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Overview for MACiE Entry M0268

Version history

General Information

EC Number: 2.1.1.13 (A member of the Transferases, Transferring one-carbon groups, Methyltransferases)

Enzyme Name: methionine synthase

Biological Species: Escherichia coli (Bacteria)

Catalytic Chain UniprotKB Accession Codes:

Representative PDB Code: 1bmt - HOW A PROTEIN BINDS B12: A 3.O ANGSTROM X-RAY STRUCTURE OFTHE B12-BINDING DOMAINS OF METHIONINE SYNTHASE (Resolution = 3.00 Å).

Catalytic CATH Codes:

"Other" CATH Codes:

Display structure information

Overall Reaction:

Image of L-Homocysteine

Image of 5-Methyltetrahydrofolate

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Image of L-Methionine

Image of Tetrahydrofolate

L-Homocysteine
C00155
CHEBI:58199
5-Methyltetrahydrofolate
C00440
CHEBI:18608
L-Methionine
C00073
CHEBI:57844
Tetrahydrofolate
C00101
CHEBI:26907

Overall Comment: This enzyme is unique in E. coli in that it utilises methylcobalamin (rather than adenosylcobalamin) and catalysis involves a heterolytic (rather than homolytic) cleavage of the Co-C bond [5]. The Cob(I)alamin intermediate generated by this heterolytic cleavage is highly reactive and is occasionally oxidised to an inactive cob(II)alamin species. The enzyme must then re reactivated by reductive methylation to form methylcobalamin, which required S-adenosyl-methionine and an electron. In vitro, this oxidation occurs once every 100-2,000 turnovers, depending on the degree of anaerobiosis achieved during turnover. The physiological electron donor required for re-activation is believed to be flavodoxin and S-adenosyl-methionine is only required in catalytic amounts. [1,2]. It has been suggested that major domain rearrangements occur to allow the cobalamin reacts with its three different substrates [3]. Kinetic studies suggest that the methyltetrahydrofolate binds first to the enzyme, followed by homocysteine, which is then methylated by the cofactor, which is in turn re-methylated by the methyltetrahydrofolate [5].


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Stepwise Description of the Reaction

Step 1The sulfur of homocysteine initiates a nulceophilic attack on the methyl of methylcobalamin, forming Co(I)alamin and the methionine product in a substitution reaction. A proton relay between His759 and bulk solvent modulates the reactivity of the cobalamin cofactor.
Step 2The cob(I)alamin initiates a nucleophilic attack on the methyl group of methyltetrahydrofolate, proceeding through a three centre two electron bond, to form the methylcobalamin and covalently bound tetrahydrofolate.
Step 3The tetrahydrofolate product dissociated from the cobalamin cofactor with concomitant protonation (assumed to be from the bulk solvent).

View similar reactions (composite manual annotation)


Catalytic Residues Involved

Type Number Chain Location of Function
His 759 A Side Chain
Asp 757 A Side Chain
Ser 810 A Side Chain

Organic Cofactors for M0268

Type Identity Chain
methylcobalamin Cob 122 A Overview

Metal Cofactors for M0268

Type Het group Number Chain
cobalt COB 122 A Overview

References

  1. C. L. Drennan et al. (1994), Science, 266, 1669-1674. How a protein binds B12: A 3.0 A x-ray structure if B12-binding domains of methionine synthase.
    Medline: 7992050
  2. C. L. Drennan et al. (1994), Curr. Opin. Struct. Biol., 4, 919-929. Cobalamin-dependent methionine synthase: the structure of a methylcobalamin-binding fragment and implications for other B12 dependent enzymes.
    Medline: 7712296
  3. V. Bandarian et al. (2002), Nat. Struct. Biol., 9, 53-56. Domain alternation switches B12-dependent methionine synthase to the activation conformation.
    Medline: 11731805
  4. R. V. Banerjee et al. (1990), FASEB J., 4, 1450-1459. Cobalamin-dependent methionine synthase.
    Medline: 2407589
  5. J. T. Jarrett et al. (1996), Biochemistry, 35, 2464-2475. Mutations in the B12-Binding Region of Methionine Synthase: How the Protein Controls Methylcobalamin Reactivity.
    Medline: 8652590
  6. A. E. Smith et al. (2000), Biochemistry, 39, 13880-13890. Protonation state of methyltetrahydrofolate in a binary complex with cobalamin-dependent methionine synthase.
    Medline: 11076529

Homologue information for M0268 (1bmt)

CSA Homologues

MACiE Homologues (within the PDB)

MACiE Homologues (within UniprotKB/SwissProt)



Entries with at least one Catalytic CATH code in common (different mechanisms):

MACiE Entry Enzyme Name
EC Number
PDB code CATH code Composite
Reaction Similarity
Catalytic Machinery
Similarity
M0063 methylaspartate mutase
5.4.99.1
1cb7 3.40.50.280
0.24240.2325Compare
M0062 methylmalonyl-CoA mutase
5.4.99.2
1req 3.40.50.280
0.28120.4189Compare

View a comparison of the other reactions in MACiE with the CATH domain 3.40.50.280


Links to this entry in other databases

Link to EC-PDB-SUM Link to PDB-SUM Link to RCSB PDB Link to PDBe Link to CSA
Link to MetaCyc Link to KEGG Link to BRENDA Link to ExplorENZ
Link to EzCatDB

GOA logo
methionine synthase activity (molecular function)
methionine biosynthetic process (biological process)
cobalamin binding (molecular function)
metal ion binding (molecular function)
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