Disease relevance of ECs1029

• The DHOdehase B purified from the E. coli strain that carried both the pyrDb and pyrK genes on a multicopy plasmid (herein called the deltakappa-enzyme) was quite different, since it was formed as a complex of equal amounts of the two polypeptides, i.e. two PyrDB and two PyrK subunits [1].
• The B form of dihydroorotate dehydrogenase from Lactococcus lactis consists of two different subunits, encoded by the pyrDb and pyrK genes, and contains FMN, FAD, and [FeS] redox centers [1].
• A second dihydroorotate dehydrogenase (Type A) of the human pathogen Enterococcus faecalis: expression, purification, and steady-state kinetic mechanism [2].
• DHOD from Escherichia coli is a typical member of family 2, which contains the membrane-associated enzymes from Gram-negative bacteria and eukaryotes [3].
• The Salmonella typhimurium pyrD gene encoding dihydroorotate dehydrogenase was cloned and sequenced [4].

High impact information on ECs1029

• Our results suggest that brequinar sodium inhibits dihydroorotate dehydrogenase by binding to the enzyme at a unique site that is distinct from the dihydroorotate or the ubiquinone-binding site [5].
• Inhibition of dihydroorotate dehydrogenase activity by brequinar sodium [5].
• Brequinar sodium inhibits L1210 dihydroorotate dehydrogenase with mixed inhibition kinetics with respect to either the substrate (dihydroorotate) or the cofactor (ubiquinone Q6) with Ki' values in the 5-8 nM range [5].
• The novel anticancer drug candidate brequinar sodium (DuP 785, NSC 368390, 6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinoline- carboxylic acid sodium salt) was shown previously to be an inhibitor of dihydroorotate dehydrogenase, the fourth enzyme of the de novo pyrimidine biosynthetic pathway [5].
• Malarial dihydroorotate dehydrogenase. Substrate and inhibitor specificity [6].

Chemical compound and disease context of ECs1029

• Dihydroorotate dehydrogenase (DHOD) from Escherichia coli is a monomeric membrane-associated flavoprotein that catalyzes the oxidation of dihydroorotate to orotate [7].
• The chemistry of the reduction of the flavin in DHOD from E. coli by the substrate dihydroorotate (DHO) was studied at 4 degrees C in anaerobic stopped-flow experiments conducted over a broad range of pH values [8].
• Insight into the chemistry of flavin reduction and oxidation in Escherichia coli dihydroorotate dehydrogenase obtained by rapid reaction studies [8].
• Dihydroorotate dehydrogenase (DHOD) is the fourth enzyme in the de novo pyrimidine biosynthetic pathway and is essential in Trypanosoma cruzi, the parasitic protist causing Chagas' disease [9].

Biological context of ECs1029

• The alternate conformations are most likely the result of the loss of van der Waals or other interactions between tyrosine 318 and FMN in the catalytic site with the mutation of Tyr318Leu, which disrupts the native structure of wild-type DHOD [7].
• Important differences were identified in some of the active-site residues which vary across the distinct DHOD families, implying significant mechanistic differences [10].
• Here we have cloned, overexpressed, purified, and characterized the product of the gene from LmjF chromosome 16: LmjF16.0530, which encodes a protein with putative dihydroorotate dehydrogenase activity [11].
• The open reading frames of all three DHOD genes are comprised of 942 bp, and encode proteins of 314 amino acids [9].
• Here, we report nucleotide sequence polymorphisms of T. cruzi DHOD genes and the kinetic properties of the recombinant enzymes [9].

Anatomical context of ECs1029

• Dihydroorotate dehydrogenase is a critical enzyme of de novo pyrimidine biosynthesis in prokaryotic and eukaryotic cells [12].

Associations of ECs1029 with chemical compounds

• The delta-enzyme exhibited dihydroorotate dehydrogenase activity with dichloroindophenol, potassium hexacyanoferrate(III), and molecular oxygen as electron acceptors but could not use NAD+ [1].
• Menadione was used as a model quinone substrate to oxidize dithionite-reduced DHOD [8].
• The flavin enzyme dihydroorotate dehydrogenase (DHOD; EC 1.3.99.11) catalyzes the oxidation of dihydroorotate to orotate, the fourth step in the de novo pyrimidine biosynthesis of UMP [13].
• The first crystal structure of the class 2 dihydroorotate dehydrogenase from rat has been determined in complex with its two inhibitors brequinar and atovaquone [13].
• E. faecalis DHODase A catalyzed the oxidation of l-dihydroorotate while reducing a number of substrates, including fumarate, coenzyme Q(0), and menadione [2].

Analytical, diagnostic and therapeutic context of ECs1029

• Crystallization and preliminary X-ray studies of membrane-associated Escherichia coli dihydroorotate dehydrogenase [3].
• Sequence analysis of a Dictyostelium discoideum gene coding for an active dihydroorotate dehydrogenase in yeast [14].

References