Substrate inhibition of uracil phosphoribosyltransferase by uracil can account for the uracil growth sensitivity of leishmania donovani pyrimidine auxotrophs

Journal of Biological Chemistry

Volumn 288, Issue 41, 2013, Pages 29954-29964

  Soysa, Radika ^a   Wilson, Zachary N ^a   Elferich, Johannes ^a   Forquer, Isaac ^b   Shinde, Ujwal ^a   Riscoe, Michael K ^b   Yates, Phillip A ^a   Ullman, Buddy ^a  

^a OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

^b PORTLAND VA MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

LEISHMANIA DONOVANI; NATURAL SUBSTRATES; PARTIAL STRUCTURES; PROTOZOAN PARASITES; PYRIMIDINE BIOSYNTHESIS; RECOMBINANT ENZYMES; SUBSTRATE INHIBITION; URACIL PHOSPHORIBOSYLTRANSFERASE;

BIOCHEMISTRY; BIOSYNTHESIS; ENZYMES; ESCHERICHIA COLI; NUCLEOTIDES; SUBSTRATES; UREA;

AROMATIC COMPOUNDS;

4 THIOURACIL; FLUOROURACIL; PHOSPHORIBOSYL PYROPHOSPHATE; PYRIMIDINE; RECOMBINANT ENZYME; URACIL; URACIL PHOSPHORIBOSYLTRANSFERASE; UREA;

ARTICLE; AUXOTROPHY; ENZYME ACTIVITY; ENZYME INHIBITION; ENZYME STRUCTURE; ENZYME SUBSTRATE; LEISHMANIA DONOVANI; MUTANT; NONHUMAN; NUCLEIC ACID SYNTHESIS; PARASITE DEVELOPMENT; PRIORITY JOURNAL;

ENZYME KINETICS; LEISHMANIA; LEISHMANIA DONOVANI; PARASITE; PARASITE METABOLISM; PYRIMIDINE; PYRIMIDINE SALVAGE; PYRIMIDINES; SUBSTRATE INHIBITION; URACIL PHOSPHORIBOSYLTRANSFERASE;

CATIONS, DIVALENT; CHROMATOGRAPHY, GEL; ENZYME STABILITY; FEEDBACK, PHYSIOLOGICAL; FLUOROURACIL; HYDROGEN-ION CONCENTRATION; KINETICS; LEISHMANIA DONOVANI; MUTATION; PENTOSYLTRANSFERASES; PHOSPHORIBOSYL PYROPHOSPHATE; PROTEIN MULTIMERIZATION; PROTOZOAN PROTEINS; PYRIMIDINES; RECOMBINANT PROTEINS; SPECTROPHOTOMETRY; SUBSTRATE SPECIFICITY; TEMPERATURE; THIOURACIL; URACIL;

EID: 84885647359     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M113.478826     Document Type: Article

References (32)

