Crystal structure of a methyltetrahydrofolate- and corrinoid-dependent methyltransferase

Citation
T. Doukov et al., Crystal structure of a methyltetrahydrofolate- and corrinoid-dependent methyltransferase, STRUCT F D, 8(8), 2000, pp. 817-830
Citations number
91
Categorie Soggetti
Biochemistry & Biophysics
Journal title
STRUCTURE WITH FOLDING & DESIGN
ISSN journal
09692126 → ACNP
Volume
8
Issue
8
Year of publication
2000
Pages
817 - 830
Database
ISI
SICI code
0969-2126(20000815)8:8<817:CSOAMA>2.0.ZU;2-7
Abstract
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).