Information on EC 2.1.1.5 - betaine-homocysteine S-methyltransferase

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The expected taxonomic range for this enzyme is: Bacteria, Eukaryota

EC NUMBER
COMMENTARY
2.1.1.5
-
RECOMMENDED NAME
GeneOntology No.
betaine-homocysteine S-methyltransferase
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
betaine + L-homocysteine = dimethylglycine + L-methionine
show the reaction diagram
mechanism
-
betaine + L-homocysteine = dimethylglycine + L-methionine
show the reaction diagram
ordered bi-bi mechanism with homocysteine the first substrate to be added and methionine the last product released
-
betaine + L-homocysteine = dimethylglycine + L-methionine
show the reaction diagram
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
methyl group transfer
-
-
-
-
PATHWAY
KEGG Link
MetaCyc Link
Cysteine and methionine metabolism
-
glycine betaine degradation
-
Glycine, serine and threonine metabolism
-
Metabolic pathways
-
methionine salvage II (mammalia)
-
SYSTEMATIC NAME
IUBMB Comments
trimethylammonioacetate:L-homocysteine S-methyltransferase
-
SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
betaine homocysteine methyltransferase
-
-
betaine homocysteine methyltransferase
O35490
-
betaine homocysteine methyltransferase-1
-
-
betaine homocysteine S-methyltransferase
-
-
betaine-homocysteine methyltransferase
-
-
-
-
betaine-homocysteine methyltransferase
-
-
betaine-homocysteine methyltransferase
-
-
betaine-homocysteine methyltransferase
Q6EI07
-
betaine-homocysteine methyltransferase
-
-
betaine-homocysteine methyltransferase
-
-
betaine-homocysteine S-methyltransferase
-
-
betaine-homocysteine S-methyltransferase
Q6EI07
-
betaine-homocysteine S-methyltransferase
Q93088
-
betaine-homocysteine S-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
Q6EI07
-
BHMT
Q93088
-
BHMT
Mus musculus C57BL/6J
-
-
-
BHMT
-
-
BHMT
O09171
-
BHMT-2
-
-
BHMT2
-
-
BHMT2
Mus musculus C57BL/6J
-
-
-
methyltransferase, betaine-homocysteine
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY
9029-78-1
-
ORGANISM
COMMENTARY
LITERATURE
SEQUENCE CODE
SEQUENCE DB
SOURCE
; fragment
SwissProt
Manually annotated by BRENDA team
recombinant
-
-
Manually annotated by BRENDA team
recombinant enzyme
SwissProt
Manually annotated by BRENDA team
rhesus monkey
-
-
Manually annotated by BRENDA team
6-week-old Balb/C male mice
-
-
Manually annotated by BRENDA team
C57BL/6J mice
-
-
Manually annotated by BRENDA team
male B57CL/6 mice
-
-
Manually annotated by BRENDA team
Mus musculus C57BL/6J
C57BL/6J mice
-
-
Manually annotated by BRENDA team
lamb
-
-
Manually annotated by BRENDA team
strain Sprague-Dawley
-
-
Manually annotated by BRENDA team
Rattus norvegicus Sprague-Dawley
strain Sprague-Dawley
-
-
Manually annotated by BRENDA team
7 to 8-d-old piglets, milk from lactating sows
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
metabolism
-
involved in homocystein metabolism
physiological function
-
betaine homocysteine methyltransferase is a potential cargo-based end-point marker for macroautophagy
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
dimethylacetothetin + L-homocysteine
? + L-methionine
show the reaction diagram
Q95332
-
-
-
?
glycinebetaine + L-homocysteine
? + L-methionine
show the reaction diagram
-
-
-
-
-
glycinebetaine + L-homocysteine
? + L-methionine
show the reaction diagram
-
-
-
-
?
L-Asp + dimethylsulfonioacetate
?
show the reaction diagram
-
-
-
-
?
L-Asp + dimethylsulfonioacetate
?
show the reaction diagram
-
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
show the reaction diagram
-
-
-
-
?
L-homocysteine + betaine
L-methionine + dimethylglycine
show the reaction diagram
-
-
-
-
?
L-homocysteine + betaine
L-methionine + dimethylglycine
show the reaction diagram
-
-
-
-
?
L-homocysteine + betaine
L-methionine + dimethylglycine
show the reaction diagram
O09171
-
-
-
?
L-homocysteine + betaine
L-methionine + dimethylglycine
show the reaction diagram
-
-
-
-
?
L-homocysteine + betaine
L-methionine + dimethylglycine
show the reaction diagram
Q95332
-
-
-
-
L-homocysteine + betaine
L-methionine + dimethylglycine
show the reaction diagram
-
-
-
-
?
