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. 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.
Palfey
B A
BA
Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan, 48109-0606, USA. brupalf@umich.edu
Björnberg
O
O
Jensen
K F
KF
D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry; D004081:Dihydroorotate Oxidase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D008024:Ligands; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry
D001565:Benzoates; D004791:Enzyme Inhibitors; D008024:Ligands; D011743:Pyrimidines; D014344:Trypanocidal Agents; D004081:Dihydroorotate Oxidase