Any feedback?
Information on EC 2.1.1.5 - betaine-homocysteine S-methyltransferase and Organism(s) Homo sapiens and UniProt Accession Q93088
for references in articles please use BRENDA:EC2.1.1.5Please wait a moment until all data is loaded. This message will disappear when all data is loaded.
EC Tree
2.1.1.5 betaine-homocysteine S-methyltransferaseSpecify your search results
Word Map
- 2.1.1.5
- cystathionine
- s-adenosylmethionine
- choline
- folate
-
remethylation
- hyperhomocysteinemia
- s-adenosylhomocysteine
-
adenosyltransferase
- n-methyltransferase
-
one-carbon
- beta-synthase
- dimethylglycine
-
transsulfuration
- methylenetetrahydrofolate
-
5-methyltetrahydrofolate-homocysteine
-
transmethylation
- medicine
- mthfd1
- guanidinoacetate
-
homocysteine-induced
-
folate-dependent
- homocystinuria
- 5-methyltetrahydrofolate
-
transcobalamin
-
b-vitamins
-
slc19a1
- hypotaurine
- molecular biology
- analysis
- nutrition
- food industry
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
Synonyms
betaine-homocysteine methyltransferase, betaine-homocysteine s-methyltransferase, betaine homocysteine methyltransferase, bhmt2, betaine:homocysteine methyltransferase, bhmt-2, bhmt1, betaine homocysteine s-methyltransferase, betaine-homocysteine s-methyltransferase 2, betaine:homocysteine s-methyltransferase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
betaine-homocysteine methyltransferase
betaine-homocysteine S-methyltransferase
betaine-homocysteine transmethylase
-
-
-
-
BHMT
methyltransferase, betaine-homocysteine
-
-
-
-
betaine-homocysteine methyltransferase
-
-
-
-
BHMT
-
-
-
-
BHMT
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
methyl group transfer
-
-
-
-
PATHWAY SOURCE
PATHWAYS
BRENDA
-
-, -, -
SYSTEMATIC NAME
IUBMB Comments
trimethylammonioacetate:L-homocysteine S-methyltransferase
-
CAS REGISTRY NUMBER
COMMENTARY
9029-78-1
-
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
L-Asp + dimethylsulfonioacetate
?
-
using the non-physiological methyl donor dimethylsulfonioacetate an O-methylation of Asp is performed by BHMT, but only in the presence of beta-mercaptoethanol
-
-
?
L-homocysteine + betaine
L-methionine + dimethylglycine
-
-
-
-
?
L-homocysteine + S-methyl-L-methionine
?
-
BHMT-2 uses S-methylmethionine as a methyl donor for the methylation of homocysteine. Unlike BHMT, BHMT-2 can not use betaine
-
-
?
N,N,N-trimethylglycine + L-homocysteine
N,N-dimethylglycine + L-methionine
-
-
-
?
N,N,N-trimethylglycine + L-homocysteine
N,N-dimethylglycine + L-methionine
-
-
-
?
N,N,N-trimethylglycine + L-homocysteine
N,N-dimethylglycine + L-methionine
-
i.e. betaine, methyl transfer directly from one substrate to the other
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
K+
Km value around 0.1 mM. The presence of potassium ions lowers the apparent KM of the enzyme for homocysteine, but it does not affect the apparent KM for betaine or the apparent kcat for either substrate
Zinc
wild-type enzyme contains zinc. Mutant enzymes H338A, R346A, W352A, R361A, P362A, Y363A, N364A, P365A maintain normal or near-normal ability to bind zinc
Zn2+
Zn2+
-
wild-type enzyme contains catalytic active zinc which is bound by three thiolates and one hydroxyl group. Long-term exposure of BHMT to reducing agent-free buffer results in the slow, irreversible loss of its catalytic Zn and a corresponding loss of activity
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
5-[3-(R,S)-3-amino-3-(hydroxyphosphorylpropyl)sulfanyl]-3,3-dimethylpentanoic acid
-
H2O2
causes a loss of catalytic Zn and a correlative loss of activity, irreversible
methyl methanethiosulfonate
causes a loss of catalytic Zn and a correlative loss of activity. Addition of beta-mercaptoethanol and exogenous Zn after methyl methanethiosulfonate treatment restores activity
(2S,11RS)-5-thia-2,11-diamino-8,8-dimethyldodecanedioic acid
-
more than 90% inhibition at 0.02 mM
(2S,11RS)-5-thia-2,11-diaminododecanedioic acid
-
about 60% inhibition at 0.02 mM
(2S,11S)-5,8-dithia-2,11-diaminododecanedioic acid
-
about 60% inhibition at 0.02 mM
(2S,5RS,8RS,11S)-5,8-dithia-2,11-diaminododecanedioic acid 5,8-dioxide
-
about 20% inhibition at 0.02 mM
(2S,8RS,11RS)-5-thia-2,11-diamino-8-methyldodecanedioic acid
-
competitive, more than 90% inhibition at 0.02 mM
(R,S)-2-(3-amino-3-carboxy-propylsulfanyl)-benzoic acid
-
ca. 43% inhibition at 0.02 mM
(R,S)-2-amino-4-(2-carboxy-ethyldisulfanyl)-butyric acid
-
ca. 30% inhibition at 0.02 mM
(R,S)-2-amino-4-(2-carboxymethylsulfanyl-ethylsulfanyl)-butyric acid
-
100% inhibition at 0.02 mM, very potent inhibitor and one of the strongest ever reported
(R,S)-2-amino-4-(2-carboxymethylsulfinyl-ethylsulfanyl)-butyric acid