L-homocysteine + betaine
L-methionine + dimethylglycine
show the reaction diagram
-
-
-
-
?
L-homocysteine + betaine
L-methionine + dimethylglycine
show the reaction diagram
-
reduced BHMT activity in cirrhotic livers may explain the elevated plasma homocysteine levels in cirrhosis
-
-
?
L-homocysteine + betaine
L-methionine + dimethylglycine
show the reaction diagram
-
the enzyme can be modified by tissue-type transglutaminase and its activity is regulated repressively by the modification, especially by the cross-linking. This regulatory reaction might be involved in the regulation of homocysteine metabolism in the liver
-
-
?
L-homocysteine + betaine
L-methionine + dimethylglycine
show the reaction diagram
-
folate-independent remethylation of homocysteine
-
-
?
L-homocysteine + betaine
L-methionine + dimethylglycine
show the reaction diagram
-
this reaction processes 25% of the cellular L-homocysteine in an in vitro model
-
-
?
L-homocysteine + betaine
dimethylglycine + L-methionine
show the reaction diagram
-
-
-
-
?
L-homocysteine + betaine
dimethylglycine + L-methionine
show the reaction diagram
-
-
-
-
?
L-homocysteine + betaine
dimethylglycine + L-methionine
show the reaction diagram
O35490
-
-
-
?
L-homocysteine + S-methyl-L-methionine
?
show the reaction diagram
-
-
-
-
?
L-homocysteine + S-methyl-L-methionine
?
show the reaction diagram
-
BHMT-2 uses S-methylmethionine as a methyl donor for the methylation of homocysteine. Unlike BHMT, BHMT-2 can not use betaine
-
-
?
L-homocysteine + S-methylmethionine
?
show the reaction diagram
-
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
show the reaction diagram
-
-
-
?
N,N,N-trimethylglycine + L-homocysteine
N,N-dimethylglycine + L-methionine
show the reaction diagram
-
-
-
?
N,N,N-trimethylglycine + L-homocysteine
N,N-dimethylglycine + L-methionine
show the reaction diagram
-
-
-
?
N,N,N-trimethylglycine + L-homocysteine
N,N-dimethylglycine + L-methionine
show the reaction diagram
-
-
-
?
N,N,N-trimethylglycine + L-homocysteine
N,N-dimethylglycine + L-methionine
show the reaction diagram
-
-
-
?
N,N,N-trimethylglycine + L-homocysteine
N,N-dimethylglycine + L-methionine
show the reaction diagram
-
-
-
?
N,N,N-trimethylglycine + L-homocysteine
N,N-dimethylglycine + L-methionine
show the reaction diagram
-
i.e. betaine, methyl transfer directly from one substrate to the other
-
?
N,N,N-trimethylglycine + L-homocysteine
N,N-dimethylglycine + L-methionine
show the reaction diagram
-
enzyme cristallin in lens
-
-
-
N,N,N-trimethylglycine + L-homocysteine
N,N-dimethylglycine + L-methionine
show the reaction diagram
-
i.e. betaine, involved in betaine metabolism
-
-
?
N,N,N-trimethylglycine + L-homocysteine
N,N-dimethylglycine + L-methionine
show the reaction diagram
Rattus norvegicus Sprague-Dawley
-
-
-
?
L-homocysteine + S-methylmethionine
2 L-methionine
show the reaction diagram
-
-
-
-
?
additional information
?
-
-
BHMT can utilize S-methylmethionine as a substrate in vitro with a very low affinity
-
-
-
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
L-homocysteine + betaine
L-methionine + dimethylglycine
show the reaction diagram
-
reduced BHMT activity in cirrhotic livers may explain the elevated plasma homocysteine levels in cirrhosis
-
-
?
L-homocysteine + betaine
L-methionine + dimethylglycine
show the reaction diagram
-
the enzyme can be modified by tissue-type transglutaminase and its activity is regulated repressively by the modification, especially by the cross-linking. This regulatory reaction might be involved in the regulation of homocysteine metabolism in the liver
-
-
?
N,N,N-trimethylglycine + L-homocysteine
N,N-dimethylglycine + L-methionine
show the reaction diagram
-
enzyme cristallin in lens
-
-
-
N,N,N-trimethylglycine + L-homocysteine
N,N-dimethylglycine + L-methionine
show the reaction diagram
-
i.e. betaine, involved in betaine metabolism
-
-
?
