DB code: M00172

CATH domain 3.20.20.- : TIM Barrel
3.20.20.- : TIM Barrel
1.10.1240.10 : Methyltransferase, Methionine Synthase (B12-binding Domains); Chain A, domain 1
3.40.50.280 : Rossmann fold Catalytic domain
3.10.196.10 : Cobalamin-dependent Methionine Synthase; domain 1
1.10.288.10 : Cobalamin-dependent Methionine Synthase; domain 2
E.C. 2.1.1.13
CSA 1bmt
M-CSA 1bmt
MACiE M0268

CATH domain Related DB codes (homologues)
3.40.50.280 : Rossmann fold M00168 T00236

Uniprot Enzyme Name
UniprotKB Protein name Synonyms RefSeq Pfam
P13009 Methionine synthase
EC 2.1.1.13
5-methyltetrahydrofolate--homocysteine methyltransferase
Methionine synthase, vitamin-B12-dependent
MS
NP_418443.1 (Protein)
NC_000913.2 (DNA/RNA sequence)
YP_492162.1 (Protein)
NC_007779.1 (DNA/RNA sequence)
PF02310 (B12-binding)
PF02607 (B12-binding_2)
PF02965 (Met_synt_B12)
PF00809 (Pterin_bind)
PF02574 (S-methyl_trans)
[Graphical View]

KEGG enzyme name
methionine synthase
5-methyltetrahydrofolate---homocysteine S-methyltransferase
5-methyltetrahydrofolate---homocysteine transmethylase
N-methyltetrahydrofolate:L-homocysteine methyltransferase
N5-methyltetrahydrofolate methyltransferase
N5-methyltetrahydrofolate-homocysteine cobalamin methyltransferase
N5-methyltetrahydrofolic---homocysteine vitamin B12 transmethylase
B12 N5-methyltetrahydrofolate homocysteine methyltransferase
methyltetrahydrofolate---homocysteine vitamin B12 methyltransferase
tetrahydrofolate methyltransferase
tetrahydropteroylglutamate methyltransferase
tetrahydropteroylglutamic methyltransferase
vitamin B12 methyltransferase
cobalamin-dependent methionine synthase
methionine synthase (cobalamin-dependent)
MetH

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P13009 METH_ECOLI 5-methyltetrahydrofolate + L-homocysteine = tetrahydrofolate + L-methionine. Cobalamin. Binds 1 zinc ion per subunit.

KEGG Pathways
Map code Pathways E.C.
MAP00271 Methionine metabolism
MAP00670 One carbon pool by folate

Compound table
Cofactors Substrates Products Intermediates
KEGG-id C05776 C05199 C00038 C00440 C00155 C00019 C00101 C00073 C00021
E.C.
Compound Vitamin B12 Flavodoxin Zinc 5-Methyltetrahydrofolate L-Homocysteine S-Adenosyl-L-methionine Tetrahydrofolate L-Methionine S-Adenosyl-L-homocysteine
Type amide group,amine group,aromatic ring (with nitrogen atoms),carbohydrate,heavy metal,nucleotide amide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carbohydrate,peptide/protein,phosphate group/phosphate ion heavy metal amino acids,amide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carboxyl group amino acids,sulfhydryl group amino acids,amine group,nucleoside,sulfonium ion amino acids,amide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carboxyl group amino acids,sulfide group amino acids,amine group,nucleoside,sulfide group
ChEBI 29105
15641
17588
58199
67040
15635
20506
16643
57844
16680
57856
PubChem 32051
439234
444412
6971015
91552
34755
5460413
91443
6137
6992087
25246222
439155
1bmtA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1bmtB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1k7yA03 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1k98A03 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1bmtA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Analogue:COB Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Intermediate-bound:COB
1bmtB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Analogue:COB Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Intermediate-bound:COB
1k7yA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:B12 Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1k98A01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:B12 Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1mskA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Bound:SAM Unbound Unbound Unbound Unbound
1k7yA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1k98A02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1mskA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1k7yA04 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1k98A04 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.
Swiss-prot;P13009 & literature [7], [27]