-
ca. 90% inhibition at 0.02 mM
(R,S)-2-amino-4-(2-phosphonomethoxy-ethylsulfanyl)-butyrate
-
ca. 26% inhibition at 0.02 mM
(R,S)-2-amino-4-(3-carboxy-propylsulfanyl)-butyric acid
-
ca. 20% inhibition at 0.02 mM
(R,S)-2-amino-4-(4-carboxymethyl-benzylsulfanyl)-butyric acid
-
ca. 10% inhibition at 0.02 mM
(R,S)-2-amino-4-(4-phosphono-butylsulfanyl)-butyric acid
-
ca. 98% inhibition at 0.02 mM
(R,S)-2-amino-4-methylsulfanylmethylsulfanyl-butyric acid
-
ca. 21% inhibition at 0.02 mM
(R,S)-2-amino-4-[(phosphonomethyl-carbamoyl)-methylsulfanyl]-butyrate
-
ca. 9% inhibition at 0.02 mM
(R,S)-3-(3-amino-3-carboxy-propylsulfanyl)-benzoic acid
-
ca. 13% inhibition at 0.02 mM
(R,S)-4-(3-amino-3-carboxy-propylsulfanyl)-benzoic acid
-
ca. 99% inhibition at 0.02 mM
(R,S)-5-(3-amino-3-carboxy-propylsulfanyl)-pentanoic acid
-
100% inhibition at 0.02 mM, very potent inhibitor and one of the strongest ever reported, competitive inhibition with respect to betaine binding
(R,S)-5-(3-amino-3-carboxy-propylsulfinyl)-pentanoic acid
-
ca. 97% inhibition at 0.02 mM
(R,S)-5-(3-amino-3-carboxy-propylsulfonyl)-pentanoic acid
-
ca. 29% inhibition at 0.02 mM
(R,S)-6-(3-amino-3-carboxy-propylsulfanyl)-hexanoic acid
-
100% inhibition at 0.02 mM, very potent inhibitor and one of the strongest ever reported
(R,S,R,S)-2-amino-4-(2-amino-2-carboxy-ethylsulfinyl)-butyric acid
-
ca. 10% inhibition at 0.02 mM
(RS)-2-amino-4-[(2-carboxyethylthio)methylthio]butanoic acid
-
97.6% inhibition at 0.02 mM
(RS)-2-amino-4-[(3-carboxypropyl)disulfanyl]butanoic acid
-
19.1% inhibition at 0.02 mM
(RS)-2-amino-4-[2-(carboxymethylamino)ethylthio]butanoic acid
-
37.1% inhibition at 0.02 mM
(RS)-2-amino-4-[2-(R)-(1-carboxyethylamino)ethylthio]butanoic acid
-
15.5% inhibition at 0.02 mM
(RS)-2-amino-4-[2-(S)-(1-carboxyethylamino)ethylthio]butanoic acid
-
19.8% inhibition at 0.02 mM
(RS)-2-amino-4-[2-[(carboxymethyl)(methyl)amino]ethylthio]-butanoic acid
-
98.5% inhibition at 0.02 mM
(RS)-2-amino-4-[3-[(carboxymethyl)(methyl)amino]propylthio]butanoic acid
-
79.01% inhibition at 0.02 mM
(RS)-2-[[2-(3-amino-3-carboxypropylthio)ethyl]dimethylammonium]acetate
-
23.8% inhibition at 0.02 mM
(RS)-2-[[3-(3-amino-3-carboxypropylthio)propyl]dimethylammonio]acetate
-
3.3% inhibition at 0.02 mM
(RS)-5-(3-amino-3-carboxypropylselanyl)pentanoic acid
-
complete inhibition at 0.02 mM
(RS)-5-(3-amino-3-carboxypropylthio)-3,3-dimethylpentanoic acid
-
highly potent inhibitor of BHMT, complete inhibition at 0.02 mM
(RS)-5-(3-amino-3-carboxypropylthio)-3-methylpentanoic acid
-
highly potent inhibitor of BHMT, complete inhibition at 0.02 mM
5-[(3-amino-3-carboxypropyl)sulfanyl]pentanoic acid
-
complete inhibition at 0.02 mM
S-(delta-carboxybutyl)-L-homocysteine
-
at 0.05 mM: 97% inhibition, at 0.5 mM: total inhibition
S-(delta-carboxybutyl)-L-homocysteine
-
weak inhibitor, at 0.5 mM: 26% inhibition
additional information
-
not inhibitory: S-(gamma-carboxypropyl)-DL-homocysteine, S-(beta-carboxyethyl)-DL-homocysteine
-
additional information
-
no inhibition by Ac-Val-DL-Ala-psi[(PO2-)-CH2]-DL-Leu-Cys-NH2, Ac-DL-Ala-psi[(PO2-)-CH2]-DL-Leu-NH2, Ac-Val-DL-Ala-psi[(PO2-)-CH2]-DL-Leu-His
-
additional information
-
not inhibited by (R)-5-(2-amino-2-carboxy-ethylsulfanyl)-pentanoic acid, (R,S)-4-allylsulfanyl-2-amino-butyric acid and (R,S)-2-amino-4-[(phosphonomethyl-carbamoyl)-methylsulfanyl]-butyric acid ester
-
additional information
S-adenosylmethionine decreases BHMT mRNA levels in dose- and time-dependent manner, down-regulates BHMT expression in part by inducing nuclear factor kappaB, which acts as a repressor for the human BHMT gene, the inhibitor is nuclear factor kappaB dependent. 5'-methylthioadenosine decreases BHMT mRNA levels in dose- and time-dependent manner, down-regulates BHMT expression in part by inducing nuclear factor kappaB, which acts as a repressor for the human BHMT gene, the inhibitor has nuclear factor kappaB dependent and -independent mechanisms
-
additional information
-
S-adenosylmethionine decreases BHMT mRNA levels in dose- and time-dependent manner, down-regulates BHMT expression in part by inducing nuclear factor kappaB, which acts as a repressor for the human BHMT gene, the inhibitor is nuclear factor kappaB dependent. 5'-methylthioadenosine decreases BHMT mRNA levels in dose- and time-dependent manner, down-regulates BHMT expression in part by inducing nuclear factor kappaB, which acts as a repressor for the human BHMT gene, the inhibitor has nuclear factor kappaB dependent and -independent mechanisms
-
additional information
-
not inhibited by (RS)-2-[[(3-amino-3-carboxypropylthio)methyl]dimethylammonium] acetate and (RS)-2-amino-4-[2-(2-carboxyethylamino)ethylthio]butanoic acid