METALS and IONS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
Zinc
Q93088
wild-type enzyme contains zinc. Mutant enzymes H338A, R346A, W352A, R361A, P362A, Y363A, N364A, P365A maintain normal or near-normal ability to bind zinc
Zn
-
Tyr160 is coordinated to Zn
Zn
-
BHMT-2 is a zinc metalloenzyme
Zn2+
-
removal of Zn2+ results in loss of activity, restoration is possible
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
Zn2+
-
BHMT is a zinc metalloenzyme
Zn2+
-
BHMT-2 is a zinc metalloenzyme
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
(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)-5-(3-amino-3-carboxypropylsulfanyl)-pentanoic acid
O35490
-
(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-amino-5-(3-carboxypropylthio)pentanoic acid
-
5.4% inhibition at 0.02 mM
(RS)-2-aminodecanedioic acid
-
2.11% 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-carboxypropoxy)pentanoic acid
-
9.8% 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
3,3-Dimethylbutyrate
-
competitive to betaine
5-[(3-amino-3-carboxypropyl)sulfanyl]pentanoic acid
-
complete inhibition at 0.02 mM
Ac-Val-Ala-Leu-His-NH2
-
0.1 mM, 25.9% inhibition
Ac-Val-DL-Ala-psi[(PO2-)-CH2]-DL-Leu-His-NH2
-
0.1 mM, 57.4% inhibition
Ac-Val-DL-Phe-psi[(PO2-)-CH2]-DL-Ala-His-NH2
-
0.1 mM, 8.7% inhibition
Ac-Val-DL-Phe-psi[(PO2-)-CH2]-DL-Leu-His-NH2
-
0.1 mM, 53.7% inhibition
actinomycin D
-
leads to a decay of Bhmt mRNA, irrespective of the ambient osmolarity, at 120 min after addition, Bhmt mRNA levels are significantly decreased under hyperosmotic conditions, compared with the Bhmt mRNA levels found under the respective normo- or hypoosmotic condition
AdoMet
-
weak inhibitor, at 2 mM: 24% inhibition
AdoMet
-
weak inhibitor, at 2.5 mM: 15% inhibition
Betaine aldehyde
-
100% inhibition at 2.5 mM
Butyrate
-
moderate, competitive to betaine
choline
-
60% inhibition at 5 mM
Dimethylglycine
-
at 0.2 mM: 80% inhibition, at 2 mM: 97% inhibition; weak inhibitor, at 2 mM: 11% inhibition
Dimethylglycine
-
at 0.25 mM: 64% inhibition, at 2.5 mM: 95% inhibition; weak inhibitor, at 2.5 mM: 19% inhibition
dimethylsulfonioacetate
-
at 2 mM: 79% inhibition; weak inhibitor, at 2 mM: 20% inhibition
dimethylsulfonioacetate
-
at 0.25 mM: 29% inhibition, at 2.5 mM: 82% inhibition
dimethylsulfoniopropionate
-
weak inhibitor, at 2 mM: 29% inhibition
dimethylsulfoniopropionate
-
weak inhibitor, at 2.5 mM: 11% inhibition; weak inhibitor, at 2.5 mM: 17% inhibition
H2O2
-
causes a loss of catalytic Zn and a correlative loss of activity, irreversible
Isovalerate
-
competitive to betaine
L-Asp
-
10 mM Asp inhibits BHMT
methionine
-
at 2 mM: 60% inhibition; weak inhibitor at 2 mM: 15% inhibition
methionine
-
at 2.5 mM: 38% inhibition; at 2.5 mM: 48% inhibition
N,N-Dimethylglycine
-
70% inhibition at 5 mM
NaCl
-
100% inhibition above 200 mM
Pinanyl N,N,N-trimethylaminomethane boronate
-
substrate analogue
-
S-(delta-Carboxybutyl)-DL-homocysteine
-
strong
S-(delta-Carboxybutyl)-DL-homocysteine
-
0.005 mM reduces BHMT activity ca. 95% in the standard assay that contains high levels (0.0025 mM) of L-homocysteine. Compared with saline-injected control mice, at 2 h postinjection, mice have 87% lower BHMT activity and a 2.7fold increase in plasma total homocysteine, effects that last nearly 8 h but return to normal by 24 h, level of BHMT protein remains constant over the 24-h period. After 6 injections (one every 12 h), the mice have 7fold higher plasma total homocysteine, a 65% reduction in the liver S-adenosylmethionine: S-adenosylhomocysteine ratio, and a marked upregulation of BHMT protein expression. When methionine is injected, postmethionine load plasma total homocysteine levels are 2.2fold higher at 2 h postinjection
S-(delta-Carboxybutyl)-DL-homocysteine
-
-
