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Information on EC 1.16.1.8 - [methionine synthase] reductase and Organism(s) Homo sapiens

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EC Tree
     1 Oxidoreductases
         1.16 Oxidizing metal ions
             1.16.1 With NAD+ or NADP+ as acceptor
                1.16.1.8 [methionine synthase] reductase
IUBMB Comments
In humans, the enzyme is a flavoprotein containing FAD and FMN. The substrate of the enzyme is the inactivated cobalt(II) form of EC 2.1.1.13, methionine synthase. Electrons are transferred from NADPH to FAD to FMN. Defects in this enzyme lead to hereditary hyperhomocysteinemia.
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This record set is specific for:
Homo sapiens
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Word Map
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Synonyms
methionine synthase reductase, nadph-dependent diflavin oxidoreductase, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Methionine synthase cob(II)alamin reductase (methylating)
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-
-
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Methionine synthase reductase
NADPH-dependent diflavin oxidoreductase
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Reductase, methionine synthase
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-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
2 [methionine synthase]-methylcob(III)alamin + 2 S-adenosyl-L-homocysteine + NADP+ = 2 [methionine synthase]-cob(II)alamin + NADPH + H+ + 2 S-adenosyl-L-methionine
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
methyl group transfer
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-
-
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PATHWAY SOURCE
PATHWAYS
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SYSTEMATIC NAME
IUBMB Comments
[methionine synthase]-methylcob(III)alamin,S-adenosyl-L-homocysteine:NADP+ oxidoreductase
In humans, the enzyme is a flavoprotein containing FAD and FMN. The substrate of the enzyme is the inactivated cobalt(II) form of EC 2.1.1.13, methionine synthase. Electrons are transferred from NADPH to FAD to FMN. Defects in this enzyme lead to hereditary hyperhomocysteinemia.
CAS REGISTRY NUMBER
COMMENTARY hide
207004-87-3
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SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
2 [methionine synthase]-cob(II)alamin + NADPH + H+ + 2 S-adenosyl-L-methionine
2 [methionine synthase]-methylcob(I)alamin + 2 S-adenosylhomocysteine + NADP+
show the reaction diagram
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-
-
?
2 [methionine synthase]-methylcob(I)alamin + 2 S-adenosylhomocysteine + NADP+
2 [methionine synthase]-cob(II)alamin + NADPH + H+ + 2 S-adenosyl-L-methionine
show the reaction diagram
[methionine synthase]-cob(II)alamin + NADH + S-adenosyl-L-methionine
[methionine synthase]methylcob(I)alamin + S-adenosylhomocysteine + NAD+
show the reaction diagram
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-
-
-
?
[Methionine synthase]-cob(II)alamin + NADPH + S-adenosyl-L-methionine
?
show the reaction diagram
[Methionine synthase]-cob(II)alamin + NADPH + S-adenosyl-L-methionine
[Methionine synthase]methylcob(I)alamin + S-adenosylhomocysteine + NADP+
show the reaction diagram
[methionine synthase]-cob(II)alamin + NADPH + S-adenosylmethionine
[methionine synthase]-methylcob(I)alamin + NADPH + S-adenosylhomocysteine
show the reaction diagram
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in presence of methionine synthase reductase, holoenzyme formation from apomethionine synthase and methylcobalamin is significantly enhanced due to stabilization of apomethionine synthase. In addition to reductase activity, methionine synthase reductase serves as a special chaperone for methionine synthase. It also has reductase activity for the reaction of aquacobalamin to cob(II)alamin
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-
?
[methionine synthase]-cob(II)alamin + S-adenosyl-L-methionine + 2,6-dichlorophenolindophenol
[methionine synthase]methylcob(I)alamin + S-adenosylhomocysteine + ?
show the reaction diagram
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-
-
?
[methionine synthase]-cob(II)alamin + S-adenosyl-L-methionine + 3-acetylpyridine adenine dinucleotide phosphate
[methionine synthase]methylcob(I)alamin + S-adenosylhomocysteine + ?
show the reaction diagram
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-
-
?
[methionine synthase]-cob(II)alamin + S-adenosyl-L-methionine + doxorubicin
[methionine synthase]methylcob(I)alamin + S-adenosylhomocysteine + ?
show the reaction diagram
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-
-
?
[methionine synthase]-cob(II)alamin + S-adenosyl-L-methionine + ferricyanide
[methionine synthase]methylcob(I)alamin + S-adenosylhomocysteine + ?
show the reaction diagram
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-
-
?