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
beta-mercaptoethanol
-
using a redox-inert methyl acceptor, it is shown that BHMT requires a thiol reducing agent for activity. Short-term exposure of BHMT to reducing agent-free buffer inactivates the enzyme without causing any loss of its catalytic zinc. Activity can be completely restored by the re-addition of a thiol reducing agent
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
3.4
S-methyl-L-methionine
wild-type, presence of 150 mM KCl, pH 7.5, 37°C
2.3
L-homocysteine
wild-type, cosubstrate S-methylmethionine, presence of 150 mM KCl, pH 7.5, 37°C
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0044
S-methyl-L-methionine
wild-type, presence of 150 mM KCl, pH 7.5, 37°C
0.0003
L-homocysteine
wild-type, cosubstrate S-methylmethionine, presence of 150 mM KCl, pH 7.5, 37°C
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000077
(2S,8RS,11RS)-5-thia-2,11-diamino-8-methyldodecanedioic acid
-
IC50 for betaine-homocysteine S-methyltransferase about 0.077 mM, pH 7.5, 37°C
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000093
5-(3-amino-3-carboxy-propylsulfanyl)-pentanoic acid
Homo sapiens
pH not specified in the publication, temperature not specified in the publication
0.0011
5-[3-(R,S)-3-amino-3-(hydroxyphosphorylpropyl)sulfanyl]-3,3-dimethylpentanoic acid
Homo sapiens
pH not specified in the publication, temperature not specified in the publication
0.005
5-[3-(R,S)-3-amino-3-(hydroxyphosphorylpropyl)sulfanyl]pentanoic acid
Homo sapiens
pH not specified in the publication, temperature not specified in the publication
0.000096
(R,S)-2-amino-4-(2-carboxymethylsulfanyl-ethylsulfanyl)-butyric acid
Homo sapiens
-
-
0.00326
(RS)-2-amino-4-[(2-carboxyethylthio)methylthio]butanoic acid
Homo sapiens
-
in 50 mM potassium phosphate buffer, at pH 7.5, at 37°C
0.0025
(RS)-2-amino-4-[2-[(carboxymethyl)(methyl)amino]ethylthio]-butanoic acid
Homo sapiens
-
in 50 mM potassium phosphate buffer, at pH 7.5, at 37°C
0.000649
(RS)-5-(3-amino-3-carboxypropylselanyl)pentanoic acid
Homo sapiens
-
in 50 mM potassium phosphate buffer, at pH 7.5, at 37°C
0.000084
(RS)-5-(3-amino-3-carboxypropylthio)-3,3-dimethylpentanoic acid
Homo sapiens
-
in 50 mM potassium phosphate buffer, at pH 7.5, at 37°C
0.000139
(RS)-5-(3-amino-3-carboxypropylthio)-3-methylpentanoic acid
Homo sapiens
-
in 50 mM potassium phosphate buffer, at pH 7.5, at 37°C
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
additional information
-
no activity in phytohemagglutinin-stimulated human peripheral blood lymphocytes and cultured human skin fibroblasts
additional information
-
no expression of BHMT2 protein is detected in liver or kidney although BHMT2 mRNA expression is observed
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
-
betaine homocysteine methyltransferase is a potential cargo-based end-point marker for macroautophagy
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). BHMT1_HUMAN
406
0
44998
Swiss-Prot
other Location (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
45000
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
tetramer
wild-type enzyme and mutant enzymes E266A, H338A, R346A, R361A, P362A, N364A and P365A
tetramer
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
molecular dynamics simulations predict that K+ ions interact with residues Asp26 and/or Glu159. Crystal structure of BHMT bound to homocysteine confirms these sites of interaction and reveals further contacts between K+ ions and BHMT residues Gly27, Gln72, Gln247, and Gly298
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
DELTA325-406
truncation mutatnt does not express well in Escherichia coli and is inactive
DELTA371-406
truncation mutant does not express well in Escherichia coli and is inactive
H338A
normal or near-normal ability to bind zinc, 10% of the wild-type activity
N364A
normal or near-normal ability to bind zinc, near-normal catalytic activity
P362A
normal or near-normal ability to bind zinc, near-normal catalytic activity
P365A
normal or near-normal ability to bind zinc, near-normal catalytic activity
R346A
normal or near-normal ability to bind zinc, negligible activity, elution as dimer, aberrant crosslinking properties
R361A
normal or near-normal ability to bind zinc, near-normal catalytic activity
W352A
negligible activity, elution as dimer, aberrant crosslinking properties
Y363A
normal or near-normal ability to bind zinc, near-normal catalytic activity
A66V
-
nonsynonymous SNP identified using 240 DNA samples from four ethnic groups
Arg16Cys
-
nonsynonymous SNP identified using 240 DNA samples from four ethnic groups, Km (mM): 0.0139 (betaine), 0.0076 (L-homocysteine)