S-(delta-carboxybutyl)-DL-homocysteine-sulfoxide
-
at 2 h after injection, there is a modest reduction in BHMT activity and a 90% increase in plasma total homocysteine
S-(delta-carboxybutyl)-L-homocysteine
-
at 0.05 mM: 97% inhibition, at 0.5 mM: total inhibition; weak inhibitor, at 0.5 mM: 26% inhibition
S-(delta-carboxybutyl)-L-homocysteine
-
at 0.025 mM: 22% inhibition, at 0.0625 mM: 36% inhibition, at 0.125 mM: 49% inhibition, at 0.5 mM: 81% inhibition; total inhibition
S-adenosyl-L-ethionine
-
irreversible, S-adenosyl-L-homocysteine and L-homocysteine prevent, but not DL-homocysteine, GSH, DTT or L-cysteine
S-adenosyl-L-homocysteine
-
non-linear/competitive to homocysteine, mixed/non-competitive to betaine
S-adenosyl-L-methionine
-
irreversible, S-adenosyl-L-homocysteine and L-homocysteine prevent, not DL-homocysteine, GSH, DTT or L-cysteine
S-adenosyl-L-methionine
-
no effect on recombinant enzyme
Val-DL-Ala-psi[(PO2-)-CH2]-DL-Leu-His-NH2
-
0.1 mM, 70.6% inhibition
Val-DL-Phe-psi[(PO2-)-CH2]-DL-Leu-His-NH2
-
0.1 mM, 80.3% inhibition
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
additional information
-
no inhibition by sarcosine
-
additional information
-
not inhibitory: taurine, cysteic acid, cysteine sulfinate, sulfate, glycine, L-serine, L-threonine; product inhibition
-
additional information
-
not inhibitory: methionine or ethionine; product inhibition
-
additional information
-
product inhibition
-
additional information
-
no inhibition by sarcosine; 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
-
insulin decreases the abundance of BHMT mRNA and the rate of de novo mRNA transcription of the gene in H4IIE cells, plays a direct role in the regulation of BHMT transcription
-
additional information
-
osmosensitivity of Bhmt mRNA expression
-
additional information
-
hyperosmotic NaCl, hyperosmotic raffinose but not hyperosmotic urea suppresses Bhmt mRNA expression, suggesting that cell shrinkage rather than increased ionic strength or hyperosmolarity per se is the trigger, osmosensitivity of Bhmt mRNA expression is impaired by inhibitors of tyrosine kinases and cyclic nucleotide-dependent kinases
-
additional information
Q6EI07
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
-
hypertonicity induces a decrease in BHMT mRNA and protein levels in liver and kidney
-
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
-
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 ACCESSION NO.
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
betaine
-
together with methionine restriction induces hepatic BHMT 4fold compared with methionine restriction alone, BHMT mRNAlevel is also increased by 3fold by betaine supplementation of methionine-replete diets
betaine
-
elevations in the liver activity
betaine
-
only slightly increased homocysteine remethylation in response to addition of betaine to diets containing 0.07 and 0.24% supplemental methionine
casein
-
included in liquid diets
choline
-
elevations in the liver activity, whereas it has no effect in the renal enzyme
choline
-
liver BHMT activity is 1.3fold higher in rats fed the methionine deficient diet containing choline than in rats fed the methionine-adequate diet containing supplemental choline
D-Cysteine
-
increase of product formation
dithiothreitol
-
-
ethanol
-
increases in BHMT activity are only observed when 4-methylpyrazole is included in the treatment
ethanol
-
included in liquid diets
Insulin
-
is effective in counteracting the stimulation of BHMT activity and mRNA levels produced by triamcinolone in rat hepatoma H4IIE cells
-
L-cysteine
-
stimulation at low concentration
L-methionine
-
independent of dietary choline, supplemental methionine increases hepatic BHMT activity by ca. 30%
S-[(2R)-2-amino-2-carboxyethyl]-L-homocysteine
-
-
streptozotocin
-
