Disease relevance of Dhodh

• A recombinant baculovirus containing the rat liver cDNA for dihydroorotate dehydrogenase was constructed and used for virus infection and protein expression in Trichoplusia ni cells [1].

High impact information on Dhodh

• Leflunomide is a new immunosuppressive drug whose active metabolite, A77 1726, impairs cellular nucleotide metabolism by inhibiting the dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme of de novo pyrimidine synthesis [2].
• Dihydroorotate dehydrogenase has been purified 6,000-fold from bovine liver mitochondria to apparent homogeneity in six steps [3].
• Dihydroorotate dehydrogenase differs from succinate dehydrogenase both in its utilization of ubiquinone and in the mechanism of cytochrome b reduction [4].
• Half of the animals in both treatment groups also received uridine to reverse DHODH activity [5].
• CONCLUSIONS: Our results demonstrate that FK778 inhibits neointima formation by way of a mechanism that is independent of DHODH inhibitory activity on vascular smooth muscle cell [5].

Biological context of Dhodh

• Southern blotting indicated DHODH gene amplification [6].
• Antimalarial naphthoquinones such as atovaquone (566c80) inhibit malarial DHOD by inhibiting electron transport [7].
• The two biochemical activities reported for the active metabolite of leflunomide, A77 1726, are inhibition of tyrosine phosphorylation and inhibition of dihydroorotate dehydrogenase, an enzyme necessary for de novo pyrimidine synthesis [8].
• Dihydroorotate dehydrogenase inhibitors: quantitative structure-activity relationship analysis [9].
• These were generated against synthetic peptides corresponding to two amino acid sequences deduced from human and rat cDNA of dihydroorotate dehydrogenase [10].

Anatomical context of Dhodh

• In mouse B-lymphocytes, which were adapted to tolerate up to a 50-fold concentration of the DHODH inhibitor leflunomide, a 20 fold protein overexpression was measured [6].
• It had been noted previously that the activity of mitochondrial dihydroorotate dehydrogenase was lower in crude tissue preparations containing cytosol than in isolated mitochondria [11].
• Localization of dihydroorotate oxidase in myocardium and kidney cortex of the rat. An electron microscopic study using the cerium technique [12].
• These data suggest the HMR 1279 and HMR 1715 mediate their antiproliferative and immunosuppressive effects in the PLN assay in vivo by decreasing the activity of DHODH in the lymph node cells and thereby inhibiting pyrimidine biosynthesis [13].
• The relation of DHODH activity versus that of cytochrome c oxidase revealed the lowest ratios in heart mitochondria and the highest in liver mitochondria [14].

Associations of Dhodh with chemical compounds

• To follow the expression of the fourth enzyme of pyrimidine de novo synthesis dihydroorotate dehydrogenase (DHODH) in cells and tissues, we studied the DHODH mRNA expression by means of RT-PCR in rat tissues [6].
• Production of superoxide radical during oxidation of dihydroorotate in rat liver mitochondria was not affected by antimycin A, thenoyltrifluoroacetone, or added ubiquinone but was inhibited by orotate, a product inhibitor of dihydroorotate dehydrogenase [4].
• Atovaquone inhibited DHOD by 76.3% at 100 microM and 36.5% at 10 microM [7].
• As expected, P. carinii DHOD activity was susceptible to respiratory inhibitors such as cyanide, antimycin A, and salicylhydroxamic acid (SHAM) [7].
• Other enzymes such as dihydroorotate dehydrogenase and galactose oxidase, which produce O2- and H2O2, respectively, are also effective in promoting the cytotoxic activity of the brainstem peroxidase [15].

Other interactions of Dhodh

• In each cycle, the order of events was as follows: decrease in dihydroorotate dehydrogenase, sequential increases in UDP kinase, CTP synthetase and CMPsialic acid synthase, and finally increases in the enzyme lactosylceramide: CMPsialic acid sialyltransferase, lipid-soluble sialic acid and total sialic acid [16].

Analytical, diagnostic and therapeutic context of Dhodh

• Rabbit polyclonal anti-DHODH immunoglobulins were applied for immunochemical quantification of the enzyme protein by Western blotting [6].
• Molecular cloning and sequence analyses of rat liver dihydroorotate dehydrogenase [17].
• On the other hand, the effect of DAA was also evaluated as an inhibitor of dihydroorotate dehydrogenase (DHO-DHase) and tested in the rat collagen-induced arthritis (CIA) model [18].

References