Arg239Gln
-
nonsynonymous SNP identified using 240 DNA samples from four ethnic groups, Km (mM): 0.012 (betaine), 0.0158 (L-homocysteine)
C104A
-
site-directed mutagenesis is used to investigate whether the loss of the DMSA-Asp activity of BHMT when in the absence of a reducing agent is due to the oxidation of an essential thiol within the protein. By individual mutation of each of the five Cys residues not involved in Zn binding to Ala, it is shown that the resulting mutants are as active as wild-type enzyme when in the presence of beta-mercaptoethanol with the DMSA-Asp assay
C131A
-
site-directed mutagenesis is used to investigate whether the loss of the DMSA-Asp activity of BHMT when in the absence of a reducing agent is due to the oxidation of an essential thiol within the protein. By individual mutation of each of the five Cys residues not involved in Zn binding to Ala, it is shown that the resulting mutants are as active as wild-type enzyme when in the presence of beta-mercaptoethanol with the DMSA-Asp assay
C186A
-
site-directed mutagenesis is used to investigate whether the loss of the DMSA-Asp activity of BHMT when in the absence of a reducing agent is due to the oxidation of an essential thiol within the protein. By individual mutation of each of the five Cys residues not involved in Zn binding to Ala, it is shown that the resulting mutants are as active as wild-type enzyme when in the presence of beta-mercaptoethanol with the DMSA-Asp assay
C201A
-
site-directed mutagenesis is used to investigate whether the loss of the DMSA-Asp activity of BHMT when in the absence of a reducing agent is due to the oxidation of an essential thiol within the protein. By individual mutation of each of the five Cys residues not involved in Zn binding to Ala, it is shown that the resulting mutants are as active as wild-type enzyme when in the presence of beta-mercaptoethanol with the DMSA-Asp assay
C217A
-
the mutation reduces zinc binding by 95% while abrogating catalytic activity, the mutation has no effect on the fold increase of GST-BHMT proteolytic fragment in the absence of nutrients
C256A
-
site-directed mutagenesis is used to investigate whether the loss of the DMSA-Asp activity of BHMT when in the absence of a reducing agent is due to the oxidation of an essential thiol within the protein. By individual mutation of each of the five Cys residues not involved in Zn binding to Ala, it is shown that the resulting mutants are as active as wild-type enzyme when in the presence of beta-mercaptoethanol with the DMSA-Asp assay
Cys217Ala
-
complete loss of activity, reduction in zinc binding, identification of zinc binding motif
Cys299Ala
-
complete loss of activity, reduction in zinc binding, identification of zinc binding motif
Cys300Ala
-
complete loss of activity, reduction in zinc binding, identification of zinc binding motif
G742A
-
in an ongoing, multicenter, case-control study including women with a clinical diagnosis of abruption an association between the homozygous mutant form of BHMT (742G to A) polymorphism and an increased risk for placental abruption is shown
Gly199Ser
-
nonsynonymous SNP identified using 240 DNA samples from four ethnic groups, Km (mM): 0.0139 (betaine), 0.0206 (L-homocysteine)
Pro197Ser
-
nonsynonymous SNP identified using 240 DNA samples from four ethnic groups, Km (mM): 0.0213 (betaine), 0.0216 (L-homocysteine)
R239Q
-
no significant association with the severity and extent of hyperhomocysteinemia
T218M
-
nonsynonymous SNP identified using 240 DNA samples from four ethnic groups
V155F
-
nonsynonymous SNP identified using 240 DNA samples from four ethnic groups
V237M
-
nonsynonymous SNP identified using 240 DNA samples from four ethnic groups
W352A
-
the mutation disrupts stable BHMT multimerization, the mutant ablates catalytic activity
additional information
additional information
both BHMT transfectants of HepG2 cells and primary mouse hepatocytes with suppressed BHMT are generated. Expression of BHMT in HepG2 cells ameliorates the homocysteine metabolism and inhibits homocysteine-induced glucose-regulated protein 78 (GRP78) and C/EBP-homologous protein (CHOP) and homocysteine-induced cell death. A betaine treatment protects primary mouse hepatocytes from a homocysteine-induced increase in GRP78 and cell death. Homocysteine induces greater CHOP expression (2.7fold) in BHMT small interfering RNA -transfected cells than in a control (1.9fold). Homocysteine-induced cell death is increased by 40% in the siRNA-treated cells in comparison with the control. Apolipoprotein B (apoB) expression is higher and triglycerides and cholesterol is lower in HepG2 expressing BHMT. In primary mouse hepatocytes, homocysteine induces the accumulation of triglycerides and cholesterol, which is reduced in the presence of betaine