increases BHMT activity and mRNA levels in the liver
Triamcinolone
-
-
additional information
-
taurine, cysteic acid, cysteine sulfinate, sulfate, glycine, L-serine, L-threonine do not affect activity
-
additional information
-
triamcinolone increases the level and rate of BHMT mRNA synthesis in H4IIE cells
-
additional information
-
after 24 h, Bhmt expression increases 1.53fold under hypoosmotic conditions, Bhmt enzymatic activity is altered under anisoosmotic conditions
-
additional information
-
diet exhibits elevations of hepatic BHMT activity
-
additional information
-
diet increases BHMT activity with small elevations in expression
-
additional information
-
choline and methionine do not affect BHMT activity, mRNA expression and immunodetectable protein in the kidney
-
additional information
-
dietary methionine level does not significantly affect BHMT-dependent homocysteine remethylation or the relative proportion of homocysteine that is remethylated by BHMT, also choline appears to have little impact on BHMT-dependent remethylation
-
KM VALUE [mM]
KM VALUE [mM] Maximum
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.002
-
betaine
-
recombinant enzyme
0.012
-
betaine
-
mutant Arg239Gln
0.0139
-
betaine
-
mutant Arg16Cys; mutant Gly199Ser
0.0213
-
betaine
-
mutant Pro197Ser
0.0227
-
betaine
-
wild-type
0.023
-
betaine
Q95332
-
0.039
0.056
betaine
-
-
0.1
-
betaine
-
-
0.139
-
betaine
-
37C, mutant enzyme E21A
0.185
-
betaine
-
37C, mutant enzyme C186A
0.195
-
betaine
-
37C, mutant enzyme E21K
0.206
-
betaine
-
37C, mutant enzyme T186S
0.258
-
betaine
-
37C, mutant enzym T73G
0.305
-
betaine
-
37C, mutant enzyme A119G
0.333
-
betaine
-
37C, wild-type enzyme
0.548
-
betaine
-
37C, mutant enzyme T184G
0.969
-
betaine
-
37C, mutant enzyme F74A
1.17
-
betaine
-
37C, mutant enzyme D26A
2
-
betaine
-
-
2.2
-
betaine
-
-
2.4
-
betaine
-
-
0.155
-
dimethylacetothetin
Q95332
-
0.008
-
DL-homocysteine
-
-
4.3
-
glycinebetaine
-
-
10
-
L-Asp
-
-
0.004
-
L-homocysteine
-
recombinant enzyme
0.0076
-
L-homocysteine
-
mutant Arg16Cys
0.012
0.021
L-homocysteine
-
-
0.0158
-
L-homocysteine
-
mutant Arg239Gln
0.017
-
L-homocysteine
-
37C, mutant enzyme E21A
0.0206
-
L-homocysteine
-
mutant Gly199Ser
0.0216
-
L-homocysteine
-
mutant Pro197Ser
0.025
-
L-homocysteine
-
37C, mutant enzyme C186A
0.029
-
L-homocysteine
-
wild-type
0.032
-
L-homocysteine
Q95332
-
0.034
-
L-homocysteine
-
37C, mutant enzyme T184G
0.049
-
L-homocysteine
-
37C, mutant enzyme T73G
0.057
-
L-homocysteine
-
37C, mutant enzyme F74A
0.063
-
L-homocysteine
-
37C, mutant enzyme D26A
0.068
-
L-homocysteine
-
37C, mutant enzyme A119G
0.073
-
L-homocysteine
-
37C, mutant enzyme E21K
0.074
-
L-homocysteine
-
37C, mutant enzyme C186S
0.106
-
L-homocysteine
-
37C, wild-type enzyme
0.12
-
L-homocysteine
-
-
0.12
-
L-homocysteine
-
betaine
0.12
-
L-homocysteine
-
-
1.3
-
L-homocysteine
-
-
0.76
-
S-methyl-L-methionine
-
-
0.94
-
S-methyl-L-methionine
-
-
3
-
S-methyl-L-methionine
-
-
TURNOVER NUMBER [1/s]
TURNOVER NUMBER MAXIMUM[1/s]
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.000082
-
betaine
-
37C, mutant enzyme E159K
0.00023
-
betaine
-
37C, mutant enzyme E159G
0.001
-
betaine
-
37C, mutant enzyme Y77A
0.0021
-
betaine
-
37C, mutant enzyme D26I
0.0045
-
betaine
-
37C, mutant enzym T73G
0.0051
-
betaine
-
37C, mutant enzyme D26A
0.0058
-
betaine
-
37C, mutant enzyme T184G
0.006
-
betaine
-
37C, mutant enzyme E21A; 37C, mutant enzyme T186S
0.0072
-
betaine
-
37C, mutant enzyme F74A
0.0075
-
betaine
-
37C, mutant enzyme A119G
0.0076
-
betaine
-
37C, mutant enzyme C186A
0.009
-
betaine
-
37C, mutant enzyme E21K
0.014
-
betaine
-
37C, wild-type enzyme
88
-
betaine
-
-
0.000082
-
L-homocysteine
-
37C, mutant enzyme E159K
0.00023
-
L-homocysteine
-
37C, mutant enzyme E159G
0.001
