Updated BioCyc iOS App now
available in iTunes store
Updated BioCyc iOS App now
available in iTunes store
Updated BioCyc iOS App now
available in iTunes store
Updated BioCyc iOS App now
available in iTunes store
Updated BioCyc iOS App now
available in iTunes store

Escherichia coli K-12 substr. MG1655 Reaction:

Superclasses: Reactions Classified By Conversion TypeSimple ReactionsChemical Reactions
Reactions Classified By SubstrateSmall-Molecule Reactions

EC Number:

Enzymes and Genes:
cobalamin-dependent methionine synthaseInferred from experiment: metH

In Pathway: L-methionine biosynthesis I, N10-formyl-tetrahydrofolate biosynthesis

The direction shown, i.e. which substrates are on the left and right sides, is in accordance with the direction in which it was curated.

Mass balance status: Balanced.

Instance reaction:
L-homocysteine + N5-methyl--tetrahydropteroyl tri-L-glutamate → L-methionine + tetrahydropteroyl tri-L-glutamate (

Enzyme Commission Primary Name: methionine synthase

Enzyme Commission Synonyms: 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

.During catalysis, an enzyme-bound cobalamine prosthetic group is used as an intermediate methyl donor and acceptor. At different points during the reaction cycle, the coordination to the cobalt of the cobalamine changes. Corodination of the His-759 residue to the cobalt center is necessary for the interconversion betwee the reactivation and catalytic conformations. Zinc is required for catalysis of methyl transfer from methylcobalamin to homocysteine. Mutations of Cys310 or Cys311 to either alanine or serine result in loss of catalytic activity. The equilibria between various conformations of MetH are sensitive to temparature, the presence or absence of ligands including methyl-tetrahydrofolate, and the beta-ligand of the cobalamine prosthetic group [Goulding97, Goulding97a, Liptak07, Fleischhacker07].

Enzyme Commission Summary:
Contains zinc and cobamide. The enzyme becomes inactivated occasionally during its cycle by oxidation of Co(I) to Co(II). Reactivation by reductive methylation is catalysed by the enzyme itself, with S-adenosyl-L-methionine as the methyl donor and a reducing system. For the mammalian enzyme, the reducing system involves NADPH and EC, [methionine synthase] reductase. In bacteria, the reducing agent is flavodoxin, and no further catalyst is needed (the flavodoxin is kept in the reduced state by NADPH and EC, ferredoxin—NADP+ reductase). Acts on the monoglutamate as well as the triglutamate folate, in contrast with EC, 5-methyltetrahydropteroyltriglutamate—homocysteine S-methyltransferase, which acts only on the triglutamate.

Citations: [Burton69, Foster64, Guest64, Loughlin64, Taylor71, Jarrett98, Hall00, Bandarian02]

Gene-Reaction Schematic

Gene-Reaction Schematic

Instance reaction of [L-homocysteine + an N5-methyl-tetrahydrofolate → L-methionine + a tetrahydrofolate] (
i1: L-homocysteine + N5-methyl--tetrahydropteroyl tri-L-glutamate → L-methionine + tetrahydropteroyl tri-L-glutamate (

Relationship Links: BRENDA:EC:, ENZYME:EC:, IUBMB-ExplorEnz:EC:

Reviewed 01-Mar-2010 by Sarker M


Bandarian02: Bandarian V, Pattridge KA, Lennon BW, Huddler DP, Matthews RG, Ludwig ML (2002). "Domain alternation switches B(12)-dependent methionine synthase to the activation conformation." Nat Struct Biol 9(1);53-6. PMID: 11731805

Burton69: Burton EG, Sakami W (1969). "The formation of methionine from the monoglutamate form of methyltetrahydrofolate by higher plants." Biochem Biophys Res Commun 36(2);228-34. PMID: 5799642

Fleischhacker07: Fleischhacker AS, Matthews RG (2007). "Ligand trans influence governs conformation in cobalamin-dependent methionine synthase." Biochemistry 46(43);12382-92. PMID: 17924667

Foster64: Foster MA, Dilworth MJ, Woods DD (1964). "Cobalamin and the synthesis of methionine by Escherichia coli." Nature 201;39-42. PMID: 14085561

Goulding97: Goulding CW, Postigo D, Matthews RG (1997). "Cobalamin-dependent methionine synthase is a modular protein with distinct regions for binding homocysteine, methyltetrahydrofolate, cobalamin, and adenosylmethionine." Biochemistry 36(26);8082-91. PMID: 9201956

Goulding97a: Goulding CW, Matthews RG (1997). "Cobalamin-dependent methionine synthase from Escherichia coli: involvement of zinc in homocysteine activation." Biochemistry 1997;36(50);15749-57. PMID: 9398304

Guest64: Guest JR, Friedman S, Foster MA, Tejerina G, Woods DD (1964). "Transfer of the methyl group from N5-methyltetrahydrofolates to homocysteine in Escherichia coli." Biochem J 92(3);497-504. PMID: 5319972

Hall00: Hall DA, Jordan-Starck TC, Loo RO, Ludwig ML, Matthews RG (2000). "Interaction of flavodoxin with cobalamin-dependent methionine synthase." Biochemistry 39(35);10711-9. PMID: 10978155

Jarrett98: Jarrett JT, Huang S, Matthews RG (1998). "Methionine synthase exists in two distinct conformations that differ in reactivity toward methyltetrahydrofolate, adenosylmethionine, and flavodoxin." Biochemistry 37(16);5372-82. PMID: 9548919

Liptak07: Liptak MD, Fleischhacker AS, Matthews RG, Brunold TC (2007). "Probing the role of the histidine 759 ligand in cobalamin-dependent methionine synthase." Biochemistry 46(27);8024-35. PMID: 17567043

Loughlin64: Loughlin RE, Elford HL, Buchanan JM (1964). "Enzymatic synthesis of the methyl group of methionine. VII. Isolation of a cobalamin-containing transmethylase (5-methyltetrahydro-folate-homocysteine) from mammalian liver." J Biol Chem 239;2888-95. PMID: 14216440

Taylor71: Taylor RT (1971). "Escherichia coli B N 5 -methyltetrahydrofolate-homocysteine cobalamin methyltransferase: gel-filtration behavior of apoenzyme and holoenzymes." Biochim Biophys Acta 242(2);355-64. PMID: 4946148

Report Errors or Provide Feedback
Please cite the following article in publications resulting from the use of EcoCyc: Nucleic Acids Research 41:D605-12 2013
Page generated by Pathway Tools version 19.5 (software by SRI International) on Wed Jan 2, 2002, biocyc12.