additional information
-
random mutagenesis of zinc binding motif, Gly214 is essential
additional information
deletion mutants ranging from -2698 to +33, construct -347/+33 has maximal promoter activity, inhibition in promoter activity by S-adenosylmethionine or 5'-methylthioadenosine most pronounced within this construct, cycloleucine treatment increases the reporter activity driven by the BHMT promoter construct -347/+33 but does not block the ability of 5'-methylthioadenosine to inhibit the BHMT promoter activity and blocks the conversion of 5'-methylthioadenosine into S-adenosylmethionine
additional information
-
deletion mutants ranging from -2698 to +33, construct -347/+33 has maximal promoter activity, inhibition in promoter activity by S-adenosylmethionine or 5'-methylthioadenosine most pronounced within this construct, cycloleucine treatment increases the reporter activity driven by the BHMT promoter construct -347/+33 but does not block the ability of 5'-methylthioadenosine to inhibit the BHMT promoter activity and blocks the conversion of 5'-methylthioadenosine into S-adenosylmethionine
additional information
-
betaine-homocysteine methyltransferase transgenic (Tg) mice are generated. BHMT transgenic mice are resistant to alcohol or high methionine low folate diet-induced hyperhomocysteinemia and liver steatosis indicating that peripheral metabolism of homocysteine protects the liver without a direct effect of BHMT in the liver
additional information
S-adenosylmethionine and 5-methylthioadenosine treatment of HepG2 cells result in a dose- and time-dependent decrease in BHMT mRNA levels, which parallels their effects on the BHMT promoter activity. Maximal suppression is observed with BHMT promoter construct -347/+33, containing a number of NF-kappaB binding sites. S-adenosylmethionine and 5-methylthioadenosine treatment increases NF-kappaB nuclear binding and NF-kappaB-driven luciferasece activities, and increases nuclear binding activity of multiple histone deacetylase co-repressors to the NF-kappaB sites. Overexpression of p50 and p65 decreases BHMT promoter activity, while blocking NF-kappaB activation increases BHMT expression and promoter activity, and prevents S-adenosylmethionine but not 5-methylthioadenosines ability to inhibit BHMT expression
additional information
-
S-adenosylmethionine and 5-methylthioadenosine treatment of HepG2 cells result in a dose- and time-dependent decrease in BHMT mRNA levels, which parallels their effects on the BHMT promoter activity. Maximal suppression is observed with BHMT promoter construct -347/+33, containing a number of NF-kappaB binding sites. S-adenosylmethionine and 5-methylthioadenosine treatment increases NF-kappaB nuclear binding and NF-kappaB-driven luciferasece activities, and increases nuclear binding activity of multiple histone deacetylase co-repressors to the NF-kappaB sites. Overexpression of p50 and p65 decreases BHMT promoter activity, while blocking NF-kappaB activation increases BHMT expression and promoter activity, and prevents S-adenosylmethionine but not 5-methylthioadenosines ability to inhibit BHMT expression
pH STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
partial digestion of ligand-free enzyme with trypsin produces two large peptides, excising a seven residue peptide with loop L2. Carboxybutylhomocysteine but not methionine slows proteolysis by trypsin
divalent cations and 2-mercaptoethanol do not stabilize during purification
-
OXIDATION STABILITY
ORGANISM
UNIPROT
LITERATURE
the enzyme is susceptible to conformation-dependent oxidative inactivation. When BHMT is incubated with up to 78 mM t-butyl hydroperoxide, no appreciable amount of ZN or activity is lost, indicating that oxidation of surface met residues are not involved in the oxidative inactivation of BHMT. Methyl methanethiosulfonate and H2O2, cause a loss of catalytic Zn and a correlative loss of activity. Addition of beta-mercaptoethanol and exogenous Zn after methyl methanethiosulfonate treatment restores activity, but oxidation due to H2O2 is irreversible. The L2 loop is involved in the conformational change associated with accupancy at the betaine binding site. This conformational change and/or occupancy at both ligand binding sites protects the enzyme from oxidative inactivation
657875
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
stable for a minimum of one month at 4°C in a mixture with human recombinant betaine-homocysteine S-methyltransferase (copurified with human recombinant betaine-homocysteine S-methyltransferase)