[methionine synthase]-cob(II)alamin + S-adenosyl-L-methionine + menadione
[methionine synthase]methylcob(I)alamin + S-adenosylhomocysteine + ?
show the reaction diagram
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-
-
?
[methionine synthase]-methylcob(I)alamin + S-adenosylhomocysteine + NADP+
[methionine synthase]-cob(II)alamin + NADPH + S-adenosyl-L-methionine
show the reaction diagram
additional information
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
2 [methionine synthase]-cob(II)alamin + NADPH + H+ + 2 S-adenosyl-L-methionine
2 [methionine synthase]-methylcob(I)alamin + 2 S-adenosylhomocysteine + NADP+
show the reaction diagram
-
-
-
?
2 [methionine synthase]-methylcob(I)alamin + 2 S-adenosylhomocysteine + NADP+
2 [methionine synthase]-cob(II)alamin + NADPH + H+ + 2 S-adenosyl-L-methionine
show the reaction diagram
-
-
-
?
[Methionine synthase]-cob(II)alamin + NADPH + S-adenosyl-L-methionine
?
show the reaction diagram
[methionine synthase]-methylcob(I)alamin + S-adenosylhomocysteine + NADP+
[methionine synthase]-cob(II)alamin + NADPH + S-adenosyl-L-methionine
show the reaction diagram
additional information
?
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
NADH
-
can replace NADPH but only at significantly higher and nonphysiological concentrations
NADP+
NADPH
additional information
-
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2',5'-ADP
NADP+
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0023 - 0.0038
2,6-dichlorophenolindophenol
0.0177 - 0.018
3-acetylpyridine adenine dinucleotide phosphate
0.0286 - 0.0366
doxorubicin
0.663 - 0.774
ferricyanide
0.0177 - 0.018
menadione
0.0024 - 0.015
NADPH
additional information
additional information
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.43
2,6-dichlorophenolindophenol
variant I22/S175
0.86
3-acetylpyridine adenine dinucleotide phosphate
variant I22/S175
1.61
doxorubicin
variant I22/S175
8.24
ferricyanide
variant I22/S175
1.61
menadione
variant I22/S175
3.6 - 7.8
NADPH
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0001 - 0.0014
2',5'-ADP
0.003 - 0.0729
NADP+
additional information
additional information
-
steady-state inhibition studies
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
1.56
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
22 - 25
assay at
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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in vivo quantitative real-time PCR analysis of MTRR mRNA in cardiac tissue samples from congenital heart disease patients, overview
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
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-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
metabolism
physiological function
additional information
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
MTRR_HUMAN
698
0
77674
Swiss-Prot
other Location (Reliability: 4)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
77000
78000
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
monomer
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1 * 78000, SDS-PAGE
additional information
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
MSR NADP(H)/FAD domain complex, sitting drop vapor diffusion method, 4°C, 10 mg/ml protein in 10 mM Tris/HCl, pH 8.0, 0.5 mM DTT, 1 mM EDTA, and 0.05% NaN3, reservoir solution comprising 0.1 M Tris/HCl, pH 7.5, 0.2 M KBr, and 15% PEG 4000, crystal soaking in saturated NADP+ solution, X-ray diffraction structure determination and analysis at 1.9 A resolution
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
A312H
site-directed mutangenesis, mutation of the catalytic residue leads to the kinetic coupling of hydride and interflavin electron transfer, and eliminates the formation of the FAD hydroquinone intermediate, substitution of Ala312 for His in MSR weakens NADP(H) binding as the Km for NADPH and Ki for NADP+ increases 6 and 1.7fold, respectively. NADPH reduction of A312H resembles that of native cytochrome P450 reductase, in that it occurs in two discrete kinetic phases, without the transient formation of the E-FADH2-FMN intermediate
A312Q
site-directed mutangenesis, the catalytic site mutant shows a 2.5fold increased Km and a slightly decreased Ki for the coenzyme FAD
A66G
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naturally occuring mutation, the MTRR polymorphism leads to a lower affinity for substrate methionine synthase compared to the wild-type enzyme
I22M
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natural occuring polymorphism, no significant association with bone mineral density or serum osteocalcin level
S175L
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natural occuring polymorphism, no significant association with bone mineral density or serum osteocalcin level
S698A
site-directed mutagenesis, the mutant shows reduced activity with cytochrome c3+ as substrate compared to the wild-type enzyme, the S698A mutant displays a 6fold reduction in kcat/Km for NADPH
W697F
