Dihydroorotase Inhibitors

Drug Design of Zinc-Enzyme Inhibitors: Functional, Structural, and Disease Applications

Volumn , Issue , 2009, Pages 951-979

  Lee, Mihwa ^a   Maher, Megan J ^b   Christopherson, Richard I ^a   Guss, J Mitchell ^a  

^a UNIVERSITY OF SYDNEY   (Australia)

^b CENTENARY INSTITUTE   (Australia)

Author keywords

DHOase attractive target for antimalarial chemotherapy; DHOase inhibitor complexes; Dihydroorotase inhibitors and de novo pathway for pyrimidine biosynthesis

Indexed keywords

EID: 84889431183     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9780470508169.ch39     Document Type: Chapter

References (87)

1. Kim, H.; Kelly, R. E.; Evans, D.R. The structural organization of the hamster multifunctional protein CAD. Controlled proteolysis, domains, and linkers. J. Biol. Chem. 1992, 267, 7177-7184.
2. Fields, C.; Brichta, D.; Shepherdson, M.; Farinha, M.; O'Donovan, G. Phylogenetic analysis and classification of dihydroorotases: a complex history for a complex enzyme. Pathways Pyrimidines: Int. Newslett. 1999, 7, 49-63.
3. Heidelberger, C.; Danenberg, P. V.; Moran, R.G. Fluorinated pyrimidines and their nucleosides. Adv. Enzymol. Relat. Areas Mol. Biol. 1983, 54, 58-119.
4. Weber, G. Biochemical strategy of cancer cells and the design of chemotherapy: G. H. A. Clowes Memorial Lecture. Cancer Res. 1983, 43, 3466-3492.
5. Sherman, I.W. Biochemistry of Plasmodium (malarial parasites). Microbiol. Rev. 1979, 43, 453-495.
6. Reyes, P.; Rathod, P. K.; Sanchez, D. J.; Mrema, J. E.; Rieckmann, K. H.; Heidrich, H.G. Enzymes of purine and pyrimidine metabolism from the human malaria parasite, Plasmodium falciparum. Mol. Biochem. Parasitol. 1982, 5, 275-290.
7. Gardner,M. J.; Hall, N.; Fung, E.; White, O.; Berriman, M.; Hyman, R.W.; Carlton, J. M.; Pain, A.; Nelson, K. E.; Bowman, S.; Paulsen, I. T.; James, K.; Eisen, J. A.; Rutherford, K.; Salzberg, S. L.; Craig, A.;Kyes, S.; Chan, M. S.; Nene,V.; Shallom, S. J.; Suh, B.; Peterson, J.; Angiuoli, S.; Pertea, M.; Allen, J.; Selengut, J.; Haft, D.; Mather,M.W.; Vaidya, A. B.; Martin, D. M.; Fairlamb, A. H.; Fraunholz, M. J.; Roos, D. S.; Ralph, S. A.; McFadden, G. I.; Cummings, L. M.; Subramanian, G. M.; Mungall, C.; Venter, J. C.; Carucci, D. J.; Hoffman, S. L.; Newbold, C.; Davis, R.W.; Fraser, C. M.; Barrell, B. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 2002, 419, 498-511.
8. Christopherson, R. I.; Lyons, S. D.; Wilson, P.K. Inhibitors of de novo nucleotide biosynthesis as drugs. Acc. Chem. Res. 2002, 35, 961-971.
9. Sherman, I.W.; Jones, L.A. Plasmodium lophurae: membrane proteins of erythrocyte-free plasmodia and malaria-infected red cells. J. Protozool. 1979, 26, 489-501.
10. Gero, A. M.; Brown, G. V.; O'Sullivan,W. J. Pyrimidine de novo synthesis during the life cycle of the intraerythrocytic stage of Plasmodium falciparum. J. Parasitol. 1984, 70, 536-541.
11. Hyde, J.E. Targeting purine and pyrimidine metabolism in human apicomplexan parasites. Curr. Drug Targets 2007, 8, 31-47.
12. Kensler, T.W.; Cooney, D. A.; Advances in Pharmacology and Chemotherapy; Academic Press: New York, 1981; Vol. 18, p 273.