-
L-homocysteine
-
37C, mutant enzyme Y77A
0.0021
-
L-homocysteine
-
37C, mutant enzyme D26I
0.0045
-
L-homocysteine
-
37C, mutant enzyme T73G
0.0051
-
L-homocysteine
-
37C, mutant enzyme D26A
0.0058
-
L-homocysteine
-
37C, mutant enzyme T184G
0.006
-
L-homocysteine
-
37C, mutant enzyme C186S; 37C, mutant enzyme E21A
0.0072
-
L-homocysteine
-
37C, mutant enzyme F74A
0.0075
-
L-homocysteine
-
37C, mutant enzyme A119G
0.0076
-
L-homocysteine
-
37C, mutant enzyme C186A
0.009
-
L-homocysteine
-
37C, mutant enzyme E21K
0.014
-
L-homocysteine
-
37C, wild-type enzyme
24
-
S-methyl-L-methionine
-
-
38
-
S-methyl-L-methionine
-
-
Ki VALUE [mM]
Ki VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
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, 37C
-
0.000012
-
(R,S)-5-(3-amino-3-carboxy-propylsulfanyl)-pentanoic acid
-
-
0.045
-
Pinanyl N,N,N-trimethylaminomethane boronate
-
-
-
IC50 VALUE [mM]
IC50 VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.000096
-
(R,S)-2-amino-4-(2-carboxymethylsulfanyl-ethylsulfanyl)-butyric acid
-
-
0.0057
-
(R,S)-2-amino-4-(4-phosphono-butylsulfanyl)-butyric acid
-
-
0.007
-
(R,S)-4-(3-amino-3-carboxy-propylsulfanyl)-benzoic acid
-
-
0.000087
-
(R,S)-5-(3-amino-3-carboxy-propylsulfanyl)-pentanoic acid
-
-
0.005
-
(R,S)-5-(3-amino-3-carboxy-propylsulfinyl)-pentanoic acid
-
-
0.0002
-
(R,S)-6-(3-amino-3-carboxy-propylsulfanyl)-hexanoic acid
-
-
0.00326
-
(RS)-2-amino-4-[(2-carboxyethylthio)methylthio]butanoic acid
-
in 50 mM potassium phosphate buffer, at pH 7.5, at 37C
0.0025
-
(RS)-2-amino-4-[2-[(carboxymethyl)(methyl)amino]ethylthio]-butanoic acid
-
in 50 mM potassium phosphate buffer, at pH 7.5, at 37C
0.000649
-
(RS)-5-(3-amino-3-carboxypropylselanyl)pentanoic acid
-
in 50 mM potassium phosphate buffer, at pH 7.5, at 37C
0.000084
-
(RS)-5-(3-amino-3-carboxypropylthio)-3,3-dimethylpentanoic acid
-
in 50 mM potassium phosphate buffer, at pH 7.5, at 37C
0.000139
-
(RS)-5-(3-amino-3-carboxypropylthio)-3-methylpentanoic acid
-
in 50 mM potassium phosphate buffer, at pH 7.5, at 37C
SPECIFIC ACTIVITY [µmol/min/mg]
SPECIFIC ACTIVITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
0.000103
-
-
-
0.000557
-
-
-
0.00084
-
-
-
0.0025
-
-
kidney
0.0187
-
-
-
0.0392
-
-
liver
0.314
-
-
-
pH OPTIMUM
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
7
-
-
assay at
7.5
-
-
assay at
8
-
-
0.05 M Tricine buffer
8
-
-
assay at
additional information
-
-
Tris, TES and HEPES decrease activity
additional information
-
-
3 active forms with pI: 7.0, 7.6 and 8.0
TEMPERATURE OPTIMUM
TEMPERATURE OPTIMUM MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
37
-
-
assay at
pI VALUE
pI VALUE MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
10
-
-
pI-value of about 10
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
-
hyperosmolarity (405 mosmol/l) suppresses Bhmt mRNA expression whereas hypoosmotic (205 mosmol/l) conditions induce Bhmt mRNA expression. Like hyperosmotic NaCl, hyperosmotic raffinose but not hyperosmotic urea suppresses Bhmt mRNA expression. Osmosensitivity of Bhmt mRNA expression is impaired by inhibitors of tyrosine kinases and cyclic nucleotide-dependent kinases
Manually annotated by BRENDA team
-
proximal tubes of cortex
Manually annotated by BRENDA team
-
high sodium chloride intake decreases betaine-homocysteine S-methyltransferase expression
Manually annotated by BRENDA team
-
low activity, involved in regulation of its tonicity
Manually annotated by BRENDA team
-
very low activity
Manually annotated by BRENDA team
-
cortex, low activity
Manually annotated by BRENDA team
Mus musculus C57BL/6J
-
-
-
Manually annotated by BRENDA team
-
represents 0.5-10% of the total protein, presence of BHMT can be related to its role in betaine removal when osmotic stress disappears, a key process, since osmotic swelling is a major factor in the development of some types of cataracts