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
stabilized by copurification with human recombinant betaine-homocysteine S-methyltransferase, chitin affinity chromatography
-
wild-type and mutant enzymes are overexpressed in Escherichia coli and purified using the ImpactTM T7 system
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
a 2.7 kb 5'-flanking region of the human BHMT gene cloned between MluI and SmaI sites of a promoterless pGL-3-basic vector creating the recombinant plasmid -2698/+33 BHMT-LUC, expression in HepG2 cells
expressed in Escherichia coli BL21(DE3) (coexpression of human recombinant betaine-homocysteine S-methyltransferase)
-
glutathione S-transferase-BHMT fusion protein is expressed in HEK-293, T98G, A-10, MCF-7, H-1299, C2C12, and NIH-3T3 cells
-
impossible to express BHMT2 in mammalian cells, protein aggregates after bacterial expression. BHMT2 is rapidly degraded in a rabbit reticulocyte lysate, but it can be stabilized by cotransfection of COS-1 cells with BHMT and, after cotransfection, it coprecipitates with BHMT
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
treatment of hepatocytes with homocysteine to follow the impact of hyperhomocysteinemia and concomittant inhibition of betaine-homocysteine S-methyltransferase BHMT. Inhibition and 0.1 mM homocysteine treatment induce only moderate changes in the hepatocyte proteome and secretome, while the changes induced by 2 mM homocysteine treatment are extensive: phosphatidylethanolamine carboxykinase and ornithine aminotransferase are up-regulated about twofold indicating an intervention into metabolism. Cellular proliferation is suspended, secretome composition is changed and signs of apoptosis are discernible. Fibrinogen gamma dimers can be detected and maturation of apolipoprotein A1 fails
molecular biology
the BHMT/betaine system directly protects hepatocytes from homocysteine-induced injury but not tunicamycin-induced injury, including an endoplasmic reticulum stress response, lipid accumulation, and cell death
analysis
-
synthesis of a series of S-substituted derivatives of homocysteine as potential inhibitors of human recombinant BHMT, some of these compounds are very potent inhibitors, having IC50 values in the nanomolar range
medicine
molecular biology
S-adenosylmethionine and 5-methylthioadenosine down-regulate BHMT expression in HepG2 cells in part by inducing NF-kappaB, which acts as a repressor for the human BHMT gene. While S-adenosylmethionines mechanism is NF-kappaB-dependent, 5-methylthioadenosine has both NF-kappaB-dependent and -independent mechanisms
additional information
medicine
-
a polymorphisms in betaine-homocysteine S-methyltransferase might be linked to an increased risk for placental abruption
medicine
-
effect of extrahepatic expression of homo sapiens betaine-homocysteine methyltransferase on alcohol or homocysteine-induced fatty liver is shown in transgenic mice
medicine
-
BHMT1 is a auto-antigen associated with anti-Golgi immune reactivity. Antibodies to BHMT1 were found in four of 80 samples with a Golgi-pattern on indirect immunofluorescence. The antibodies are not associated with a specific clinical condition
medicine
-
in serum from healthy individuals, the median value is 1.83 ng/ml. In serum from patients with acute liver injury, the median value of BHMT is 748.48 ng/ml. The detection range of the ELISA assay is from 1.56 to 100 ng/ml with good sensitivity and specificity. In five acute liver injury cases with time course samples available, BHMT and alanine transaminase both follow the rise and fall temporal pattern with the disease progression. The slopes of BHMT curves are steeper than alanine transaminase curves. In three out of the five cases, BHMT levels peak 1 day earlier than alanine transaminase levels
additional information
lower BHMT expression can impair homocysteine metabolism, which can induce endoplasmic reticulum stress
additional information
-
lower BHMT expression can impair homocysteine metabolism, which can induce endoplasmic reticulum stress
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Wang, J.; Dudman, N.P.; Lynch, J.; Wilcken, D.E.L.
Betaine:homocysteine methyltransferase - a new assay for the liver enzyme and its absence from human skin fibroblasts and peripheral blood lymphocytes
Clin. Chim. Acta
204
239-249
1991
Gallus gallus, Ovis aries, Homo sapiens
Skiba, W.E.; Wells, M.S.; Mangum, J.H.; Awad, W.M.
Betaine-homocysteine S-methyltransferase (human)
Methods Enzymol.
143
384-388
1987
Equus caballus, Homo sapiens
Skiba, W.E.; Taylor, M.P.; Wells, M.S.; Mangum, J.H.; Awad, W.M.
