Four families of folate-independent methionine synthases

PLoS Genet. 2021 Feb 3;17(2):e1009342. doi: 10.1371/journal.pgen.1009342. eCollection 2021 Feb.


Although most organisms synthesize methionine from homocysteine and methyl folates, some have "core" methionine synthases that lack folate-binding domains and use other methyl donors. In vitro, the characterized core synthases use methylcobalamin as a methyl donor, but in vivo, they probably rely on corrinoid (vitamin B12-binding) proteins. We identified four families of core methionine synthases that are distantly related to each other (under 30% pairwise amino acid identity). From the characterized enzymes, we identified the families MesA, which is found in methanogens, and MesB, which is found in anaerobic bacteria and archaea with the Wood-Ljungdahl pathway. A third uncharacterized family, MesC, is found in anaerobic archaea that have the Wood-Ljungdahl pathway and lack known forms of methionine synthase. We predict that most members of the MesB and MesC families accept methyl groups from the iron-sulfur corrinoid protein of that pathway. The fourth family, MesD, is found only in aerobic bacteria. Using transposon mutants and complementation, we show that MesD does not require 5-methyltetrahydrofolate or cobalamin. Instead, MesD requires an uncharacterized protein family (DUF1852) and oxygen for activity.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / genetics*
  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / metabolism
  • Archaeal Proteins / genetics*
  • Archaeal Proteins / metabolism
  • Bacterial Proteins / genetics*
  • Bacterial Proteins / metabolism
  • Biosynthetic Pathways / genetics
  • Folic Acid / chemistry
  • Folic Acid / metabolism
  • Homocysteine / chemistry
  • Homocysteine / metabolism
  • Iron-Sulfur Proteins / metabolism
  • Methionine / chemistry
  • Methionine / metabolism
  • Models, Chemical
  • Molecular Structure
  • Multigene Family*
  • Oxygen / metabolism
  • Tetrahydrofolates / chemistry
  • Tetrahydrofolates / metabolism
  • Vitamin B 12 / analogs & derivatives
  • Vitamin B 12 / chemistry
  • Vitamin B 12 / metabolism


  • Archaeal Proteins
  • Bacterial Proteins
  • Iron-Sulfur Proteins
  • Tetrahydrofolates
  • Homocysteine
  • Folic Acid
  • Methionine
  • mecobalamin
  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
  • Vitamin B 12
  • Oxygen
  • 5-methyltetrahydrofolate

Associated data

  • figshare/10.6084/m9.figshare.13146419.v1

Grant support

This work was funded by ENIGMA, a Scientific Focus Area Program at Lawrence Berkeley National Laboratory, supported by the U.S. Department of Energy, Office of Science, Office of Biological and Environmental Research ( under contract DE-AC02-05CH11231 and granted to AMD and APA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.