EzCatDB: M00172

DB codeM00172
CATH domainDomain 13.20.20.-
Domain 23.20.20.-
Domain 31.10.1240.10
Domain 43.40.50.280Catalytic domain
Domain 53.10.196.10
Domain 61.10.288.10
E.C.2.1.1.13
CSA1bmt
MACiEM0268

CATH domainRelated DB codes (homologues)
3.40.50.280M00168,T00236

Enzyme Name
Swiss-protKEGG

P13009
Protein nameMethionine synthasemethionine 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
SynonymsEC 2.1.1.13
5-methyltetrahydrofolate--homocysteine methyltransferase
Methionine synthase, vitamin-B12-dependent
MS

KEGG pathways
MAP codePathways
MAP00271Methionine metabolism
MAP00670One carbon pool by folate

Swiss-prot:Accession NumberP13009
Entry nameMETH_ECOLI
Activity5-methyltetrahydrofolate + L-homocysteine = tetrahydrofolate + L-methionine.
Subunit
Subcellular location
CofactorCobalamin.,Binds 1 zinc ion per subunit.


CofactorsSubstratesProductsintermediates
KEGG-idC05776C05199C00038C00440C00155C00019C00101C00073C00021
CompoundVitamin B12FlavodoxinZinc5-MethyltetrahydrofolateL-HomocysteineS-Adenosyl-L-methionineTetrahydrofolateL-MethionineS-Adenosyl-L-homocysteine
Typeamide group,amine group,aromatic ring (with nitrogen atoms),carbohydrate,heavy metal,nucleotideamide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carbohydrate,peptide/protein,phosphate group/phosphate ionheavy metalamino acids,amide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carboxyl groupamino acids,sulfhydryl groupamino acids,amine group,nucleoside,sulfonium ionamino acids,amide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carboxyl groupamino acids,sulfide groupamino acids,amine group,nucleoside,sulfide group
1bmtA01UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1bmtB01UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1k7yA03UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1k98A03UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1bmtA02Analogue:COBUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundIntermediate-bound:COB
1bmtB02Analogue:COBUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundIntermediate-bound:COB
1k7yA01Bound:B12UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1k98A01Bound:B12UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1mskA01UnboundUnboundUnboundUnboundUnboundBound:SAMUnboundUnboundUnboundUnbound
1k7yA02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1k98A02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1mskA02UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1k7yA04UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1k98A04UnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound

Active-site residues
resource
Swiss-prot;P13009 & literature [7], [27]
pdbCatalytic residuesCofactor-binding residuescomment
1bmtA01


1bmtB01


1k7yA03


1k98A03


1bmtA02ASP 757;HIS 759;SER 810
HIS 759(Cobamide binding)

1bmtB02ASP 757;HIS 759;SER 810
HIS 759(Cobamide binding)