Human hepatic methionine biosynthesis. Purification and characterization of betaine:homocysteine S-methyltransferase
J. Biol. Chem.
257
14944-14948
1982
Homo sapiens
Awad, W.M.; Whitney, P.L.; Skiba, W.E.; Mangum, J.H.; Wells, M.S.
Evidence for direct methyl transfer in betaine: homocysteine S-methyl-transferase
J. Biol. Chem.
258
12790-12792
1983
Homo sapiens
Bose, N.; Momany, C.
Crystallization and preliminary x-ray crystallographic studies of recombinant human betaine-homocysteine S-methyltransferase
Acta Crystallogr. Sect. D
57
431-433
2001
Homo sapiens
Millian, N.S.; Garrow, T.A.
Human betaine-homocysteine methyltransferase is a zinc metalloenzyme
Arch. Biochem. Biophys.
356
93-98
1998
Homo sapiens
Garrow, T.A.
Purification, kinetic properties, and cDNA cloning of mammalian betaine-homocysteine methyltransferase
J. Biol. Chem.
271
22831-22838
1996
Homo sapiens (Q93088), Homo sapiens, Sus scrofa (Q95332), Sus scrofa
Breksa, A.P.; Garrow, T.A.
Recombinant human liver betaine-homocysteine S-methyltransferase: Identification of three cysteine residues critical for zinc binding
Biochemistry
38
13991-13998
1999
Homo sapiens
Bose, N.; Greenspan, P.; Momany, C.
Expression of recombinant human betaine:homocysteine S-methyltransferase for x-ray crystallographic studies and further characterization of interaction with S-adenosylmethionine
Protein Expr. Purif.
25
73-80
2002
Homo sapiens
Delgado-Reyes, C.V.; Wallig, M.A.; Garrow, T.A.
Immunohistochemical detection of betaine-homocysteine S-methyltransferase in human, pig, and rat liver and kidney
Arch. Biochem. Biophys.
393
184-186
2001
Homo sapiens, Rattus norvegicus, Sus scrofa
Breksa, A.P.; Garrow, T.A.
Random mutagenesis of the zinc-binding motif of betaine-homocysteine methyltransferase reveals that Gly214 Is essential
Arch. Biochem. Biophys.
399
73-80
2002
Homo sapiens
Szegedi, S.S.; Garrow, T.A.
Oligomerization is required for betaine-homocysteine S-methyltransferase function
Arch. Biochem. Biophys.
426
32-42
2004
Homo sapiens (Q93088)
Miller, C.M.; Szegedi, S.S.; Garrow, T.A.
Conformation-dependent inactivation of human betaine-homocysteine S-methyltransferase by hydrogen peroxide in vitro
Biochem. J.
392
443-448
2005
Homo sapiens (Q93088), Homo sapiens
Collinsova, M.; Castro, C.; Garrow, T.A.; Yiotakis, A.; Dive, V.; Jiracek, J.
Combining combinatorial chemistry and affinity chromatography: highly selective inhibitors of human betaine: homocysteine S-methyltransferase
Chem. Biol.
10
113-122
2003
Homo sapiens
Ou, X.; Yang, H.; Ramani, K.; Ara, A.I.; Chen, H.; Mato, J.M.; Lu, S.C.
Inhibition of human betaine-homocysteine methyltransferase expression by S-adenosylmethionine and methylthioadenosine
Biochem. J.
401
87-96
2007
Homo sapiens (Q6EI07), Homo sapiens
Pajares, M.A.; Perez-Sala, D.
Betaine homocysteine S-methyltransferase: just a regulator of homocysteine metabolism?
Cell. Mol. Life Sci.
63
2792-2803
2006
Cavia porcellus, Homo sapiens, Macaca mulatta, Mesocricetus auratus, Mus musculus, Mus musculus C57/BL6J, Ovis aries, Rattus norvegicus, Sus scrofa
Jiracek, J.; Collinsova, M.; Rosenberg, I.; Budesinsky, M.; Protivinska, E.; Netusilova, H.; Garrow, T.A.
S-alkylated homocysteine derivatives: new inhibitors of human betaine-homocysteine S-methyltransferase
J. Med. Chem.
49
3982-3989
2006
Homo sapiens
Ji, C.; Shinohara, M.; Vance, D.; Than, T.A.; Ookhtens, M.; Chan, C.; Kaplowitz, N.
Effect of transgenic extrahepatic expression of betaine-homocysteine methyltransferase on alcohol or homocysteine-induced fatty liver
Alcohol. Clin. Exp. Res.
32
1049-1058
2008
Homo sapiens
Castro, C.; Millian, N.S.; Garrow, T.A.
Liver betaine-homocysteine S-methyltransferase activity undergoes a redox switch at the active site zinc
Arch. Biochem. Biophys.
472
26-33
2008
Homo sapiens, Mus musculus
Ji, C.; Shinohara, M.; Kuhlenkamp, J.; Chan, C.; Kaplowitz, N.
Mechanisms of protection by the betaine-homocysteine methyltransferase/betaine system in HepG2 cells and primary mouse hepatocytes
Hepatology
46
1586-1596
2007
Homo sapiens (Q93088)
Szegedi, S.S.; Castro, C.C.; Koutmos, M.; Garrow, T.A.
