Cobalamin-Dependent and Cobalamin-Independent Methionine Synthases: Are There Two Solutions to the Same Chemical Problem?

Two enzymes in Escherichia coli, cobalamin-independent methionine synthase (MetE) and cobalamin-dependent methionine synthase (MetH), catalyze the conversion of homocysteine (Hcy) to methionine using N(5) -methyltetrahydrofolate (CH₃-H₄folate) as the Me donor. Despite the absence of sequence homology, these enzymes employ very similar catalytic strategies. In each case, the pK_a for the SH group of Hcy is lowered by coordination to Zn²⁺, which increases the concentration of the reactive thiolate at neutral pH. In each case, activation of CH₃-H₄folate appears to involve protonation at N(5). CH3-H₄folate remains unprotonated in binary E · CH₃-H₄folate complexes, and protonation occurs only in the ternary E · CH₃-H₄folate · Hcy complex in MetE, or in the ternary E · CH₃-H₄folate · cob(I)alamin complex in MetH. Surprisingly, the similarities are proposed to extend to the structures of these two unrelated enzymes. The structure of a homologue of the Hcy-binding region of MetH, betaine-homocysteine methyltransferase, has been determined. A search of the three-dimensional-structure data base by means of the structure-comparison program DALI indicates similarity of the BHMT structure with that of uroporphyrin decarboxylase (UroD), a homologue of the MT2-A and MT2-M proteins from Archaea. which catalyze Me transfers from methylcorrinoids to coenzyme M and share the Zn-binding scaffold of MetE. Here, we present a model for the Zn binding site of MetE, obtained by grafting the Zn ligands of MT2-A onto the structure of UroD.