site-directed mutagenesis, the mutant shows enhanced catalysis, noted by increases in kcat and kcat/Km(NADPH) for steady-state cytochrome c3+ reduction and a 10fold increase in the rate constant associated with hydride transfer, W697F shows a 2.4fold increase in kcat and a 4.8fold increase in catalytic efficiency for NADPH. The mutant displays modest decreases in cytochrome c3+ reduction, a 30fold decrease in the rate of FAD reduction, accumulation of a FADH2-NADP+ charge-transfer complex, and dramatically suppressed rates of interflavin electron transfer
W697H
site-directed mutagenesis, the mutant shows increased activity with cytochrome c3+ as substrate compared to the wild-type enzyme
W697S
site-directed mutagenesis, the mutant shows reduced activity with cytochrome c3+ as substrate compared to the wild-type enzyme
W697Y
site-directed mutagenesis, the mutant shows enhanced catalysis, noted by increases in kcat and kcat/Km(NADPH) for steady-state cytochrome c3+ reduction and a 10fold increase in the rate constant associated with hydride transfer. W697Y shows a 3.4fold increase in kcat and a 6.7fold increase in catalytic efficiency for NADPH. The mutant displays modest decreases in cytochrome c3+ reduction, a 3.5fold decrease in the rate of FAD reduction, accumulation of a FADH2-NADP+ charge-transfer complex, and dramatically suppressed rates of interflavin electron transfer
additional information
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
after expression by baculovirus-infected insect cells. the flavin mononuleotide cofactor dissociates readily from enzyme upon dilution, hence it is important to keep the concentration high during purification
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recombinant enzyme
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recombinant GST-tagged full-length enzyme and flavin-binding domain by glutathione affinity and anion exchange chromatography, followed by ultrafiltration
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression in Escherichia coli
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expression of full-length enzyme and flavin-binding domain as GST-tagged proteins
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gene MTRR, genotyping
gene MTRR, genotyping for the A66G polymorphism and analysis of the association with cancer risk, overview. The G allele and GG variant genotypes are associated with a significantly increased cancer risk
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gene MTRR, genotyping, and identification and mapping of single nucleotide polymorphisms
MTRR genotyping, quantitative real-time PCR enzyme expression analysis
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recombinant expression of wild-type and mutant enzymes in Escherichia coli strain Rosetta2(DE3)pLysS
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
the c.56+781 A>C (rs326119) variant of intron-1 of MTRR significantly increases the risk of congenital heart disease in the Han Chinese population. The c.56+781 C allele profoundly decreases MTRR transcription
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
diagnostics
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the MTRR A66G polymorphism is a potential biomarker for cancer risk
medicine
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Leclerc, D.; Wilson, A.; Dumas, R.; Gafuik, C.; Song, D.; Watkins, D.; Heng, H.H.Q.; Rommens, J.M.; Scherer, S.W.; Rosenblatt, D.S.; Gravel, R.A.
Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria
Proc. Natl. Acad. Sci. USA
95
3059-3064
1998
Homo sapiens (Q9UBK8), Homo sapiens
Manually annotated by BRENDA team
Olteanu, H.; Munson, T.; Banerjee, R.
Differences in the efficiency of reductive activation of methionine synthase and exogenous electron acceptors between the common polymorphic variants of human methionine synthase reductase
Biochemistry
41
13378-13385
2002
Homo sapiens (Q9UBK8), Homo sapiens
Manually annotated by BRENDA team
Olteanu, H.; Wolthers, K.R.; Munro, A.W.; Scrutton, N.S.; Banerjee, R.
Kinetic and thermodynamic characterization of the common polymorphic variants of human methionine synthase reductase
Biochemistry
43
1988-1997
2004
Homo sapiens
Manually annotated by BRENDA team
Olteanu, H.; Banerjee, R.
Human methionine synthase reductase, a soluble P-450 reductase-like dual flavoprotein, is sufficient for NADPH-dependent methionine synthase activation
J. Biol. Chem.
276
35558-35563
2001
Homo sapiens
Manually annotated by BRENDA team
Wilson, A.; Platt, R.; Wu, Q.; Leclerc, D.; Christensen, B.; Yang, H.; Gravel, R.A.; Rozen, R.
A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida
Mol. Genet. Metab.
67
317-323
1999
Homo sapiens
Manually annotated by BRENDA team
Kim, D.J.; Park, B.L.; Koh, J.M.; Kim, G.S.; Kim, L.H.; Cheong, H.S.; Shin, H.D.; Hong, J.M.; Kim, T.H.; Shin, H.I.; Park, E.K.; Kim, S.Y.
Methionine synthase reductase polymorphisms are associated with serum osteocalcin levels in postmenopausal women
Exp. Mol. Med.
