Disease relevance of Dhodh

• Effect of 6-azauridine on de novo pyrimidine biosynthesis in cultured Ehrlich ascites cells. Orotate inhibition of dihydroorotase and dihydroorotate dehydrogenase [1].
• Pyrimidine de novo biosynthesis, at the stage of respiratory chain-dependent dihydroorotate dehydrogenase, was found to be a biochemical target site for oxygen deficiency as well as for Brequinar Sodium (6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinoline carboxylic acid sodium salt) (Brequinar) [2].
• On the role of dihydroorotate dehydrogenase in growth cessation of Ehrlich ascites tumor cells cultured under oxygen deficiency [3].

High impact information on Dhodh

• Brequinar, a noncompetitive inhibitor of mitochondrial dihydroorotate dehydrogenase has been shown to achieve a tumor-specific modulation of the therapeutic effect of 5-fluorouracil [4].
• The antiproliferative and immunosuppressive activities of brequinar sodium (BQR) are thought to be due to the inhibition of the activity of dihydroorotate dehydrogenase, which results in a suppression of de novo pyrimidine synthesis [5].
• Two activities have been identified for the immunosuppressive metabolite of leflunomide, A77 1726: inhibition of dihydroorotate dehydrogenase (DHO-DHase), an enzyme involved in the biosynthesis of pyrimidine nucleotides (PyN); and inhibition of protein tyrosine kinases [6].
• By capitalizing on the target enzyme-bound (DHODH) structure 1b of one of these compounds, leflunomide, and modulating part of its multiple mechanisms of action to gain selectivity, the quinoline-8-carboxamide 3 was designed as a potentially weak enzyme inhibitor but effective immunosuppressant [7].
• Our observations suggest that BQR may not only affect dihydroorotate dehydrogenase activity, but may also inhibit the enzyme cytidine deaminase, which converts cytidine to uridine [8].

Biological context of Dhodh

• Similarly, the IC50 values of another DHODH inhibitor, brequinar sodium, were also attenuated by uridine from 0.04 to 1 microm for IgM, and 0.012 to 10 microm for IgG [9].
• Structure-activity relationship of quinoline carboxylic acids. A new class of inhibitors of dihydroorotate dehydrogenase [10].
• In pyrimidine biosynthesis the oxidation of dihydroorotate is catalyzed by dihydroorotate dehydrogenase, which is linked to the mitochondrial electron transport chain in vertebrates [3].
• It is concluded that in the absence of oxygen cell proliferation may be arrested by inhibition of the dihydroorotate dehydrogenase alone [3].

Anatomical context of Dhodh

• Three marker enzymes, dihydroorotate dehydrogenase, cytochrome c reductase, and cytochrome c oxidase, were assessed during the organelle separation [11].
• Comparative studies on dihydroorotate dehydrogenase from P. berghei and the mouse reticulocyte [12].

Associations of Dhodh with chemical compounds

• The objective was to demonstrate that the immunosuppressive agent HR325 (an inhibitor of dihydroorotate dehydrogenase, DHODH) inhibits immunoglobulin (Ig) secretion both in vitro and in vivo and that this effect can be reversed with exogenous uridine [9].
• 5-Fluoro orotate and orotate were the most effective inhibitors for dihydroorotate dehydrogenase [13].
• Previous studies have demonstrated that the active metabolite of leflunomide, A77 1726 [N-(4-trifluoromethylphenyl-2-cyano-3-hydroxycrotoamide)], is capable of inhibiting the activities of tyrosine kinases and dihydroorotate dehydrogenase (DHO-DHase) [14].
• Brequinar sodium (DUP-785; Brequinar) is a potent inhibitor of the pyrimidine de novo enzyme dihydroorotate dehydrogenase (DHO-DH), leading to a depletion of pyrimidine nucleotides, which could be reversed by uridine [15].
• Sixty-nine quinoline 4-carboxylic acid analogs were analyzed as inhibitors of L1210 dihydroorotate dehydrogenase [10].

Analytical, diagnostic and therapeutic context of Dhodh

• The results are interpreted as supporting the concept that the biosynthetic pathway of pyrimidine (deoxy)nucleotides--because of two oxygen-dependent enzymes, dihydroorotate dehydrogenase and ribonucleotide reductase--is a potential transducer of environmental limitations in oxygen tension to the proliferative capacity of cells [16].

References