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1bmtA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1bmtB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1k7yA03 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1k98A03 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1bmtA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 757;HIS 759;SER 810 HIS 759(Cobamide binding)
1bmtB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 757;HIS 759;SER 810 HIS 759(Cobamide binding)
1k7yA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 757;;SER 810 mutant H759G
1k98A01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 757;;SER 810 mutant H759G
1mskA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1k7yA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1k98A02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1mskA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1k7yA04 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1k98A04 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[3]
p.1451-1453, p.1455-1458
[5]
Fig.1
[6]
p.924-925
[7]
p.1663-1664
[8]
Fig.8, p.1673-1674
[9]
Fig.1, Fig.2
[10]
[11]
Scheme 1, p.2472-2475
[12]
Fig.1, p.1271-1272
[13]
Fig.5,Fig.7, p.278-283
[15]
Fig.1, Fig.7, p.8089-8091
[17]
Fig.1, Fig.2, Fig.10, p.15745-15747
[18]
p.334-335
[19]
Fig.8, p.5380-5381
[20]
Fig.1, Fig.9, p.10718-10719
[21]
Fig.8, p.13888-13889
[22]
Fig.1, Fig.8, p.5062-5064
[26]
eq. 3
[27]
Scheme 1, p.2555
[28]
p.53-55
[29]
Fig.1
[30]
Fig.1, Table 1

