Overview for MACiE Entry M0268
EC Number: 22.214.171.124 (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).
Display structure information
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 . 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 . 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 .
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Stepwise Description of the Reaction
|Step 1||The 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 2||The 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 3||The tetrahydrofolate product dissociated from the cobalamin cofactor with concomitant protonation (assumed to be from the bulk solvent).|
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Catalytic Residues Involved
||Location of Function
Organic Cofactors for M0268
Metal Cofactors for M0268
- 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.
- 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.
- V. Bandarian et al. (2002), Nat. Struct. Biol., 9, 53-56. Domain alternation switches B12-dependent methionine synthase to the activation conformation.
- R. V. Banerjee et al. (1990), FASEB J., 4, 1450-1459. Cobalamin-dependent methionine synthase.
- 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.
- A. E. Smith et al. (2000), Biochemistry, 39, 13880-13890. Protonation state of methyltetrahydrofolate in a binary complex with cobalamin-dependent methionine synthase.
Homologue information for M0268 (1bmt)
MACiE Homologues (within the PDB)
MACiE Homologues (within UniprotKB/SwissProt)
Entries with at least one Catalytic CATH code in common (different mechanisms):
|M0063 ||methylaspartate mutase |
|M0062 ||methylmalonyl-CoA mutase |
View a comparison of the other reactions in MACiE with the CATH domain 126.96.36.1990
Links to this entry in other databases