Electrostatic stress in catalysis: Structure and mechanism of the enzyme orotidine monophosphate decarboxylase

Ning Wu, Yirong Mo, Jiali Gao, Emil F. Pai

Research output: Contribution to journalArticlepeer-review

214 Scopus citations

Abstract

Orotidine 5'-monophosphate decarboxylase catalyzes the conversion of orotidine 5'-monophosphate to uridine 5'-monophosphate, the last step in biosynthesis of pyrimidine nucleotides. As part of a Structural Genomics Initiative, the crystal structures of the ligand-free and the6-azauridine 5'- monophosphate-complexed forms have been determined at 1.8 and 1.5 Å, respectively. The protein assumes a TIM-barrel fold with one side of the barrel closed off and the other side binding the inhibitor. A unique array of alternating charges (Lys-Asp-Lys-Asp) in the active site prompted us to apply quantum mechanical and molecular dynamics calculations to analyze the relative contributions of ground state destabilization and transition state stabilization to catalysis. The remarkable catalytic power of orotidine 5'- monophosphate decarboxylase is almost exclusively achieved via destabilization of the reactive part of the substrate, which is compensated for by strong binding of the phosphate and ribose groups. The computational results are consistent with a catalytic mechanism that is characterized by Jencks's Circe effect.

Original languageEnglish (US)
Pages (from-to)2017-2022
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number5
DOIs
StatePublished - Feb 29 2000

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