13. Mitchell, A.; Finch, L.R. Pathways of nucleotide biosynthesis in Mycoplasma mycoides subsp. mycoides. J. Bacteriol. 1977, 130, 1047-1054.
14. Heyworth, P. G.; Gutteridge,W. E.; Ginger, C.D. Pyrimidine metabolism in Trichomonas vaginalis. FEBS Lett. 1984, 176, 55-60.
15. McClarty, G.; Qin, B. Pyrimidine metabolism by intracellular Chlamydia psittaci. J. Bacteriol. 1993, 175, 4652-4661.
16. Xu, P.;Widmer, G.;Wang,Y.; Ozaki, L. S.; Alves, J. M.; Serrano, M. G.; Puiu, D.; Manque, P.; Akiyoshi, D.; Mackey, A. J.; Pearson,W. R.; Dear, P. H.; Bankier, A. T.; Peterson, D. L.; Abrahamsen, M. S.; Kapur, V.; Tzipori, S.; Buck, G.A. The genome of Cryptosporidium hominis. Nature 2004, 431, 1107-1112.
17. Lieberman, I.; Kornberg, A. Enzymatic synthesis and breakdown of a pyrimidine, orotic acid. I. Dihydroortic acid, ureidosuccinic acid, and 5-carboxymethylhydantoin. J. Biol. Chem. 1954, 207, 911-924.
18. Taylor, W. H.; Taylor, M. L.; Balch, W. E.; Gilchrist, P.S. Purification of properties of dihydroorotase, a zinc-containing metalloenzyme in Clostridium oroticum. J. Bacteriol. 1976, 127, 863-873.
19. Pettigrew, D. W.; Bidigare, R. R.; Mehta, B. J.; Williams, M. I.; Sander, E.G. Dihydroorotase from Clostridium oroticum. Purification and reversible removal of essential zinc. Biochem. J. 1985, 230, 101-108.
20. Sander, E. G.; Heeb, M.J. Purification and properties of dihydroorotase from Escherichia coli B. Biochim. Biophys. Acta 1971, 227, 442-452.
21. Washabaugh, M.W.; Collins, K.D. Dihydroorotase from Escherichia coli. Purification and characterization. J. Biol. Chem. 1984, 259, 3293-3298.
22. Krungkrai, J.; Cerami, A.; Henderson, G.B. Pyrimidine biosynthesis in parasitic protozoa: purification of a monofunctional dihydroorotase from Plasmodium berghei and Crithidia fasciculata. Biochemistry 1990, 29, 6270-6275.
23. Ogawa, J.; Shimizu, S. Purification and characterization of dihydroorotase from Pseudomonas putida. Arch. Microbiol. 1995, 164, 353-357.
24. Christopherson, R. I.; Jones, M.E. The overall synthesis of L-5,6-dihydroorotate by multienzymatic protein pyr1-3 from hamster cells. Kinetic studies, substrate channeling, and the effects of inhibitors. J. Biol. Chem. 1980, 255, 11381-11395.
25. Kelly, R. E.; Mally, M. I.; Evans, D.R. The dihydroorotase domain of the multifunctional protein CAD. Subunit structure, zinc content, and kinetics. J. Biol. Chem. 1986, 261, 6073-6083.
26. Brown, D. C.; Collins, K.D. Dihydroorotase from Escherichia coli. Cloning the pyrC gene and production of tryptic peptide maps. J. Biol. Chem. 1986, 261, 5917-5919.
27. Brown, D. C.; Collins, K.D. Dihydroorotase from Escherichia coli. Substitution of Co(II) for the active site Zn(II). J. Biol. Chem. 1991, 266, 1597-1604.
28. Purcarea, C.; Martin, P.; Vickrey, J. F.; Guy, H. I.; Edwards, B. F.; Evans, D.R. Cloning, expression and preliminary X-ray analysis of the dihydroorotase from the hyperthermophilic eubacterium Aquifex aeolicus. Acta Crystallogr., D Biol. Crystallogr. 2002, 58, 154-156.
