Specific Inhibition of a Family 1A Dihydroorotate Dehydrogenase by Benzoate Pyrimidine Analogues

Dihydroorotate dehydrogenases (DHODs) catalyze the conversion of dihydroorotate to orotate in de novo pyrimidine biosynthesis. We have found that 3,4-dihydroxybenzoate and 3,5-dihydroxybenzoate are competitive inhibitors vs dihydroorotate with the prototypical family 1A DHOD from Lactococcus lactis....

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Bibliographic Details
Published in:Journal of medicinal chemistry 2001-08, Vol.44 (18), p.2861-2864
Main Authors: Palfey, Bruce A, Björnberg, Olof, Jensen, Kaj Frank
Format: Article
Language:English
Subjects:
Analytical, structural and metabolic biochemistry
Benzoates - chemical synthesis
Benzoates - chemistry
Biological and medical sciences
Dihydroorotate Oxidase - antagonists & inhibitors
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzymes and enzyme inhibitors
Fundamental and applied biological sciences. Psychology
Ligands
Medical sciences
Miscellaneous
Oxidoreductases
Pharmacology. Drug treatments
Pyrimidines - chemical synthesis
Pyrimidines - chemistry
Structure-Activity Relationship
Trypanocidal Agents - chemical synthesis
Trypanocidal Agents - chemistry
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Summary:Dihydroorotate dehydrogenases (DHODs) catalyze the conversion of dihydroorotate to orotate in de novo pyrimidine biosynthesis. We have found that 3,4-dihydroxybenzoate and 3,5-dihydroxybenzoate are competitive inhibitors vs dihydroorotate with the prototypical family 1A DHOD from Lactococcus lactis. The dissociation constants of these compounds, determined by spectral titrations, were similar to the dissociation constant of orotate, the enzymatic reaction product, suggesting that hydroxybenzoates could be developed into useful drugs for treating infections by certain protozoan parasites.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm015535x