulfuration
- 5-methyltetrahydrofolate
- medicine
-
folate-dependent
- n-methylglycine
-
s-methyltransferase
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glycine-n-methyltransferase
- guanidinoacetate
-
folate-deficient
- pentaglutamate
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pah-binding
-
adohcy
- diagnostics
The taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Synonyms
gnmt, glycine n-methyltransferase, glycine methyltransferase, s-adenosyl-l-methionine:glycine n-methyltransferase, glycine-n methyltransferase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
glycine methyltransferase
GNMT
methyltransferase, glycine
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-
-
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S-adenosyl-L-methionine:glycine methyltransferase
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-
-
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glycine methyltransferase
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-
-
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GNMT
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-
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
S-adenosyl-L-methionine + glycine = S-adenosyl-L-homocysteine + sarcosine
overview mechanism
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
methyl group transfer
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-
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PATHWAY SOURCE
PATHWAYS
BRENDA
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-, -
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.
CAS REGISTRY NUMBER
COMMENTARY
37228-72-1
-
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
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
-
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
-
-
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
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
-
-
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
-
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
-
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 + sarcosine
-
-
-
-
?
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + sarcosine
-
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
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-
?
additional information
?
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GNMT is phosphorylated by cAMP-dependent protein kinase at Ser9, Ser71, Ser139, Ser182, and Ser241
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-
?
additional information
?
-
-
GNMT is phosphorylated by cAMP-dependent protein kinase at Ser9, Ser71, Ser139, Ser182, and Ser241
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-
?
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
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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
S-adenosyl-L-methionine + glycine
S-adenosyl-L-homocysteine + N-methylglycine
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
-
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
-
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
-
?
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
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
5-Methyltetrahydrofolate pentaglutamate
noncompetitive inhibitor regarding substrates S-adenosyl-L-methionine and glycine
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
construction of GNMT knockout mice, loss of enzyme results in highly elevated levels of free methionine and S-adenosyl-L-methionine
SwissProt
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
GNMT is expressed in the epithelium of the colon under normal conditions, and with dextran sulfate sodium treatment, its expression is predominant in infiltrated leukocytes of lesions
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GNMT is expressed in the epithelium of the colon under normal conditions, and with dextran sulfate sodium treatment, its expression is predominant in infiltrated leukocytes of lesions
additional information
additional information
no GNMT activity is detected in fetal liver, Novikoff hepatoma cells, Morris hepatoma cells, and Ehrlich ascites cells
additional information
-
no GNMT activity is detected in fetal liver, Novikoff hepatoma cells, Morris hepatoma cells, and Ehrlich ascites cells
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
malfunction
metabolism
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GNMT is involved in both hepatic methyl group and one-carbon metabolism
physiological function
physiological function
experimental autoimmune encephalomyelitis severity is reduced significantly in Gnmt-/- mice. Gnmt-/- mice have significantly lower levels of mononuclear cell infiltration and demyelination than the wild-type mice. Expression levels of proinflammatory cytokines, including interferon-gamma and interleukin 17A, are much lower in the spinal cord of Gnmt-/- than in that of wild-type mice. Myelin oligodendrocyte glycoprotein-specific T-cell proliferation and induction of T-helper Th1 and Th17 cells are markedly suppressed in myelin oligodendrocyte glycoprotein-induced Gnmt-/- mice. The number of regulatory T cells is significantly increased in these mice
physiological function
GNMT affects transmethylation kinetics and S-adenosylmethionine synthesis, and facilitates the conservation of methyl groups by limiting homocysteine remethylation fluxes. Restoring GNMT assists methylfolate-dependent reactions and ameliorates the consequences of folate depletion. GNMT expression in vivo improves folate retention and bioavailability in the liver. Loss of GNMT impairs nucleotide biosynthesis. Over-expression of GNMT enhances nucleotide biosynthesis and improves DNA integrity by reducing uracil misincorporation in DNA both in vitro and in vivo
physiological function
in the liver of liver-specific IRS1 KO mice, expression of GNMT is increased
malfunction
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Gnmt knockout mice develop fatty livers when they have increased S-adenosyl-L-methionine
malfunction
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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
physiological function
-
GNMT plays a major role in maintaining normal S-adenosyl-L-methionine levels
physiological function
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mice with genetic deletion of GNMT show increased susceptibility to dextran sulfate sodium induction of colitis. Severe colonic inflammation, including increased crypt loss, leukocyte infiltration, and hemorrhage, are greater with dextran sulfate sodium treatment in GNMT?/? than wild-type mice. The expression of adhesion molecule and inflammatory mediators in the colon is significantly higher with dextran sulfate sodium treatment in GNMT?/? than wild-type mice. Loss of GNMT decreases cell apoptosis in colitis lesions with dextran sulfate sodium treatment
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). GNMT_MOUSE
293
0
32675
Swiss-Prot
other Location (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
130000
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystals are grown at 22°C 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
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
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
additional information
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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
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
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
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
GNMT expression is down-regulated or even completely blocked in liver and prostate tumor tissue
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
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GNMT is a tumor suppressor gene for liver cancer, and is associated with gender disparity in liver cancer susceptibility
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Ogawa, H.; Gomi, T.; Takusagawa, F.; Fujioka, M.