Manually annotated by BRENDA team
-
high sodium chloride intake decreases betaine-homocysteine S-methyltransferase expression
Manually annotated by BRENDA team
-
reduced BHMT activity in cirrhotic livers may explain the elevated plasma homocysteine levels in cirrhosis
Manually annotated by BRENDA team
-
BHMT mRNA and activity increases about 2fold in diabetic rats compared with the nondiabetic animals
Manually annotated by BRENDA team
-
very abundant, involved in regulation of its tonicity
Manually annotated by BRENDA team
-
very abundant
Manually annotated by BRENDA team
Mus musculus C57BL/6J
-
very abundant
-
Manually annotated by BRENDA team
Rattus norvegicus Sprague-Dawley
-
-
-
Manually annotated by BRENDA team
-
high sodium chloride intake has no effect on betaine-homocysteine S-methyltransferase expression
Manually annotated by BRENDA team
-
highest levels of activity
Manually annotated by BRENDA team
additional information
-
no activity in phytohemagglutinin-stimulated human peripheral blood lymphocytes and cultured human skin fibroblasts
Manually annotated by BRENDA team
additional information
-
no expression of BHMT2 protein is detected in liver or kidney although BHMT2 mRNA expression is observed
Manually annotated by BRENDA team
MOLECULAR WEIGHT
MOLECULAR WEIGHT MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
40300
-
-
sequence analysis of BHMT2
45000
-
-
about 45000 Da, SDS-PAGE
270000
-
-
gel filtration
270000
-
-
gel filtration
350000
-
-
gel filtration
additional information
-
-
amino acid composition
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
?
-
x * 52000, SDS-PAGE
?
-
x * 40300, 363 amino acid residues
dimer
Q93088
mutant enzmyes R346A and W352A with negligible activity
hexamer
-
6 * 45000, SDS-PAGE
hexamer
-
6 * 45000, SDS-PAGE
hexamer
Rattus norvegicus Sprague-Dawley
-
6 * 45000, SDS-PAGE
-
octamer
-
8 * 45000, SDS-PAGE
tetramer
-
4 * 45000, recombinant His-tagged enzyme, SDS-PAGE
tetramer
Q93088
wild-type enzyme and mutant enzymes E266A, H338A, R346A, R361A, P362A, N364A and P365A
tetramer
-
crystallization data and sedimentation velocity experiments
tetramer
-
-
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
additional information
-
the enzyme can be modified by tissue-type transglutaminase and its activity is regulated repressively by the modification, especially by the cross-linking. This regulatory reaction might be involved in the regulation of homocysteine metabolism in the liver
Crystallization/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
by multiple anomalous diffraction
-
recombinant enzyme
-
crystals with P2(1) symmetry, assymetric unit contains the whole functional tetramer showing point symmetry 222
-
recombinant enzyme
-
pH STABILITY
pH STABILITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
5.5
-
-
above, 4 h stable at 37C
TEMPERATURE STABILITY
TEMPERATURE STABILITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
additional information
-
-
significant heat stability
GENERAL STABILITY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
divalent cations and 2-mercaptoethanol do not stabilize during purification
-
lyophilization inactivates
-
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
-
substrates stabilize during purification
-
glycerol does not stabilize
-
mechanism of unfolding by urea includes two intermediate states, a tetramer and a monomer. Dissociation is concomitant with alterations in the dimerization arm and the loop connecting the C-terminal helix, and intermediate conformations originate from perturbations in these structures
-
OXIDATION STABILITY
ORGANISM
UNIPROT ACCESSION NO.
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 ACCESSION NO.