1k7yA01ASP 757;       ;SER 810
                         
mutant H759G
1k98A01ASP 757;       ;SER 810
                         
mutant H759G
1mskA01


1k7yA02


1k98A02


1mskA02


1k7yA04


1k98A04



References for Catalytic Mechanism
ReferencesSectionsNo. 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]
PubMed ID2853966
JournalBiochemistry
Year1988
Volume27
Pages8458-65
AuthorsFrasca V, Banerjee RV, Dunham WR, Sands RH, Matthews RG
TitleCobalamin-dependent methionine synthase from Escherichia coli B: electron paramagnetic resonance spectra of the inactive form and the active methylated form of the enzyme.
[2]
PubMed ID2157485
JournalBiochemistry
Year1990
Volume29
Pages1129-35
AuthorsBanerjee RV, Harder SR, Ragsdale SW, Matthews RG
TitleMechanism of reductive activation of cobalamin-dependent methionine synthase: an electron paramagnetic resonance spectroelectrochemical study.
[3]
CommentsREVIEW
Medline ID90169372
PubMed ID2407589
JournalFASEB J
Year1990
Volume4
Pages1450-9
AuthorsBanerjee RV, Matthews RG
TitleCobalamin-dependent methionine synthase.
Related Swiss-protP13009
[4]
CommentsX-RAY CRYSTALLOGRAPHY.
Medline ID92277660
PubMed ID1593636
JournalJ Mol Biol
Year1992
Volume225
Pages557-60
AuthorsLuschinsky CL, Drummond JT, Matthews RG, Ludwig ML
TitleCrystallization and preliminary X-ray diffraction studies of the cobalamin-binding domain of methionine synthase from Escherichia coli.
Related Swiss-protP13009
[5]
PubMed ID8369297
JournalBiochemistry
Year1993
Volume32
Pages9290-5
AuthorsDrummond JT, Huang S, Blumenthal RM, Matthews RG
TitleAssignment of enzymatic function to specific protein regions of cobalamin-dependent methionine synthase from Escherichia coli.
[6]
PubMed ID7712296
JournalCurr Opin Struct Biol
Year1994
Volume4
Pages919-29
AuthorsDrennan CL, Matthews RG, Ludwig ML
TitleCobalamin-dependent methionine synthase: the structure of a methylcobalamin-binding fragment and implications for other B12-dependent enzymes.
[7]
PubMed ID7992049
JournalScience
Year1994
Volume266
Pages1663-4
AuthorsStubbe J
TitleBinding site revealed of nature's most beautiful cofactor.
[8]
CommentsX-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS).
Medline ID95084154
PubMed ID7992050
JournalScience
Year1994
Volume266
Pages1669-74
AuthorsDrennan CL, Huang S, Drummond JT, Matthews RG, Lidwig ML
TitleHow a protein binds B12: A 3.0 A X-ray structure of B12-binding domains of methionine synthase.
Related PDB1bmt
Related Swiss-protP13009
[9]
PubMed ID7743126
JournalStructure
Year1995
Volume3
Pages121-2
AuthorsEvans PR
TitleA tail of B12 binding.
[10]
PubMed ID8823155
JournalBiochemistry
Year1996
Volume35
Pages12228-34
AuthorsGonzalez JC, Peariso K, Penner-Hahn JE, Matthews RG
TitleCobalamin-independent methionine synthase from Escherichia coli: a zinc metalloenzyme.
[11]
PubMed ID8652590
JournalBiochemistry
Year1996
Volume35
Pages2464-75
AuthorsJarrett JT, Amaratunga M, Drennan CL, Scholten JD, Sands RH, Ludwig ML, Matthews RG
TitleMutations in the B12-binding region of methionine synthase: how the protein controls methylcobalamin reactivity.
[12]
CommentsX-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 900-1226.
Medline ID97094983
PubMed ID8939751
JournalStructure
Year1996
Volume4
Pages1263-75
AuthorsDixon MM, Huang S, Matthews RG, Ludwig M
TitleThe structure of the C-terminal domain of methionine synthase: presenting S-adenosylmethionine for reductive methylation of B12.
Related PDB1msk
Related Swiss-protP13009
[13]
PubMed ID9242908
JournalAnnu Rev Biochem
Year1997
Volume66
Pages269-313
AuthorsLudwig ML, Matthews RG
TitleStructure-based perspectives on B12-dependent enzymes.
[14]
PubMed ID9398304
JournalBiochemistry
Year1997
Volume36
Pages15749-57
AuthorsGoulding CW, Matthews RG
TitleCobalamin-dependent methionine synthase from Escherichia coli: involvement of zinc in homocysteine activation.
[15]
PubMed ID9201956
JournalBiochemistry
Year1997
Volume36
Pages8082-91
AuthorsGoulding CW, Postigo D, Matthews RG
TitleCobalamin-dependent methionine synthase is a modular protein with distinct regions for binding homocysteine, methyltetrahydrofolate, cobalamin, and adenosylmethionine.