29. Ahuja, A.; Purcarea, C.; Ebert, R.; Sadecki, S.; Guy, H. I.; Evans, D.R. Aquifex aeolicus dihydroorotase: association with aspartate transcarbamoylase switches on catalytic activity. J. Biol. Chem. 2004, 279, 53136-53144.
30. Huang, D. T.; Kaplan, J.; Menz, R. I.; Katis, V. L.; Wake, R. G.; Zhao, F.; Wolfenden, R.; Christopherson, R.I. Thermodynamic analysis of catalysis by the dihydroorotases from hamster and Bacillus caldolyticus, as compared with the uncatalyzed reaction. Biochemistry 2006, 45, 8275-8283.
31. Robles Lopez, S. M.; Hortua Triana, M. A.; Zimmermann, B.H. Cloning and preliminary characterization of the dihydroorotase from Toxoplasma gondii. Mol. Biochem. Parasitol. 2006, 148, 93-98.
32. Krungkrai, S. R.; Wutipraditkul, N.; Krungkrai, J. Dihydroorotase of human malarial parasite Plasmodium falciparum differs from host enzyme. Biochem. Biophys. Res. Commun. 2008, 366, 821-826.
33. Williams, N. K.; Peide, Y.; Seymour, K. K.; Ralston, G. B.; Christopherson, R.I. Expression of catalytically active hamster dihydroorotase domain in Escherichia coli: purification and characterization. Protein Eng. 1993, 6, 333-340.
34. Huang, D. T.; Thomas, M. A.; Christopherson, R.I. Divalent metal derivatives of the hamster dihydroorotase domain. Biochemistry 1999, 38, 9964-9970.
35. Christopherson, R. I.; Jones, M.E. Interconversion of carbamayl-L-aspartate and L-dihydroorotate by dihydroorotase from mouse Ehrlich ascites carcinoma. J. Biol. Chem. 1979, 254, 12506-12512.
36. Porter, T. N.; Li, Y.; Raushel, F.M. Mechanism of the dihydroorotase reaction. Biochemistry 2004, 43, 16285-16292.
37. Coleman, P. F.; Suttle, D. P.; Stark, G.R. Purification from hamster cells of the multifunctional protein that initiates de novo synthesis of pyrimidine nucleotides. J. Biol. Chem. 1977, 252, 6379-6385.
38. Van de Casteele, M.; Chen, P.; Roovers, M.; Legrain, C.; Glansdorff, N. Structure and expression of a pyrimidine gene cluster from the extreme thermophile Thermus strain ZO5. J. Bacteriol. 1997, 179, 3470-3481.
39. McPhail, D.; Shepherdson, M. The aspartate transcarbamoylase-dihydroorotase complex in Deinococcus radiophilus has an active dihydroorotase. Arch. Microbiol. 2006, 185, 78-81.
40. Hughes, L. E.; Hooshdaran, M. Z.; O'Donovan, G.A. Streptomyces aspartate transcarbamoylase is a dodecamer with dihydroorotase activity. Curr. Microbiol. 1999, 39, 175-179.
41. Wild, J. R.; Belser, W.L. Pyrimidine biosynthesis in Serratia marcescens: polypeptide interactions of three nonsequential enzymes. Biochem. Genet. 1977, 15, 173-193.
42. Guyonvarch, A.; Nguyen-Juilleret, M.; Hubert, J. C.; Lacroute, F. Structure of the Saccharomyces cerevisiae URA4 gene encoding dihydroorotase. Mol. Gen. Genet. 1988, 212, 134-141.
43. Souciet, J. L.; Nagy, M.; Le Gouar, M.; Lacroute, F.; Potier, S. Organization of the yeast URA2 gene: identification of a defective dihydroorotase-like domain in the multifunctional carbamoylphosphate synthetase-aspartate transcarbamylase complex. Gene 1989, 79, 59-70.
44. Penverne, B.; Belkaid, M.; Herve, G. In situ behavior of the pyrimidine pathway enzymes in Saccharomyces cerevisiae. 4. The channeling of carbamylphosphate to aspartate transcarbamylase and its partition in the pyrimidine and arginine pathways. Arch. Biochem. Biophys. 1994, 309, 85-93.