Betaine-homocysteine S-methyltransferase-2 is an S-methylmethionine-homocysteine methyltransferase
J. Biol. Chem.
283
8939-8945
2008
Homo sapiens, Mus musculus
Ananth, C.V.; Elsasser, D.A.; Kinzler, W.L.; Peltier, M.R.; Getahun, D.; Leclerc, D.; Rozen, R.R.; Rozen, R.R.
Polymorphisms in methionine synthase reductase and betaine-homocysteine S-methyltransferase genes: risk of placental abruption
Mol. Genet. Metab.
91
104-110
2007
Homo sapiens
Li, F.; Feng, Q.; Lee, C.; Wang, S.; Pelleymounter, L.L.; Moon, I.; Eckloff, B.W.; Wieben, E.D.; Schaid, D.J.; Yee, V.; Weinshilboum, R.M.
Human betaine-homocysteine methyltransferase (BHMT) and BHMT2: common gene sequence variation and functional characterization
Mol. Genet. Metab.
94
326-335
2008
Homo sapiens
Mercer, C.; Kaliappan, A.; Dennis, P.
Macroautophagy-dependent, intralysosomal cleavage of a betaine homocysteine methyltransferase fusion protein requires stable multimerization
Autophagy
4
185-194
2008
Homo sapiens
Xu, Y.Y.; Guan, D.Y.; Yang, M.; Wang, H.; Shen, Z.H.
All-trans-retinoic acid intensifies endoplasmic reticulum stress in N-acetylglucosaminyltransferase V repressed human hepatocarcinoma cells by perturbing homocysteine metabolism
J. Cell. Biochem.
109
468-477
2010
Homo sapiens
Vanek, V.; Budesinsky, M.; Kabeleova, P.; Sanda, M.; Kozisek, M.; Hanclova, I.; Mladkova, J.; Brynda, J.; Rosenberg, I.; Koutmos, M.; Garrow, T.A.; Jiracek, J.
Structure-activity study of new inhibitors of human betaine-homocysteine S-methyltransferase
J. Med. Chem.
52
3652-3665
2009
Homo sapiens
Korinek, M.; Sistek, V.; Mladkova, J.; Mikes, P.; Jiracek, J.; Selicharova, I.
Quantification of homocysteine-related metabolites and the role of betaine-homocysteine S-methyltransferase in HepG2 cells
Biomed. Chromatogr.
27
111-121
2013
Homo sapiens (Q93088)
Mladkova, J.; Vanek, V.; Budesinsky, M.; Elbert, T.; Demianova, Z.; Garrow, T.A.; Jiracek, J.
Double-headed sulfur-linked amino acids as first inhibitors for betaine-homocysteine S-methyltransferase 2
J. Med. Chem.
55
6822-6831
2012
Homo sapiens
Selicharova, I.; Korinek, M.; Demianova, Z.; Chrudinova, M.; Mladkova, J.; Jiracek, J.
Effects of hyperhomocysteinemia and betaine-homocysteine S-methyltransferase inhibition on hepatocyte metabolites and the proteome
Biochim. Biophys. Acta
1834
1596-1606
2013
Homo sapiens (Q93088), Homo sapiens
Ma, H.; Ning, J.; Jin, X.; Mao, C.; Bu, X.; Wang, M.; Liu, H.; Wang, K.; Lausted, C.; Hood, L.; Chen, J.; Hu, Z.
Betaine homocysteine methyltransferase (BHMT) as a specific and sensitive blood marker for acute liver injury
Biomarkers
19
578-584
2014
Homo sapiens
Van den Bergh, K.; Vercammen, M.; Regenass, S.; Derua, R.; Vermeersch, P.; Pokreisz, P.; Ocmant, A.; de Beeck, K.; Janssens, S.; Waelkens, E.; Bossuyt, X.
Betaine homocysteine methyl transferase 1, a novel auto-antigen associated with anti-Golgi immune reactivity
Clin. Chim. Acta
413
105-108
2012
Homo sapiens
Picha, J.; Vanek, V.; Budesinsky, M.; Mladkova, J.; Garrow, T.A.; Jiracek, J.
The development of a new class of inhibitors for betaine-homocysteine S-methyltransferase
Eur. J. Med. Chem.
65
256-275
2013
Homo sapiens (Q93088), Homo sapiens
Mladkova, J.; Hladilkova, J.; Diamond, C.E.; Tryon, K.; Yamada, K.; Garrow, T.A.; Jungwirth, P.; Koutmos, M.; Jiracek, J.
Specific potassium ion interactions facilitate homocysteine binding to betaine-homocysteine S-methyltransferase
Proteins
82
2552-2564
2014
Homo sapiens (Q93088), Homo sapiens
EXTERNAL LINKS (specific for EC-Number 2.1.1.5)
Use of this online version of BRENDA is free under the CC BY 4.0 license. See terms of use for full details.
Release 2023.1 (January 2023)
Legal
Curated at
Member of