References
[1]
Resource
Comments
Medline ID
PubMed ID 2853966
Journal Biochemistry
Year 1988
Volume 27
Pages 8458-65
Authors Frasca V, Banerjee RV, Dunham WR, Sands RH, Matthews RG
Title Cobalamin-dependent methionine synthase from Escherichia coli B: electron paramagnetic resonance spectra of the inactive form and the active methylated form of the enzyme.
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID 2157485
Journal Biochemistry
Year 1990
Volume 29
Pages 1129-35
Authors Banerjee RV, Harder SR, Ragsdale SW, Matthews RG
Title Mechanism of reductive activation of cobalamin-dependent methionine synthase: an electron paramagnetic resonance spectroelectrochemical study.
Related PDB
Related UniProtKB
[3]
Resource
Comments REVIEW
Medline ID 90169372
PubMed ID 2407589
Journal FASEB J
Year 1990
Volume 4
Pages 1450-9
Authors Banerjee RV, Matthews RG
Title Cobalamin-dependent methionine synthase.
Related PDB
Related UniProtKB P13009
[4]
Resource
Comments X-RAY CRYSTALLOGRAPHY.
Medline ID 92277660
PubMed ID 1593636
Journal J Mol Biol
Year 1992
Volume 225
Pages 557-60
Authors Luschinsky CL, Drummond JT, Matthews RG, Ludwig ML
Title Crystallization and preliminary X-ray diffraction studies of the cobalamin-binding domain of methionine synthase from Escherichia coli.
Related PDB
Related UniProtKB P13009
[5]
Resource
Comments
Medline ID
PubMed ID 8369297
Journal Biochemistry
Year 1993
Volume 32
Pages 9290-5
Authors Drummond JT, Huang S, Blumenthal RM, Matthews RG
Title Assignment of enzymatic function to specific protein regions of cobalamin-dependent methionine synthase from Escherichia coli.
Related PDB
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID 7712296
Journal Curr Opin Struct Biol
Year 1994
Volume 4
Pages 919-29
Authors Drennan CL, Matthews RG, Ludwig ML
Title Cobalamin-dependent methionine synthase: the structure of a methylcobalamin-binding fragment and implications for other B12-dependent enzymes.
Related PDB
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID 7992049
Journal Science
Year 1994
Volume 266
Pages 1663-4
Authors Stubbe J
Title Binding site revealed of nature's most beautiful cofactor.
Related PDB
Related UniProtKB
[8]
Resource
Comments X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS).
Medline ID 95084154
PubMed ID 7992050
Journal Science
Year 1994
Volume 266
Pages 1669-74
Authors Drennan CL, Huang S, Drummond JT, Matthews RG, Lidwig ML
Title How a protein binds B12: A 3.0 A X-ray structure of B12-binding domains of methionine synthase.
Related PDB 1bmt
Related UniProtKB P13009
[9]
Resource
Comments
Medline ID
PubMed ID 7743126
Journal Structure
Year 1995
Volume 3
Pages 121-2
Authors Evans PR
Title A tail of B12 binding.
Related PDB
Related UniProtKB
[10]
Resource
Comments
Medline ID
PubMed ID 8823155
Journal Biochemistry
Year 1996
Volume 35
Pages 12228-34
Authors Gonzalez JC, Peariso K, Penner-Hahn JE, Matthews RG
Title Cobalamin-independent methionine synthase from Escherichia coli: a zinc metalloenzyme.
Related PDB
Related UniProtKB
[11]
Resource
Comments
Medline ID
PubMed ID 8652590
Journal Biochemistry
Year 1996
Volume 35
Pages 2464-75
Authors Jarrett JT, Amaratunga M, Drennan CL, Scholten JD, Sands RH, Ludwig ML, Matthews RG
Title Mutations in the B12-binding region of methionine synthase: how the protein controls methylcobalamin reactivity.
Related PDB
Related UniProtKB
[12]
Resource
Comments X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 900-1226.
Medline ID 97094983
PubMed ID 8939751
Journal Structure
Year 1996
Volume 4
Pages 1263-75
Authors Dixon MM, Huang S, Matthews RG, Ludwig M
Title The structure of the C-terminal domain of methionine synthase: presenting S-adenosylmethionine for reductive methylation of B12.
Related PDB 1msk
Related UniProtKB P13009
[13]
Resource
Comments
Medline ID
PubMed ID 9242908
Journal Annu Rev Biochem
Year 1997
Volume 66
Pages 269-313
Authors Ludwig ML, Matthews RG
Title Structure-based perspectives on B12-dependent enzymes.
Related PDB
Related UniProtKB
[14]
Resource
Comments
Medline ID
PubMed ID 9398304
Journal Biochemistry
Year 1997
Volume 36
Pages 15749-57
Authors Goulding CW, Matthews RG
Title Cobalamin-dependent methionine synthase from Escherichia coli: involvement of zinc in homocysteine activation.
Related PDB
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID 9201956
Journal Biochemistry
Year 1997
Volume 36
Pages 8082-91
Authors Goulding CW, Postigo D, Matthews RG
Title Cobalamin-dependent methionine synthase is a modular protein with distinct regions for binding homocysteine, methyltetrahydrofolate, cobalamin, and adenosylmethionine.
Related PDB
Related UniProtKB
[16]
Resource
Comments
Medline ID
PubMed ID 8993326
Journal Biochemistry
Year 1997
Volume 36
Pages 127-38
Authors Hoover DM, Jarrett JT, Sands RH, Dunham WR, Ludwig ML, Matthews RG
Title Interaction of Escherichia coli cobalamin-dependent methionine synthase and its physiological partner flavodoxin: binding of flavodoxin leads to axial ligand dissociation from the cobalamin cofactor.
Related PDB
Related UniProtKB
[17]
Resource
Comments
Medline ID
PubMed ID 9398303
Journal Biochemistry
Year 1997
Volume 36
Pages 15739-48
Authors Jarrett JT, Choi CY, Matthews RG
Title Changes in protonation associated with substrate binding and Cob(I)alamin formation in cobalamin-dependent methionine synthase.
