Four families of folate-independent methionine synthases

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. Author summary Methionine is one of the amino acids that make up proteins, and the final step in methionine synthesis is the transfer of a methyl group. In most organisms, the methyl group is obtained from methyl folates, but some anaerobic bacteria and archaea are thought to use corrinoid (vitamin B12-binding) proteins instead. By analyzing the sequences of the potential methionine synthases across the genomes of diverse bacteria and archaea, we identified four families of folate-independent methionine synthases. For three of these families, we can use co-occurrence with corrinoid proteins to predict their likely partners. We show that the fourth family does not require vitamin B12; instead, it obtains methyl groups from an oxygen-dependent partner protein. Our results will help us understand the growth requirements of diverse bacteria and archaea.

Automated summary

The study investigated the roles and mechanisms of different families of methionine synthases in methionine synthesis, identifying four folate-independent methionine synthase families. Some of these families co-occur with corrinoid proteins, while another family interacts with oxygen for activity.