Spectroscopic Studies of the EutT Adenosyltransferase from Salmonella enterica: Mechanism of Four-Coordinate Co(II)Cbl Formation

J Am Chem Soc. 2016 Mar 23;138(11):3694-704. doi: 10.1021/jacs.5b11708. Epub 2016 Mar 9.

Abstract

EutT from Salmonella enterica is a member of a class of enzymes termed ATP:Co(I)rrinoid adenosyltransferases (ACATs), implicated in the biosynthesis of adenosylcobalamin (AdoCbl). In the presence of cosubstrate ATP, ACATs raise the Co(II)/Co(I) reduction potential of their cob(II)alamin [Co(II)Cbl] substrate by >250 mV via the formation of a unique four-coordinate (4c) Co(II)Cbl species, thereby facilitating the formation of a "supernucleophilic" cob(I)alamin intermediate required for the formation of the AdoCbl product. Previous kinetic studies of EutT revealed the importance of a HX11CCX2C(83) motif for catalytic activity and have led to the proposal that residues in this motif serve as the binding site for a divalent transition metal cofactor [e.g., Fe(II) or Zn(II)]. This motif is absent in other ACAT families, suggesting that EutT employs a distinct mechanism for AdoCbl formation. To assess how metal ion binding to the HX11CCX2C(83) motif affects the relative yield of 4c Co(II)Cbl generated in the EutT active site, we have characterized several enzyme variants by using electronic absorption, magnetic circular dichroism, and electron paramagnetic resonance spectroscopies. Our results indicate that Fe(II) or Zn(II) binding to the HX11CCX2C(83) motif of EutT is required for promoting the formation of 4c Co(II)Cbl. Intriguingly, our spectroscopic data also reveal the presence of an equilibrium between five-coordinate "base-on" and "base-off" Co(II)Cbl species bound to the EutT active site at low ATP concentrations, which shifts in favor of "base-off" Co(II)Cbl in the presence of excess ATP, suggesting that the base-off species serves as a precursor to 4c Co(II)Cbl.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism
  • Alkyl and Aryl Transferases / chemistry*
  • Alkyl and Aryl Transferases / metabolism
  • Bacterial Proteins / chemistry*
  • Bacterial Proteins / metabolism
  • Calcium Compounds / chemistry*
  • Calcium Compounds / metabolism
  • Catalytic Domain
  • Circular Dichroism
  • Cobamides / chemistry*
  • Cobamides / metabolism
  • Electron Spin Resonance Spectroscopy
  • Ferrous Compounds / chemistry
  • Ferrous Compounds / metabolism
  • Models, Molecular
  • Salmonella enterica / enzymology*
  • Zinc Compounds / chemistry
  • Zinc Compounds / metabolism

Substances

  • Bacterial Proteins
  • Calcium Compounds
  • Cobamides
  • Ferrous Compounds
  • Zinc Compounds
  • Adenosine Triphosphate
  • Alkyl and Aryl Transferases
  • ATP-corrinoid adenosyltransferase
  • cobamamide