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Proc Natl Acad Sci U S A. 2000 Feb 29;97(5):2017-22.

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

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  • 1Department of Biochemistry, Centres of Excellence, University of Toronto, 1 King's College Circle, Toronto, ON Canada M5S 1A8.

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 A, 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.

PMID:
10681441
[PubMed - indexed for MEDLINE]
PMCID:
PMC15746
Free PMC Article
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