Related PDB
Related UniProtKB
[18]
Resource
Comments
Medline ID
PubMed ID 9667865
Journal Curr Opin Chem Biol
Year 1997
Volume 1
Pages 332-9
Authors Matthews RG, Goulding CW
Title Enzyme-catalyzed methyl transfers to thiols: the role of zinc.
Related PDB
Related UniProtKB
[19]
Resource
Comments
Medline ID
PubMed ID 9548919
Journal Biochemistry
Year 1998
Volume 37
Pages 5372-82
Authors Jarrett JT, Huang S, Matthews RG
Title Methionine synthase exists in two distinct conformations that differ in reactivity toward methyltetrahydrofolate, adenosylmethionine, and flavodoxin.
Related PDB
Related UniProtKB
[20]
Resource
Comments
Medline ID
PubMed ID 10978155
Journal Biochemistry
Year 2000
Volume 39
Pages 10711-9
Authors Hall DA, Jordan-Starck TC, Loo RO, Ludwig ML, Matthews RG
Title Interaction of flavodoxin with cobalamin-dependent methionine synthase.
Related PDB
Related UniProtKB
[21]
Resource
Comments
Medline ID
PubMed ID 11076529
Journal Biochemistry
Year 2000
Volume 39
Pages 13880-90
Authors Smith AE, Matthews RG
Title Protonation state of methyltetrahydrofolate in a binary complex with cobalamin-dependent methionine synthase.
Related PDB
Related UniProtKB
[22]
Resource
Comments
Medline ID
PubMed ID 11305922
Journal Biochemistry
Year 2001
Volume 40
Pages 5056-64
Authors Bandarian V, Matthews RG
Title Quantitation of rate enhancements attained by the binding of cobalamin to methionine synthase.
Related PDB
Related UniProtKB
[23]
Resource
Comments
Medline ID
PubMed ID 11170420
Journal Biochemistry
Year 2001
Volume 40
Pages 987-93
Authors Peariso K, Zhou ZS, Smith AE, Matthews RG, Penner-Hahn JE
Title Characterization of the zinc sites in cobalamin-independent and cobalamin-dependent methionine synthase using zinc and selenium X-ray absorption spectroscopy.
Related PDB
Related UniProtKB
[24]
Resource
Comments
Medline ID
PubMed ID 11327851
Journal Biochemistry
Year 2001
Volume 40
Pages 2317-25
Authors Tsuji SY, Wu N, Khosla C
Title Intermodular communication in polyketide synthases: comparing the role of protein-protein interactions to those in other multidomain proteins.
Related PDB
Related UniProtKB
[25]
Resource
Comments
Medline ID
PubMed ID 11493691
Journal Proc Natl Acad Sci U S A
Year 2001
Volume 98
Pages 9521-6
Authors Hall DA, Vander Kooi CW, Stasik CN, Stevens SY, Zuiderweg ER, Matthews RG
Title Mapping the interactions between flavodoxin and its physiological partners flavodoxin reductase and cobalamin-dependent methionine synthase.
Related PDB
Related UniProtKB
[26]
Resource
Comments
Medline ID
PubMed ID 12444763
Journal Inorg Chem
Year 2002
Volume 41
Pages 6217-24
Authors Dorweiler JS, Matthews RG, Finke RG
Title Providing a chemical basis toward understanding the histidine base-on motif of methylcobalamin-dependent methionine synthase: an improved purification of methylcobinamide, plus thermodynamic studies of methylcobinamide binding exogenous imidazole and pyridine bases.
Related PDB
Related UniProtKB
[27]
Resource
Comments
Medline ID
PubMed ID 11978125
Journal Inorg Chem
Year 2002
Volume 41
Pages 2548-55
Authors Zheng D, Yan L, Birke RL
Title Electrochemical and spectral studies of the reactions of aquocobalamin with nitric oxide and nitrite ion.
Related PDB
Related UniProtKB
[28]
Resource
Comments
Medline ID
PubMed ID 11731805
Journal Nat Struct Biol
Year 2002
Volume 9
Pages 53-6
Authors Bandarian V, Pattridge KA, Lennon BW, Huddler DP, Matthews RG, Ludwig ML
Title Domain alternation switches B(12)-dependent methionine synthase to the activation conformation.
Related PDB 1k7y 1k98
Related UniProtKB
[29]
Resource
Comments
Medline ID
PubMed ID 12832615
Journal Proc Natl Acad Sci U S A
Year 2003
Volume 100
Pages 8156-63
Authors Bandarian V, Ludwig ML, Matthews RG
Title Factors modulating conformational equilibria in large modular proteins: a case study with cobalamin-dependent methionine synthase.
Related PDB
Related UniProtKB
[30]
Resource
Comments
Medline ID
PubMed ID 15051336
Journal Methods Enzymol
Year 2004
Volume 380
Pages 152-69
Authors Bandarian V, Matthews RG
Title Measurement of energetics of conformational change in cobalamin-dependent methionine synthase.
Related PDB
Related UniProtKB

Comments
This enzyme is composed of the N-terminal homocysteine(Hcy)-binding domain, pterin-binding domain, cobalamin-binding domain, and the C-terminal AdoMet activation domain. Although the structures of the N-terminal domains, Hcy-binding domain and pterin-binding domain, have not been determined yet, their structures must be (alpha/beta)8 barrel structures, comparing the sequence data with their counterparts in Thermotoga maritima (Swissprot; Q9WYA5, PDB;1q7m).
This enzyme catalyzes several reactions, according to the literature [3]
In primary turnover cycle, this enzyme catalyzes methyl transfer from 5-methyl THF to the cobalt of Cobalamin (Vitamin B12), and then transfer of the methyl group to homocysteine, to produce methionine. On the other hand, in catalytic reactivation, the inactive form of this enzyme, cob(II)alamin form, accepts an electron from reduced flavodoxin, and also accepts a methyl group from AdoMet, giving oxidized flavodoxin and AdoHcy.
The N-terminal Hcy-binding domain must bind zinc ion, which activates the nucleophile, homocystein.

Created Updated
2004-11-25 2009-02-26