38
519-524
2006
Homo sapiens
Manually annotated by BRENDA team
Yamada, K.; Gravel, R.A.; Toraya, T.; Matthews, R.G.
Human methionine synthase reductase is a molecular chaperone for human methionine synthase
Proc. Natl. Acad. Sci. USA
103
9476-9481
2006
Homo sapiens
Manually annotated by BRENDA team
Wolthers, K.R.; Lou, X.; Toogood, H.S.; Leys, D.; Scrutton, N.S.
Mechanism of coenzyme binding to human methionine synthase reductase revealed through the crystal structure of the FNR-like module and isothermal titration calorimetry
Biochemistry
46
11833-11844
2007
Homo sapiens
Manually annotated by BRENDA team
Wolthers, K.R.; Scrutton, N.S.
Protein interactions in the human methionine synthase-methionine synthase reductase complex and implications for the mechanism of enzyme reactivation
Biochemistry
46
6696-6709
2007
Homo sapiens
Manually annotated by BRENDA team
Rigby, S.; Lou, X.; Toogood, H.; Wolthers, K.; Scrutton, N.
ELDOR spectroscopy reveals that energy landscapes in human methionine synthase reductase are extensively remodelled following ligand and partner protein binding
ChemBioChem
12
863-867
2011
Homo sapiens
Manually annotated by BRENDA team
Han, D.; Shen, C.; Meng, X.; Bai, J.; Chen, F.; Yu, Y.; Jin, Y.; Fu, S.
Methionine synthase reductase A66G polymorphism contributes to tumor susceptibility: evidence from 35 case-control studies
Mol. Biol. Rep.
39
805-816
2012
Homo sapiens
Manually annotated by BRENDA team
Meints, C.E.; Gustafsson, F.S.; Scrutton, N.S.; Wolthers, K.R.
Tryptophan 697 modulates hydride and interflavin electron transfer in human methionine synthase reductase
Biochemistry
50
11131-11142
2011
Homo sapiens (Q9UBK8), Homo sapiens
Manually annotated by BRENDA team
Zhao, J.; Yang, X.; Gong, X.; Gu, Z.; Duan, W.; Wang, J.; Ye, Z.; Shen, H.; Shi, K.; Hou, J.; Huang, G.; Jin, L.; Qiao, B.; Wang, H.
A functional variant in MTRR intron-1 significantly increases the risk of congenital heart disease in han Chinese population
Circulation
125
482-490
2012
Homo sapiens
Manually annotated by BRENDA team
Meints, C.E.; Simtchouk, S.; Wolthers, K.R.
Aromatic substitution of the FAD-shielding tryptophan reveals its differential role in regulating electron flux in methionine synthase reductase and cytochrome P450 reductase
FEBS J.
280
1460-1474
2013
Homo sapiens (Q9UBK8)
Manually annotated by BRENDA team
Meints, C.E.; Parke, S.M.; Wolthers, K.R.
Proximal FAD histidine residue influences interflavin electron transfer in cytochrome P450 reductase and methionine synthase reductase
Arch. Biochem. Biophys.
547
18-26
2014
Homo sapiens (Q9UBK8), Homo sapiens
Manually annotated by BRENDA team
Haque, M.M.; Bayachou, M.; Tejero, J.; Kenney, C.T.; Pearl, N.M.; Im, S.C.; Waskell, L.; Stuehr, D.J.
Distinct conformational behaviors of four mammalian dual-flavin reductases (cytochrome P450 reductase, methionine synthase reductase, neuronal nitric oxide synthase, endothelial nitric oxide synthase) determine their unique catalytic profiles
FEBS J.
281
5325-5340
2014
Homo sapiens (Q9UBK8)
Manually annotated by BRENDA team
Garcia-Minguillan, C.J.; Fernandez-Ballart, J.D.; Ceruelo, S.; Rios, L.; Bueno, O.; Berrocal-Zaragoza, M.I.; Molloy, A.M.; Ueland, P.M.; Meyer, K.; Murphy, M.M.
Riboflavin status modifies the effects of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) polymorphisms on homocysteine
Genes Nutr.
9
435
2014
Homo sapiens (Q9UBK8)
Manually annotated by BRENDA team
Cheng, H.; Li, H.; Bu, Z.; Zhang, Q.; Bai, B.; Zhao, H.; Li, R.K.; Zhang, T.; Xie, J.
Functional variant in methionine synthase reductase intron-1 is associated with pleiotropic congenital malformations
Mol. Cell. Biochem.
407
51-56
2015
Homo sapiens (Q9UBK8)
Manually annotated by BRENDA team