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Gene Review

DHODH  -  dihydroorotate dehydrogenase (quinone)

Homo sapiens

Synonyms: DHOdehase, Dihydroorotate dehydrogenase (quinone), mitochondrial, Dihydroorotate oxidase, POADS, URA1
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Disease relevance of DHODH


High impact information on DHODH


Chemical compound and disease context of DHODH

  • Dihydroorotate dehydrogenase and succinate dehydrogenase activity in Ehrlich ascites tumor cells grown in suspension culture were quantified by application of nitroblue tetrazolium or cyanotolyl tetrazolium and subsequent extraction of the insoluble formazans with organic solvents [11].

Biological context of DHODH


Anatomical context of DHODH

  • Thus the inhibition of DHODH by A77 1726 prevents lymphocytes from accumulating sufficient pyrimidines to support DNA synthesis [15].
  • Deletion of the cationic portion of this N-terminal sequence from the rat DHODH protein blocked its import into isolated yeast mitochondria, whereas deletion of the adjacent hydrophobic segment resulted in import of the protein into the matrix [12].
  • Analysis of fractionated rat liver mitochondria revealed that DHODH is an integral membrane protein exposed to the intermembrane space [12].
  • Rabbit anti-DHODH IgG, which was generated using an immunization protocol with truncated recombinant human DHODH protein and purified by an immunosorbent method, was used for immunocytochemical detection and localization of this enzyme in ejaculated human spermatozoa [16].
  • The MNAs inhibit both T-cell and B-cell function by blocking de novo pyrimidine synthesis, through blockade of the pivotal mitochondrial enzyme dihyroorotic acid dehydrogenase (DHODH), and the inhibition of tyrosine kinase activity [17].

Associations of DHODH with chemical compounds

  • In the cell DHODH catalyzes the rate-limiting step of the de novo pyrimidine biosynthesis [18].
  • The active metabolite (2) of the novel immunosuppressive agent leflunomide (1) has been shown to inhibit the enzyme dihydroorotate dehydrogenase (DHODH) [1].
  • The initial set of phases was obtained using multiwavelength anomalous diffraction phasing with selenomethionine-containing DHODH [2].
  • DHODH inhibition occurs at lower concentrations of A77 1726 than that of tyrosine kinases and is currently considered the major mode of action [19].
  • Whereas the presence of the N-terminus of dihydroorotate dehydrogenase was essentially irrelevant for the efficacy of the malononitrilamides A77-1726, MNA715 and MNA279 with the rat and human enzyme, the N-termini were found to be important for the efficacy of the dianisidine derivative redoxal [3].

Regulatory relationships of DHODH

  • We report here that inhibition of cytochrome c oxidase by nitric oxide (NO) indirectly inhibits DHODH activity [20].

