Background: Methyltetrahydrofolate, corrinoid iron-sulfur protein methyltra
nsferase (MeTr), catalyzes a key step in the Wood-Ljungdahl pathway of carb
on dioxide fixation, It transfers the N-5-methyl group from methyltetrahydr
ofolate (CH3-H(4)folate) to a cob(I)amide center in another protein, the co
rrinoid iron-sulfur protein. MeTr is a member of a family of proteins that
includes methionine synthase and methanogenic enzymes that activate the met
hyl group of methyltetra-hydromethano(or -sarcino)pterin. We report the fir
st structure of a protein in this family.
Results: We determined the crystal structure of MeTr from Clostridium therm
oaceticum at 2.2 Angstrom resolution using multiwavelength anomalous diffra
ction methods. The overall architecture presents a new functional class of
the versatile triose phosphate isomerase (TIM) barrel fold. The MeTr tertia
ry structure is surprisingly similar to the crystal structures of dihydropt
eroate synthetases despite sharing less than 20% sequence identity. This ho
mology permitted the methyl-H(4)folate binding site to be modeled. The mode
l suggests extensive conservation of the pterin ring binding residues in th
e polar active sites of the methyltransferases and dihydropteroate syntheta
ses. The most significant structural difference between these enzymes is in
a loop structure above the active site. It is quite open in MeTr, where it
can be modeled as the cobalamin binding site.
Conclusions: The MeTr structure consists of a TIM barrel that embeds methyl
-H(4)folate and cobamide. All related methyltransferases are predicted to f
old into a similar TIM barrel pattern and have a similar pterin and cobamid
e binding site. The observed structure is consistent with either a 'front'
(N-5) or 'back' (C-8a) side protonation of CH3-H(4)folate, a key step that
enhances the electrophilic character of the methyl group, activating it for
nucleophilic attack by Co(I).