45. Schurr, M. J.; Vickrey, J. F.; Kumar, A. P.; Campbell, A. L.; Cunin, R.; Benjamin, R. C.; Shanley, M. S.; O'Donovan, G.A. Aspartate transcarbamoylase genes of Pseudomonas putida: requirement for an inactive dihydroorotase for assembly into the dodecameric holoenzyme. J. Bacteriol. 1995, 177, 1751-1759.
46. Brichta, D. M.; Azad, K. N.; Ralli, P.; O'Donovan, G.A. Pseudomonas aeruginosa dihydroorotases: a tale of three pyrCs. Arch. Microbiol. 2004, 182, 7-17.
47. Thoden, J. B.; Phillips, G. N., Jr.; Neal, T. M.; Raushel, F. M.; Holden, H.M. Molecular structure of dihydroorotase: a paradigm for catalysis through the use of a binuclear metal center. Biochemistry 2001, 40, 6989-6997.
48. Martin, P. D.; Purcarea, C.; Zhang, P.; Vaishnav, A.; Sadecki, S.; Guy-Evans, H. I.; Evans, D. R.; Edwards, B.F. The crystal structure of a novel, latent dihydroorotase from Aquifex aeolicus at 1.7A resolution. J. Mol. Biol. 2005, 348, 535-547.
49. Holm, L.; Sander, C. An evolutionary treasure: unification of a broad set of amidohydrolases related to urease. Proteins 1997, 28, 72-82.
50. Seibert, C. M.; Raushel, F.M. Structural and catalytic diversity within the amidohydrolase superfamily. Biochemistry 2005, 44, 6383-6391.
51. Reardon, D.; Farber, G.K. The structure and evolution of alpha/beta barrel proteins. FASEB J. 1995, 9, 497-503.
52. Buchbinder, J. L.; Stephenson, R. C.; Dresser,M. J.; Pitera, J.W.; Scanlan, T. S.; Fletterick, R.J. Biochemical characterization and crystallographic structure of an Escherichia coli protein from the phosphotriesterase gene family. Biochemistry 1998, 37, 5096-5106.
53. Karplus, P. A.; Pearson, M. A.; Hausinger, R. P. 70 years of crystalline urease: what havewe learned? Acc. Chem. Res. 1997, 30, 330-337.
54. Benning, M. M.; Shim, H.; Raushel, F. M.; Holden, H.M. High resolution X-ray structures of different metal-substituted forms of phosphotriesterase from Pseudomonas diminuta. Biochemistry 2001, 40, 2712-2722.
55. Ireton, G. C.; McDermott, G.; Black, M. E.; Stoddard, B.L. The structure of Escherichia coli cytosine deaminase. J. Mol. Biol. 2002, 315, 687-697.
56. Nam, S. H.; Park, H. S.; Kim, H.S. Evolutionary relationship and application of a superfamily of cyclic amidohydrolase enzymes. Chem. Rec. 2005, 5, 298-307.
57. Kim, G. J.; Kim, H.S. Identification of the structural similarity in the functionally related amidohydrolases acting on the cyclic amide ring. Biochem. J. 330,Pt 1 1998, 295-302.
58. Abendroth, J.; Niefind, K.; May, O.; Siemann, M.; Syldatk, C.; Schomburg, D. The structure of L-hydantoinase from Arthobacter aurescens leads to an understanding of dihydropyrimidinase substrate and enantio specificity. Biochemistry 2002, 41, 8589-8597.
59. Lohkamp, B.; Andersen, B.; Piskur, J.; Dobritzsch, D. The crystal structures of dihydropyrimidinases reaffirm the close relationship between cyclic amidohydrolases and explain their substrate specificity. J. Biol. Chem. 2006, 281, 13762-13776.
60. Sander, E. G.; Wright, L. D.; McCormick, D.B. Evidence for function of a metal ion in the activity of dihydroorotase from Zymobacterium oroticum. J. Biol. Chem. 1965, 240, 3628-3630.
