2.1.1.5: betaine-homocysteine S-methyltransferase
This is an abbreviated version!
For detailed information about betaine-homocysteine S-methyltransferase, go to the full flat file.
Word Map on EC 2.1.1.5
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2.1.1.5
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cystathionine
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s-adenosylmethionine
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choline
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folate
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remethylation
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hyperhomocysteinemia
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s-adenosylhomocysteine
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adenosyltransferase
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n-methyltransferase
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one-carbon
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beta-synthase
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dimethylglycine
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transsulfuration
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methylenetetrahydrofolate
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5-methyltetrahydrofolate-homocysteine
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transmethylation
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medicine
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mthfd1
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guanidinoacetate
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homocysteine-induced
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folate-dependent
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homocystinuria
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5-methyltetrahydrofolate
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transcobalamin
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b-vitamins
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slc19a1
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hypotaurine
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molecular biology
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analysis
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nutrition
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food industry
- 2.1.1.5
- cystathionine
- s-adenosylmethionine
- choline
- folate
-
remethylation
- hyperhomocysteinemia
- s-adenosylhomocysteine
-
adenosyltransferase
- n-methyltransferase
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one-carbon
- beta-synthase
- dimethylglycine
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transsulfuration
- methylenetetrahydrofolate
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5-methyltetrahydrofolate-homocysteine
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transmethylation
- medicine
- mthfd1
- guanidinoacetate
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homocysteine-induced
-
folate-dependent
- homocystinuria
- 5-methyltetrahydrofolate
-
transcobalamin
-
b-vitamins
-
slc19a1
- hypotaurine
- molecular biology
- analysis
- nutrition
- food industry
Reaction
Synonyms
betaine homocysteine methyltransferase, betaine homocysteine methyltransferase-1, betaine homocysteine S-methyltransferase, betaine-homocysteine methyltransferase, betaine-homocysteine S-methyltransferase, betaine-homocysteine S-methyltransferase 2, betaine-homocysteine S-methyltransferase-2, betaine-homocysteine transmethylase, betaine:homocysteine methyltransferase, betaine:homocysteine S-methyltransferase, BHMT, BHMT-1, BHMT-2, BHMT1, BHMT2, methyltransferase, betaine-homocysteine
ECTree
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Engineering
Engineering on EC 2.1.1.5 - betaine-homocysteine S-methyltransferase
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A66V
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nonsynonymous SNP identified using 240 DNA samples from four ethnic groups
Arg16Cys
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nonsynonymous SNP identified using 240 DNA samples from four ethnic groups, Km (mM): 0.0139 (betaine), 0.0076 (L-homocysteine)
Arg239Gln
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nonsynonymous SNP identified using 240 DNA samples from four ethnic groups, Km (mM): 0.012 (betaine), 0.0158 (L-homocysteine)
C104A
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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
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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
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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
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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
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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
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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
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complete loss of activity, reduction in zinc binding, identification of zinc binding motif
Cys299Ala
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complete loss of activity, reduction in zinc binding, identification of zinc binding motif
Cys300Ala
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complete loss of activity, reduction in zinc binding, identification of zinc binding motif
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
G742A
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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
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nonsynonymous SNP identified using 240 DNA samples from four ethnic groups, Km (mM): 0.0139 (betaine), 0.0206 (L-homocysteine)
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
Pro197Ser
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nonsynonymous SNP identified using 240 DNA samples from four ethnic groups, Km (mM): 0.0213 (betaine), 0.0216 (L-homocysteine)
R239Q
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no significant association with the severity and extent of hyperhomocysteinemia
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
T218M
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nonsynonymous SNP identified using 240 DNA samples from four ethnic groups
V155F
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nonsynonymous SNP identified using 240 DNA samples from four ethnic groups
V237M
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nonsynonymous SNP identified using 240 DNA samples from four ethnic groups
W352A
Y363A
normal or near-normal ability to bind zinc, near-normal catalytic activity
A119G
1.9fold reduced turnover-number for betaine and L-homocysteine, 1.6fold reduced KM-value for L-homocysteine, 1.1fold decrease in Km-value for betaine
C186A
1.8fold reduced turnover-number for betaine and L-homocysteine, 4.3fold reduced KM-value for L-homocysteine, 1.8fold increase in Km-value for betaine
C186S
2.3fold reduced turnover-number for betaine and L-homocysteine, 1.4fold reduced KM-value for L-homocysteine, 111.6fold decrease in Km-value for betaine
D26A
2.7fold reduced turnover-number for betaine and L-homocysteine, 1.7fold reduced KM-value for L-homocysteine, 3.5fold increase in Km-value for betaine
D26I
67fold reduced turnover-number for betaine and L-homocysteine, maximal velocity is 6.5fold lower than the wild-type value
E159G
60fold reduced turnover-number for betaine and L-homocysteine, maximal velocity is 61.2fold lower than the wild-type value
E159K
170fold reduced turnover-number for betaine and L-homocysteine, maximal velocity is 169.7fold lower than the wild-type value
E21A
2.3fold reduced turnover-number for betaine and L-homocysteine, 6fold reduced KM-value for L-homocysteine, 2.4fold reduced Km-value for betaine
E21K
1.6fold reduced turnover-number for betaine and L-homocysteine, 1.4fold reduced KM-value for L-homocysteine, 1.7fold reduced Km-value for betaine
F74A
1.9fold reduced turnover-number for betaine and L-homocysteine, 1.9fold reduced KM-value for L-homocysteine, 2.9fold increase in Km-value for betaine
T184G
2.4fold reduced turnover-number for betaine and L-homocysteine, 3.19fold reduced KM-value for L-homocysteine, 1.6fold increase in Km-value for betaine
T73G
3.1fold reduced turnover-number for betaine and L-homocysteine, 2.2fold reduced KM-value for L-homocysteine, 1.3fold reduced Km-value for betaine
Y77A
14fold reduced turnover-number for betaine and L-homocysteine, maximal velocity is 13.7fold lower than the wild-type value
additional information
negligible activity, elution as dimer, aberrant crosslinking properties
W352A
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the mutation disrupts stable BHMT multimerization, the mutant ablates catalytic activity
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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
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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
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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
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
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
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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
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experiments using the glutamate-cysteine ligase modifier subunit knockout mice Gclm(-/-), which are severely impaired in glutathione synthesis, show that the DMSA-Asp dependent BHMT activity is 75% lower in Gclm(-/-) than Gclm(+/+) mice. The Bet-Hcy dependent BHMT activity is essentially identical between both groups. This results show that the loss of DMSA-Asp dependent activity in Gclm(-/-) is due to the lower level of free thiols in those livers
additional information
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changes at positions E159 and Y77 show the largest decreases in activity, but D26 and F74 seem to have a role in betaine binding, whereas E21 and C186 also influence L-homocysteine binding