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

Rowena G. Matthews, April E. Smith, Zhaohui S. Zhou, Rebecca E. Taurog, Vahe Bandarian, John C. Evans, Martha Ludwig

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

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 pKa 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.

Original languageEnglish (US)
Pages (from-to)3939-3954
Number of pages16
JournalHelvetica Chimica Acta
Volume86
Issue number12
DOIs
StatePublished - 2003

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methionine
5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
Homocysteine
Vitamin B 12
Enzymes
Uroporphyrins
Protonation
Carboxy-Lyases
enzymes
Betaines
Coenzymes
Betaine-Homocysteine S-Methyltransferase
Binding sites
Mesna
Scaffolds
Escherichia coli
Archaea
coenzymes
Sequence Homology
betaines

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Cobalamin-Dependent and Cobalamin-Independent Methionine Synthases : Are There Two Solutions to the Same Chemical Problem? / Matthews, Rowena G.; Smith, April E.; Zhou, Zhaohui S.; Taurog, Rebecca E.; Bandarian, Vahe; Evans, John C.; Ludwig, Martha.

In: Helvetica Chimica Acta, Vol. 86, No. 12, 2003, p. 3939-3954.

Research output: Contribution to journalArticle

Matthews, Rowena G. ; Smith, April E. ; Zhou, Zhaohui S. ; Taurog, Rebecca E. ; Bandarian, Vahe ; Evans, John C. ; Ludwig, Martha. / Cobalamin-Dependent and Cobalamin-Independent Methionine Synthases : Are There Two Solutions to the Same Chemical Problem?. In: Helvetica Chimica Acta. 2003 ; Vol. 86, No. 12. pp. 3939-3954.
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AU - Matthews, Rowena G.

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AB - 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 pKa 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.

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