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A Surprise Proton Donor

The methyltetrahydrofolate corrinoid-iron-sulfur protein methyltransferase catalyzes transfer of the methyl group of methyltetrahydrofolate to cob(I)amide. This transfer requires electrophilic activation of methyltetrahydrofolate's methyl group, which includes proton transfer to the N5 group of the pterin ring. However, the crystal structure of the methyl-transferase contains no obvious proton donor within H-bonding distance of the N5 position of methyltetrahydrofolate.

The active site of methyltransferase with bound CH3H4folate.

In this Paper of the Week, Tzanko I. Doukov and colleagues use a combination of kinetic and structural evidence to show that in this methyltransferase, an extended H-bonding net-work is involved in proton transfer to N5. This includes an asparagine, a conserved aspartate, and a water molecule. The asparagine residue swings from a distant position to within H-bonding distance of the N5 atom upon methyltetrahydrofolate binding. The evidence in this paper suggests that even a poor hydrogen-bonding residue such as asparagine can contribute to a cumulative hydrogen-bonding network such that the overall effect on the transition state is greater than suggested by the individual components alone.

FOOTNOTES

See referenced article, J. Biol. Chem. 2007, 282, 6609-6618

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