A proficient enzyme: Insights on the mechanism of orotidine monophosphate decarboxylase from computer simulations

Simone Raugei, Michele Cascella, Paolo Carloni

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22 Citations (Scopus)


Decarboxylation of orotidine 5′-monophosphate (Omp) to uridine 5′-monophosphate by orotidine 5′-monophosphate decarboxylase (ODCase) is currently the object of vivid debate. Here, we clarify its enzymatic activity with long time scale classical molecular dynamics and hybrid ab initio Car-Parrinello/ molecular mechanics simulations. The lack of structural (experimental) information on the ground state of ODCase/Omp complex is overcome by a careful construction of the model and the analysis of three different strains of the enzyme. We find that the ODCase/substrate complex is characterized by a very stable charged network Omp-Lys-Asp-Lys-Asp, which is incompatible with the previously proposed direct decarboxylation driven by a ground-state destabilization. A direct decarboxylation induced by a transition-state electrostatic stabilization is consistent with our findings. The calculated activation free energy for the direct decarboxylation with the formation of a C6 carboanionic intermediate yields an overall rate enhancement by the enzyme (kcat/Kwat = 3.5 × 1016) in agreement with experiments (kcat/kwat = 1.7 × 1017). The decarboxylation is accompanied by the movement of a fully conserved lysine residue toward the developing negative charge at the C6 position.

Original languageEnglish
Pages (from-to)15730-15737
Number of pages8
JournalJournal of the American Chemical Society
Issue number48
Publication statusPublished - Dec 8 2004


ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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