Other interactions of DHODH


Analytical, diagnostic and therapeutic context of DHODH


  1. Synthesis, structure-activity relationships, and pharmacokinetic properties of dihydroorotate dehydrogenase inhibitors: 2-cyano-3-cyclopropyl-3-hydroxy-N-[3'-methyl-4'-(trifluoromethyl)phenyl ] propenamide and related compounds. Kuo, E.A., Hambleton, P.T., Kay, D.P., Evans, P.L., Matharu, S.S., Little, E., McDowall, N., Jones, C.B., Hedgecock, C.J., Yea, C.M., Chan, A.W., Hairsine, P.W., Ager, I.R., Tully, W.R., Williamson, R.A., Westwood, R. J. Med. Chem. (1996) [Pubmed]
  2. Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents. Liu, S., Neidhardt, E.A., Grossman, T.H., Ocain, T., Clardy, J. Structure (2000) [Pubmed]
  3. Recombinant expression of N-terminal truncated mutants of the membrane bound mouse, rat and human flavoenzyme dihydroorotate dehydrogenase. A versatile tool to rate inhibitor effects? Ullrich, A., Knecht, W., Fries, M., Löffler, M. Eur. J. Biochem. (2001) [Pubmed]
  4. Functional expression of a fragment of human dihydroorotate dehydrogenase by means of the baculovirus expression vector system, and kinetic investigation of the purified recombinant enzyme. Knecht, W., Bergjohann, U., Gonski, S., Kirschbaum, B., Löffler, M. Eur. J. Biochem. (1996) [Pubmed]
  5. Helicobacter pylori-selective antibacterials based on inhibition of pyrimidine biosynthesis. Copeland, R.A., Marcinkeviciene, J., Haque, T.S., Kopcho, L.M., Jiang, W., Wang, K., Ecret, L.D., Sizemore, C., Amsler, K.A., Foster, L., Tadesse, S., Combs, A.P., Stern, A.M., Trainor, G.L., Slee, A., Rogers, M.J., Hobbs, F. J. Biol. Chem. (2000) [Pubmed]
  6. Single-molecule kinetics reveals signatures of half-sites reactivity in dihydroorotate dehydrogenase A catalysis. Shi, J., Dertouzos, J., Gafni, A., Steel, D., Palfey, B.A. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  7. Phase I clinical and pharmacokinetic trial of Brequinar sodium (DuP 785; NSC 368390). Arteaga, C.L., Brown, T.D., Kuhn, J.G., Shen, H.S., O'Rourke, T.J., Beougher, K., Brentzel, H.J., Von Hoff, D.D., Weiss, G.R. Cancer Res. (1989) [Pubmed]
  8. Intracellular location of the multidomain protein CAD in mammalian cells. Chaparian, M.G., Evans, D.R. FASEB J. (1988) [Pubmed]
  9. Mechanism of action of the novel anticancer agent 6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarbo xylic acid sodium salt (NSC 368390): inhibition of de novo pyrimidine nucleotide biosynthesis. Chen, S.F., Ruben, R.L., Dexter, D.L. Cancer Res. (1986) [Pubmed]
  10. High-throughput screening for potent and selective inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. Baldwin, J., Michnoff, C.H., Malmquist, N.A., White, J., Roth, M.G., Rathod, P.K., Phillips, M.A. J. Biol. Chem. (2005) [Pubmed]
  11. Catalytic enzyme histochemistry and biochemical analysis of dihydroorotate dehydrogenase/oxidase and succinate dehydrogenase in mammalian tissues, cells and mitochondria. Löffler, M., Becker, C., Wegerle, E., Schuster, G. Histochem. Cell Biol. (1996) [Pubmed]
  12. Requirements for the mitochondrial import and localization of dihydroorotate dehydrogenase. Rawls, J., Knecht, W., Diekert, K., Lill, R., Löffler, M. Eur. J. Biochem. (2000) [Pubmed]
  13. Plant dihydroorotate dehydrogenase differs significantly in substrate specificity and inhibition from the animal enzymes. Ullrich, A., Knecht, W., Piskur, J., Löffler, M. FEBS Lett. (2002) [Pubmed]
  14. Discovery of a novel series of DHODH inhibitors by a docking procedure and QSAR refinement. Leban, J., Saeb, W., Garcia, G., Baumgartner, R., Kramer, B. Bioorg. Med. Chem. Lett. (2004) [Pubmed]
  15. Leflunomide: mode of action in the treatment of rheumatoid arthritis. Breedveld, F.C., Dayer, J.M. Ann. Rheum. Dis. (2000) [Pubmed]
  16. Immunocytochemical detection of mitochondrial dihydroorotate dehydrogenase in human spermatozoa. Dietz, C., Hinsch, E., Löffler, M. Int. J. Androl. (2000) [Pubmed]
  17. FK778, a synthetic malononitrilamide. Fitzsimmons, W.E., First, M.R. Yonsei Med. J. (2004) [Pubmed]
  18. Dual binding mode of a novel series of DHODH inhibitors. Baumgartner, R., Walloschek, M., Kralik, M., Gotschlich, A., Tasler, S., Mies, J., Leban, J. J. Med. Chem. (2006) [Pubmed]
  19. Mechanism of action of leflunomide in rheumatoid arthritis. Fox, R.I. The Journal of rheumatology. Supplement. (1998) [Pubmed]
  20. Indirect inhibition of mitochondrial dihydroorotate dehydrogenase activity by nitric oxide. Beuneu, C., Auger, R., Löffler, M., Guissani, A., Lemaire, G., Lepoivre, M. Free Radic. Biol. Med. (2000) [Pubmed]
  21. Mechanism of action for leflunomide in rheumatoid arthritis. Fox, R.I., Herrmann, M.L., Frangou, C.G., Wahl, G.M., Morris, R.E., Strand, V., Kirschbaum, B.J. Clin. Immunol. (1999) [Pubmed]
  22. Immunosuppressive drugs: the first 50 years and a glance forward. Allison, A.C. Immunopharmacology (2000) [Pubmed]
  23. Dicoumarol impairs mitochondrial electron transport and pyrimidine biosynthesis in human myeloid leukemia HL-60 cells. Gonz??lez-Arag??n, D., Ariza, J., Villalba, J.M. Biochem. Pharmacol. (2007) [Pubmed]
  24. Anti-peptide immunoglobulins from rabbit and chicken eggs recognise recombinant human dihydroorotate dehydrogenase and a 44-kDa protein from rat liver mitochondria. Knecht, W., Köhler, R., Minét, M., Löffler, M. Eur. J. Biochem. (1996) [Pubmed]
  25. The interaction of 5-fluoroorotic acid with transition metals: synthesis and characterisation of Ni(II), Cu(II) and Zn(II) complexes. Schneider, A.G., Schmalle, H.W., Arod, F., Dubler, E. J. Inorg. Biochem. (2002) [Pubmed]
  26. Anti-arthritic effects of KF20444, a new immunosuppressive compound inhibiting dihydroorotate dehydrogenase, on rat collagen-induced arthritis. Kobayashi, K., Nakashima, A., Nagata, H., Nakajima, H., Yamaguchi, K., Sato, S., Miki, I. Inflamm. Res. (2001) [Pubmed]
  27. Heteroatom- and carbon-linked biphenyl analogs of Brequinar as immunosuppressive agents. Batt, D.G., Petraitis, J.J., Sherk, S.R., Copeland, R.A., Dowling, R.L., Taylor, T.L., Jones, E.A., Magolda, R.L., Jaffee, B.D. Bioorg. Med. Chem. Lett. (1998) [Pubmed]
  28. Inhibition of human cytomegalovirus signaling and replication by the immunosuppressant FK778. Evers, D.L., Wang, X., Huong, S.M., Andreoni, K.A., Huang, E.S. Antiviral Res. (2005) [Pubmed]
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