61. Lee, M.; Chan, C.W.; Guss, J. M.; Christopherson, R. I.; Maher, M. J. Dihydroorotase from Escherichia coli: loop movement and cooperativity between subunits. J. Mol. Biol. 2005, 348, 523-533.
62. Lee, M.; Maher, M. J.; Guss, J.M. Structure of the T109S mutant of Escherichia coli dihydroorotase complexed with the inhibitor 5-fluoroorotate: catalytic activity is reflected by the crystal form. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 2007, 63, 154-161.
63. Lee, M.; Maher,M. J.; Christopherson, R. I.; Guss, J.M. Kinetic and structural analysis of mutant Escherichia coli dihydroorotases: a flexible loop stabilizes the transition state. Biochemistry 2007, 46, 10538-10550.
64. Deckert, G.; Warren, P. V.; Gaasterland, T.; Young, W. G.; Lenox, A. L.; Graham, D. E.; Overbeek, R.; Snead, M. A.;Keller, M.; Aujay, M.; Huber, R.; Feldman, R. A.; Short, J. M.; Olsen, G. J.; Swanson, R.V. The complete genome of the hyperthermophilic bacterium Aquifex aeolicus. Nature 1998, 392, 353-358.
65. Nelson, K. E.; Fleischmann, R. D.; DeBoy, R. T.; Paulsen, I. T.; Fouts, D. E.; Eisen, J. A.; Daugherty, S. C.; Dodson, R. J.; Durkin, A. S.; Gwinn, M.; Haft, D. H.; Kolonay, J. F.; Nelson,W. C.; Mason, T.; Tallon, L.; Gray, J.; Granger, D.; Tettelin, H.; Dong, H.; Galvin, J. L.; Duncan, M. J.; Dewhirst, F. E.; Fraser, C.M. Complete genome sequence of the oral pathogenic bacterium Porphyromonas gingivalis strain W83. J. Bacteriol. 2003, 185, 5591-5601.
66. Altschul, S. F.; Madden, T. L.; Schaffer, A. A.; Zhang, J.; Zhang, Z.; Miller, W.; Lipman, D.J. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 1997, 25, 3389-3402.
67. Van de Casteele,M.; Legrain, C.; Desmarez, L.; Chen, P. G.; Pierard, A.; Glansdorff,N. Molecular physiology of carbamoylation under extreme conditions: what can we learn from extreme thermophilic microorganisms? Comp. Biochem. Physiol. A Physiol. 1997, 118, 463-473.
68. Williams, N. K.; Manthey, M. K.; Hambley, T. W.; O'Donoghue, S. I.; Keegan, M.; Chapman, B. E.; Christopherson, R.I. Catalysis by hamster dihydroorotase: zinc binding, site-directed mutagenesis, and interaction with inhibitors. Biochemistry 1995, 34, 11344-11352.
69. Zimmermann, B. H.; Kemling, N. M.; Evans, D.R. Function of conserved histidine residues in mammalian dihydroorotase. Biochemistry 1995, 34, 7038-7046.
70. Anderson, M. A.; Cleland, W. W.; Huang, D. T.; Chan, C.; Shojaei, M.; Christopherson, R. I. 13C and 15N isotope effects for conversion of L-dihydroorotate to N-carbamyl-Laspartate using dihydroorotase from hamster and Bacillus caldolyticus. Biochemistry 2006, 45, 7132-7139.
71. Uhlemann, A. C.; Cameron, A.; Eckstein-Ludwig, U.; Fischbarg, J.; Iserovich, P.; Zuniga, F. A.; East, M.; Lee, A.; Brady, L.; Haynes, R. K.; Krishna, S. A single amino acid residue can determine the sensitivity of SERCAs to artemisinins. Nat. Struct. Mol. Biol. 2005, 12, 628-629.
72. Lee, M.; Chan, C. W.; Graham, S. C.; Christopherson, R. I.; Guss, J. M.; Maher, M.J. Structures of ligand-free and inhibitor complexes of dihydroorotase from Escherichia coli: implications for loop movement in inhibitor design. J Mol. Biol. 2007, 370, 812-825.