[16]
PubMed ID8993326
JournalBiochemistry
Year1997
Volume36
Pages127-38
AuthorsHoover DM, Jarrett JT, Sands RH, Dunham WR, Ludwig ML, Matthews RG
TitleInteraction of Escherichia coli cobalamin-dependent methionine synthase and its physiological partner flavodoxin: binding of flavodoxin leads to axial ligand dissociation from the cobalamin cofactor.
[17]
PubMed ID9398303
JournalBiochemistry
Year1997
Volume36
Pages15739-48
AuthorsJarrett JT, Choi CY, Matthews RG
TitleChanges in protonation associated with substrate binding and Cob(I)alamin formation in cobalamin-dependent methionine synthase.
[18]
PubMed ID9667865
JournalCurr Opin Chem Biol
Year1997
Volume1
Pages332-9
AuthorsMatthews RG, Goulding CW
TitleEnzyme-catalyzed methyl transfers to thiols: the role of zinc.
[19]
PubMed ID9548919
JournalBiochemistry
Year1998
Volume37
Pages5372-82
AuthorsJarrett JT, Huang S, Matthews RG
TitleMethionine synthase exists in two distinct conformations that differ in reactivity toward methyltetrahydrofolate, adenosylmethionine, and flavodoxin.
[20]
PubMed ID10978155
JournalBiochemistry
Year2000
Volume39
Pages10711-9
AuthorsHall DA, Jordan-Starck TC, Loo RO, Ludwig ML, Matthews RG
TitleInteraction of flavodoxin with cobalamin-dependent methionine synthase.
[21]
PubMed ID11076529
JournalBiochemistry
Year2000
Volume39
Pages13880-90
AuthorsSmith AE, Matthews RG
TitleProtonation state of methyltetrahydrofolate in a binary complex with cobalamin-dependent methionine synthase.
[22]
PubMed ID11305922
JournalBiochemistry
Year2001
Volume40
Pages5056-64
AuthorsBandarian V, Matthews RG
TitleQuantitation of rate enhancements attained by the binding of cobalamin to methionine synthase.
[23]
PubMed ID11170420
JournalBiochemistry
Year2001
Volume40
Pages987-93
AuthorsPeariso K, Zhou ZS, Smith AE, Matthews RG, Penner-Hahn JE
TitleCharacterization of the zinc sites in cobalamin-independent and cobalamin-dependent methionine synthase using zinc and selenium X-ray absorption spectroscopy.
[24]
PubMed ID11327851
JournalBiochemistry
Year2001
Volume40
Pages2317-25
AuthorsTsuji SY, Wu N, Khosla C
TitleIntermodular communication in polyketide synthases: comparing the role of protein-protein interactions to those in other multidomain proteins.
[25]
PubMed ID11493691
JournalProc Natl Acad Sci U S A
Year2001
Volume98
Pages9521-6
AuthorsHall DA, Vander Kooi CW, Stasik CN, Stevens SY, Zuiderweg ER, Matthews RG
TitleMapping the interactions between flavodoxin and its physiological partners flavodoxin reductase and cobalamin-dependent methionine synthase.
[26]
PubMed ID12444763
JournalInorg Chem
Year2002
Volume41
Pages6217-24
AuthorsDorweiler JS, Matthews RG, Finke RG
TitleProviding 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.
[27]
PubMed ID11978125
JournalInorg Chem
Year2002
Volume41
Pages2548-55
AuthorsZheng D, Yan L, Birke RL
TitleElectrochemical and spectral studies of the reactions of aquocobalamin with nitric oxide and nitrite ion.
[28]
PubMed ID11731805
JournalNat Struct Biol
Year2002
Volume9
Pages53-6
AuthorsBandarian V, Pattridge KA, Lennon BW, Huddler DP, Matthews RG, Ludwig ML
TitleDomain alternation switches B(12)-dependent methionine synthase to the activation conformation.
Related PDB1k7y,1k98
[29]
PubMed ID12832615
JournalProc Natl Acad Sci U S A
Year2003
Volume100
Pages8156-63
AuthorsBandarian V, Ludwig ML, Matthews RG
TitleFactors modulating conformational equilibria in large modular proteins: a case study with cobalamin-dependent methionine synthase.
[30]
PubMed ID15051336
JournalMethods Enzymol
Year2004
Volume380
Pages152-69
AuthorsBandarian V, Matthews RG
TitleMeasurement of energetics of conformational change in cobalamin-dependent methionine synthase.

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.

createdupdated
2004-11-252009-02-26


Copyright: Nozomi Nagano, JST & CBRC-AIST
Funded by PRESTO/Japan Science and Technology Corporation (JST) (December 2001 - November 2004)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2010)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)

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