Structure, function and physiological role of glycine N-methyltransferase
Int. J. Biochem. Cell Biol.
30
13-26
1998
Homo sapiens, Mus musculus, Oryctolagus cuniculus, Rattus norvegicus
Aida, K.; Tawata, M.; Negishi, M.; Onaya, T.
Mouse glycine N-methyltransferase is sexually dimorphic and regulated by growth hormone
Horm. Metab. Res.
29
646-649
1997
Mus musculus
Luka, Z.; Wagner, C.
Expression and purification of glycine N-methyltransferases in Escherichia coli
Protein Expr. Purif.
28
280-286
2003
Homo sapiens, Mus musculus, Rattus norvegicus
Pakhomova, S.; Luka, Z.; Grohmann, S.; Wagner, C.; Newcomer, M.E.
Glycine N-methyltransferases: a comparison of the crystal structures and kinetic properties of recombinant human, mouse and rat enzymes
Proteins
57
331-337
2004
Homo sapiens, Mus musculus
Luka, Z.; Capdevila, A.; Mato, J.M.; Wagner, C.
A glycine N-methyltransferase knockout mouse model for humans with deficiency of this enzyme
Transgenic Res.
15
393-397
2006
Homo sapiens, Mus musculus (Q9QXF8), Mus musculus
Martinez-Chantar, M.L.; Vazquez-Chantada, M.; Ariz, U.; Martinez, N.; Varela, M.; Luka, Z.; Capdevila, A.; Rodriguez, J.; Aransay, A.M.; Matthiesen, R.; Yang, H.; Calvisi, D.F.; Esteller, M.; Fraga, M.; Lu, S.C.; Wagner, C.; Mato, J.M.
Loss of the glycine N-methyltransferase gene leads to steatosis and hepatocellular carcinoma in mice
Hepatology
47
1191-1199
2008
Mus musculus
Liu, S.; Li, Y.; Chen, Y.; Chiang, E.; Li, A.F.; Lee, Y.; Tsai, T.; Hsiao, M.; Huang, S.; Chen, Y.A.
Glycine N-methyltransferase -/- mice develop chronic hepatitis and glycogen storage disease in the liver
Hepatology
47
768-769
2008
Mus musculus
-
Liao, Y.J.; Liu, S.P.; Lee, C.M.; Yen, C.H.; Chuang, P.C.; Chen, C.Y.; Tsai, T.F.; Huang, S.F.; Lee, Y.H.; Chen, Y.M.
Characterization of a glycine N-methyltransferase gene knockout mouse model for hepatocellular carcinoma: Implications of the gender disparity in liver cancer susceptibility
Int. J. Cancer
124
816-826
2009
Mus musculus
Luka, Z.; Mudd, S.H.; Wagner, C.
Glycine N-methyltransferase and regulation of S-adenosylmethionine levels
J. Biol. Chem.
284
22507-22511
2009
Danio rerio, Oryctolagus cuniculus, Homo sapiens, Mus musculus, Sus scrofa, Rattus norvegicus (P13255)
Luka, Z.
Methyltetrahydrofolate in folate-binding protein glycine N-methyltransferase
Vitam. Horm.
79
325-345
2008
Oryctolagus cuniculus, Homo sapiens, Rattus norvegicus, Sus scrofa (Q29555), Mus musculus (Q9QXF8), Mus musculus
Chou, W.Y.; Zhao, J.F.; Chen, Y.M.; Lee, K.I.; Su, K.H.; Shyue, S.K.; Lee, T.S.
Role of glycine N-methyltransferase in experimental ulcerative colitis
J. Gastroenterol. Hepatol.
29
494-501
2014
Mus musculus
Li, C.H.; Lin, M.H.; Chu, S.H.; Tu, P.H.; Fang, C.C.; Yen, C.H.; Liang, P.I.; Huang, J.C.; Su, Y.C.; Sytwu, H.K.; Chen, Y.M.
Role of glycine N-methyltransferase in the regulation of T-cell responses in experimental autoimmune encephalomyelitis
Mol. Med.
20
684-696
2014
Mus musculus (Q9QXF8)
Tain, L.S.; Jain, C.; Nespital, T.; Froehlich, J.; Hinze, Y.; Groenke, S.; Partridge, L.
Longevity in response to lowered insulin signaling requires glycine N-methyltransferase-dependent spermidine production
Aging Cell
19
e13043
2019
Mus musculus (Q9QXF8), Drosophila melanogaster (Q9VG42)
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