LITERATURE
-20C, many months in 50% v/v glycerol
-
-20C, over a year in 50% v/v glycerol
-
stable for a minimum of one month at 4C in a mixture with human recombinant betaine-homocysteine S-methyltransferase (copurified with human recombinant betaine-homocysteine S-methyltransferase)
-
-20C, 2 weeks in the presence of substrates
-
-20C, 40% loss of activity after 4 weeks in the presence of substrates
-
-20C, 70% loss of activity after 10 weeks in the presence of substrates
-
Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
partial
-
stabilized by copurification with human recombinant betaine-homocysteine S-methyltransferase, chitin affinity chromatography
-
two forms of the enzyme
-
wild-type and mutant enzymes are overexpressed in Escherichia coli and purified using the ImpactTM T7 system
-
FPLC-chromatofocusing, 3 active forms
-
Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
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
Q6EI07
expressed in COS-1 cells and in Escherichia coli; 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
-
expressed in Escherichia coli BL21(DE3) (coexpression of human recombinant betaine-homocysteine S-methyltransferase)
-
expressed in Hep-G2 cell
-
glutathione S-transferase-BHMT fusion protein is expressed in HEK-293, T98G, A-10, MCF-7, H-1299, C2C12, and NIH-3T3 cells
-
transiently expressed in HepG2-cells and primary mouse hepatocytes
-
EXPRESSION
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
decreased expression after exogenous addition of all-trans-retinoic acid
-
corticosteroids down-regulate in kidney expression and activity
-
significant upregulation of betaine homocysteine methyltransferase-1 in livers of rats fed a betaine supplemented ethanol diet
-
the activity of hepatic BHMT significantly increases with increase in both dietary casein level and dietary methionine level, hepatic level of mRNA for BHMT is parallel to the enzyme activity
-
corticosteroids stimulate activity in the liver and also up-regulate the gene expression
-
ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
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
DELTA325-406
Q93088
truncation mutatnt does not express well in Escherichia coli and is inactive
DELTA371-406
Q93088
truncation mutant does not express well in Escherichia coli and is inactive
E266A
Q93088
near-normal catalytic activity
G199S
-
in vascular patients with hyperhomocysteinemia
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)
N364A
Q93088
normal or near-normal ability to bind zinc, near-normal catalytic activity
P362A
Q93088
normal or near-normal ability to bind zinc, near-normal catalytic activity
P365A
Q93088
normal or near-normal ability to bind zinc, near-normal catalytic activity
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
R346A
Q93088
normal or near-normal ability to bind zinc, negligible activity, elution as dimer, aberrant crosslinking properties
R361A
Q93088
normal or near-normal ability to bind zinc, near-normal catalytic activity
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
Q93088
negligible activity, elution as dimer, aberrant crosslinking properties
W352A
-
the mutation disrupts stable BHMT multimerization, the mutant ablates 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
R346A
-
shows alterations in the association state
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
W352A
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shows alterations in the association state
Y363A
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shows alterations in the association state
Y77A
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14fold reduced turnover-number for betaine and L-homocysteine, maximal velocity is 13.7fold lower than the wild-type value
H338A
Q93088
normal or near-normal ability to bind zinc, 10% of the wild-type activity
additional information
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random mutagenesis of zinc binding motif, Gly214 is essential
additional information
Q6EI07
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; 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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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
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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
Y363A
Q93088
normal or near-normal ability to bind zinc, near-normal catalytic activity
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
F74A
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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
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
APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
analysis
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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
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effect of extrahepatic expression of homo sapiens betaine-homocysteine methyltransferase on alcohol or homocysteine-induced fatty liver is shown in transgenic mice
medicine
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a polymorphisms in betaine-homocysteine S-methyltransferase might be linked to an increased risk for placental abruption
molecular biology
Q6EI07
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
medicine
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decreased plasma homocysteine in various models of diabetes may be due to enhanced homocysteine removal brought about by a combination of increased transsulfuration of homocysteine to cysteine and increased remethylation of homocysteine to methionine by BHMT
medicine
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upregulation of BHMT may indicate an increased choline requirement in the diabetic rat
medicine
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Zucker diabetic fatty rats show increased BHMT activity and mRNA levels
medicine
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methionine-deficient diet produces large increase in enzyme activity
additional information
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in contrast to previous suppositions based on enzyme activity, under most dietary conditions, the quantity of homocysteine remethylated by methionine synthase appeared to exceed that remethylated by the alternate betaine-homocysteine methyltransferase pathway
molecular biology
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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
additional information
Q6EI07
lower BHMT expression can impair homocysteine metabolism, which can induce endoplasmic reticulum stress
medicine
-
transient inhibition of BHMT in vivo causes transient hyperhomocysteinemia
additional information
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Bhmt expression is strongly regulated by changes in ambient osmolarity, osmotic regulation of BHMT may be part of a cell volume-regulatory response and additionally leads to metabolic alterations that depend on the availability of betaine-derived methyl groups
additional information
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sequence of the pseudogene BHMT2 shows 97% homology to mouse BHMT
additional information
Mus musculus C57BL/6J
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sequence of the pseudogene BHMT2 shows 97% homology to mouse BHMT
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molecular biology
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osmotic regulation of BHMT may be part of a cell volume-regulatory response and additionally lead to metabolic alterations that depend on the availability of betaine-derived methyl groups
additional information
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Bhmt expression is strongly regulated by changes in ambient osmolarity, osmotic regulation of BHMT may be part of a cell volume-regulatory response and additionally leads to metabolic alterations that depend on the availability of betaine-derived methyl groups
additional information
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relationship between BHMT expression and ApoB mRNA in transfected McA cells recapitulated in vivo through dietary BHMT induction, providing additional support for a physiologic linkage between 1-carbon metabolism and apob gene expression