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1',4'-iminopyrimidine tautomer of thiamin diphosphate is poised for catalysis in asymmetric active centers on enzymes

Nemeria, Natalia ; Chakraborty, Sumit ; Baykal, Ahmet ; Korotchkina, Lioubov G ; Patel, Mulchand S ; Jordan, Frank

Proceedings of the National Academy of Sciences - PNAS, 2007-01, Vol.104 (1), p.78-82 [Periódico revisado por pares]

United States: National Academy of Sciences

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  • Título:
    1',4'-iminopyrimidine tautomer of thiamin diphosphate is poised for catalysis in asymmetric active centers on enzymes
  • Autor: Nemeria, Natalia ; Chakraborty, Sumit ; Baykal, Ahmet ; Korotchkina, Lioubov G ; Patel, Mulchand S ; Jordan, Frank
  • Assuntos: Active sites ; Binding Sites ; Biochemistry ; Biological Sciences ; Catalysis ; Circular Dichroism ; Dehydrogenases ; Diphosphates ; Enzymes ; Escherichia coli ; Humans ; Lactobacillus plantarum ; Protein Subunits ; Protons ; Pyruvate Decarboxylase - chemistry ; Pyruvate Dehydrogenase Complex - chemistry ; Pyruvate Oxidase - chemistry ; Spectroscopy ; Spectrum analysis ; Tautomers ; Thiamine Pyrophosphate - chemistry ; Wavelengths
  • É parte de: Proceedings of the National Academy of Sciences - PNAS, 2007-01, Vol.104 (1), p.78-82
  • Notas: ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
    content type line 23
    Communicated by Perry A. Frey, University of Wisconsin, Madison, WI, November 13, 2006
    Author contributions: F.J. designed research; N.N., S.C., A.B., and L.G.K. performed research; S.C. and A.B. contributed new reagents/analytic tools; N.N., S.C., A.B., L.G.K., M.S.P., and F.J. analyzed data; and N.N., M.S.P., and F.J. wrote the paper.
  • Descrição: Thiamin diphosphate, a key coenzyme in sugar metabolism, is comprised of the thiazolium and 4'-aminopyrimidine aromatic rings, but only recently has participation of the 4'-aminopyrimidine moiety in catalysis gained wider acceptance. We report the use of electronic spectroscopy to identify the various tautomeric forms of the 4'-aminopyrimidine ring on four thiamin diphosphate enzymes, all of which decarboxylate pyruvate: the E1 component of human pyruvate dehydrogenase complex, the E1 subunit of Escherichia coli pyruvate dehydrogenase complex, yeast pyruvate decarboxylase, and pyruvate oxidase from Lactobacillus plantarum. It is shown that, according to circular dichroism spectroscopy, both the 1',4'-iminopyrimidine and the 4'-aminopyrimidine tautomers coexist on the E1 component of human pyruvate dehydrogenase complex and pyruvate oxidase. Because both tautomers are seen simultaneously, these two enzymes provide excellent evidence for nonidentical active centers (asymmetry) in solution in these multimeric enzymes. Asymmetry of active centers can also be induced upon addition of acetylphosphinate, an excellent electrostatic pyruvate mimic, which participates in an enzyme-catalyzed addition to form a stable adduct, resembling the common predecarboxylation thiamin-bound intermediate, which exists in its 1',4'-iminopyrimidine form. The identification of the 1',4'-iminopyrimidine tautomer on four enzymes is almost certainly applicable to all thiamin diphosphate enzymes: this tautomer is the intramolecular trigger to generate the reactive ylide/carbene at the thiazolium C2 position in the first fundamental step of thiamin catalysis.
  • Editor: United States: National Academy of Sciences
  • Idioma: Inglês
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