73. Adams, J. L.; Meek, T. D.; Mong, S. M.; Johnson, R. K.; Metcalf, B.W. cis-4-Carboxy-6-(mercaptomethyl)-3,4,5,6-tetrahydropyrimidin-2(1 H)-one, a potent inhibitor of mammalian dihydroorotase. J. Med. Chem. 1988, 31, 1355-1359.
74. Christopherson, R. I.; Schmalzl, K. J.; Szabados, E.; Goodridge, R. J.; Harsanyi, M. C.; Sant, M. E.; Algar, E. M.; Anderson, J. E.; Armstrong, A.; Sharma, S. C. et al. Mercaptan and dicarboxylate inhibitors of hamster dihydroorotase. Biochemistry 1989, 28, 463-470.
75. Manthey, M. K.; Huang, D. T.; Bubb,W. A.; Christopherson, R.I. Synthesis and enzymic evaluation of 4-mercapto-6-oxo-1, 4-azaphosphinane-2-carboxylic acid 4-oxide as an inhibitor of mammalian dihydroorotase. J. Med. Chem. 1998, 41, 4550-4555.
76. Cao, Y.; Christopherson, R. I.; Elix, J. A.; Gaul, K.L. Synthesis of a phosphinic acid transition state analogue inhibitor of dihydroorotase. Aust. J. Chem. 1994, 47, 903-911.
77. Levenson, C. H.; Meyer, R. B., Jr. Design and synthesis of tetrahedral intermediate analogues as potential dihydroorotase inhibitors. J. Med. Chem. 1984, 27, 228-232.
78. Rathod, P. K.; Khatri, A.; Hubbert, T.; Milhous, W.K. Selective activity of 5-fluoroorotic acid against Plasmodium falciparum in vitro. Antimicrob. Agents Chemother. 1989, 33, 1090-1094.
79. Queen, S. A.; Jagt, D. L.; Reyes, P. In vitro susceptibilities of Plasmodium falciparum to compounds which inhibit nucleotide metabolism. Antimicrob. Agents Chemother. 1990, 34, 1393-1398.
80. Krungkrai, J.; Krungkrai, S. R.; Phakanont, K. Antimalarial activity of orotate analogs that inhibit dihydroorotase and dihydroorotate dehydrogenase. Biochem. Pharmacol. 1992, 43, 1295-1301.
81. Gomez, Z. M.; Rathod, P.K. Antimalarial activity of a combination of 5-fluoroorotate and uridine in mice. Antimicrob. Agents Chemother. 1990, 34, 1371-1375.
82. Rathod, P. K.; Gomez, Z.M. Plasmodium yoelii: oral delivery of 5-fluoroorotate to treat malaria in mice. Exp. Parasitol. 1991, 73, 512-514.
83. Li,Y.; Raushel, F.M. Inhibitors designed for the active site of dihydroorotase. Bioorg. Chem. 2005, 33, 470-483.
84. Hambley, T. W.; Phillips, L.; Poiner, A. C.; Christopherson, R. I. A crystallographic and molecular mechanics study of inhibitors of dihydroorotase. Acta Crystallogr. Sect. B 1993, 49, 130-136.
85. Daniel, R.; Kokel, B.; Caminade, E.; Martel, A.; Le Goffic, F. Assay of Escherichia coli dihydroorotase with enantiomeric substrate: practical preparation of carbamyl L-aspartate and high-performance liquid chromatography analysis of catalysis product. Anal. Biochem. 1996, 239, 130-135.
86. Zimmermann, B. H.; Evans, D.R. Cloning, overexpression, and characterization of the functional dihydroorotase domain of the mammalian multifunctional protein CAD. Biochemistry 1993, 32, 1519-1527.
87. Maher,M. J.; Huang, D. T.; Guss, J. M.; Collyer,C. A.; Christopherson, R.I. Crystallization of hamster dihydroorotase: involvement of a disulfide-linked tetrameric form. Acta Crystallogr. D Biol. Crystallogr. 2003, 59, 381-384.