Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 135, Issue 46, Pages 17432-17443Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ja408197k
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Funding
- Japan Society for the Promotion of Science [24570130, 23550035, 20770081, 2277012]
- Uehara Memorial Foundation
- Canadian Institutes for Health Research
- Canada Research Chairs Program
- U.S. Department of Energy, Basic Energy Sciences, Office of Science [DE-AC02-06CH11357]
- National Institute of General Medical Sciences of the National Institutes of Health [R24GM111072]
- Grants-in-Aid for Scientific Research [24570130, 23550035, 20770081] Funding Source: KAKEN
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Orotidine 5'-monophosphate decarboxylase (OD-Case) accelerates the decarboxylation of orotidine 5'-monophosphate (OMP) to uridine 5'-monophosphate (UMP) by 17 orders of magnitude. Eight new crystal structures with ligand analogues combined with computational analyses of the enzyme's short-lived intermediates and the intrinsic electronic energies to distort the substrate and other ligands improve our understanding of the still controversially discussed reaction mechanism. In their respective complexes, 6-methyl-UMP displays significant distortion of its methyl substituent bond, 6-amino-UMP shows the competition between the K72 and C6 substituents for a position close to D70, and the methyl and ethyl esters of OMP both induce rotation of the carboxylate group substituent out of the plane of the pyrimidine ring. Molecular dynamics and quantum mechanics/molecular mechanics computations of the enzyme-substrate complex also show the bond between the carboxylate group and the pyrimidine ring to be distorted, with the distortion contributing a 10-15% decrease of the Delta Delta G(double dagger) value. These results are consistent with ODCase using both substrate distortion and transition-state stabilization, primarily exerted by K72, in its catalysis of the OMP decarboxylation reaction.
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