1. Carter, N., Rager, N., and Ullman, B. (2003) Purine and pyrimidine transport and metabolism, in Molecular and Medical Parasitology (Marr, J. J., and R. Komuniecki, eds) pp. 197-223, Academic Press Limited, London
2. El-Sayed, N. M., Myler, P. J., Blandin, G., Berriman, M., Crabtree, J., Aggarwal, G., Caler, E., Renauld, H., Worthey, E. A., Hertz-Fowler, C., Ghedin, E., Peacock, C., Bartholomeu, D. C., Haas, B. J., Tran, A. N., Wortman, J. R., Alsmark, U. C., Angiuoli, S., Anupama, A., Badger, J., Bringaud, F., Cadag, E., Carlton, J. M., Cerqueira, G. C., Creasy, T., Delcher, A. L., Djikeng, A., Embley, T. M., Hauser, C., Ivens, A. C., Kummerfeld, S. K., Pereira-Leal, J. B., Nilsson, D., Peterson, J., Salzberg, S. L., Shallom, J., Silva, J. C., Sundaram, J., Westenberger, S., White, O., Melville, S. E., Donelson, J. E., Andersson, B., Stuart, K. D., and Hall, N. (2005) Comparative genomics of trypanosomatid parasitic protozoa. Science 309, 404-409
3. French, J. B., Yates, P. A., Soysa, D. R., Boitz, J. M., Carter, N. S., Chang, B., Ullman, B., and Ealick, S. E. (2011) The Leishmania donovani UMP synthase is essential for promastigote viability and has an unusual tetrameric structure that exhibits substrate-controlled oligomerization. J. Biol. Chem. 286, 20930-20941
4. Ivens, A. C., Peacock, C. S., Worthey, E. A., Murphy, L., Aggarwal, G., Berriman, M., Sisk, E., Rajandream, M. A., Adlem, E., Aert, R., Anupama, A., Apostolou, Z., Attipoe, P., Bason, N., Bauser, C., Beck, A., Beverley, S. M., Bianchettin, G., Borzym, K., Bothe, G., Bruschi, C. V., Collins, M., Cadag, E., Ciarloni, L., Clayton, C., Coulson, R. M., Cronin, A., Cruz, A. K., Davies, R. M., De Gaudenzi, J., Dobson, D. E., Duesterhoeft, A., Fazelina, G., Fosker, N., Frasch, A. C., Fraser, A., Fuchs, M., Gabel, C., Goble, A., Goffeau, A., Harris, D., Hertz-Fowler, C., Hilbert, H., Horn, D., Huang, Y., Klages, S., Knights, A., Kube, M., Larke, N., Litvin, L., Lord, A., Louie, T., Marra, M., Masuy, D., Matthews, K., Michaeli, S., Mottram, J. C., Muller-Auer, S., Munden, H., Nelson, S., Norbertczak, H., Oliver, K., O'Neil, S., Pentony, M., Pohl, T. M., Price, C., Purnelle, B., Quail, M. A., Rabbinowitsch, E., Reinhardt, R., Rieger, M., Rinta, J., Robben, J., Robertson, L., Ruiz, J. C., Rutter, S., Saunders, D., Schafer, M., Schein, J., Schwartz, D. C., Seeger, K., Seyler, A., Sharp, S., Shin, H., Sivam, D., Squares, R., Squares, S., Tosato, V., Vogt, C., Volckaert, G., Wambutt, R., Warren, T., Wedler, H., Woodward, J., Zhou, S., Zimmermann, W., Smith, D. F., Blackwell, J. M., Stuart, K. D., Barrell, B., and Myler, P. J. (2005) The genome of the kinetoplastid parasite, Leishmania major. Science 309, 436-442
5. Wilson, Z. N., Gilroy, C. A., Boitz, J. M., Ullman, B., and Yates, P. A. (2012) Genetic dissection of pyrimidine biosynthesis and salvage in Leishmania donovani. J. Biol. Chem. 287, 12759-12770
6. Stark, G. R., and Wahl, G. M. (1984) Gene amplification. Annu. Rev. Biochem. 53, 447-491
7. Wahl, G. M., Padgett, R. A., and Stark, G. R. (1979) Gene amplification causes overproduction of the first three enzymes of UMP synthesis in N-(phosphonacetyl)-L-aspartate-resistant hamster cells. J. Biol. Chem. 254, 8679-8689
8. Suttle, D. P., and Stark, G. R. (1979) Coordinate overproduction of orotate phosphoribosyltransferase and orotidine-5'-phosphate decarboxylase in hamster cells resistant to pyrazofurin and 6-azauridine. J. Biol. Chem. 254, 4602-4607
9. Opperdoes, F. R. (1987) Compartmentation of carbohydrate metabolism in trypanosomes. Annu. Rev. Microbiol. 41, 127-151
10. Opperdoes, F. R. (1988) Glycosomes may provide clues to the import of peroxisomal proteins. Trends. Biochem. Sci. 13, 255-260
11. Fox, B. A., and Bzik, D. J. (2002) De novo pyrimidine biosynthesis is required for virulence of Toxoplasma gondii. Nature 415, 926-929
12. Hashimoto, M., Morales, J., Fukai, Y., Suzuki, S., Takamiya, S., Tsubouchi, A., Inoue, S., Inoue, M., Kita, K., Harada, S., Tanaka, A., Aoki, T., and Nara, T. (2012) Critical importance of the de novo pyrimidine biosynthesis pathway for Trypanosoma cruzi growth in the mammalian host cell cytoplasm. Biochem. Biophys. Res. Commun. 417, 1002-1006
13. Ali, J. A., Tagoe, D. N., Munday, J. C., Donachie, A., Morrison, L. J., and de Koning, H. P. (2013) Pyrimidine biosynthesis is not an essential function for Trypanosoma brucei bloodstream forms. PLoS One 8, e58034
14. Arakaki, T. L., Buckner, F. S., Gillespie, J. R., Malmquist, N. A., Phillips, M. A., Kalyuzhniy, O., Luft, J. R., Detitta, G. T., Verlinde, C. L., Van Voorhis, W. C., Hol, W. G., and Merritt, E. A. (2008) Characterization of Trypanosoma brucei dihydroorotate dehydrogenase as a possible drug target. Structural, kinetic and RNAi studies. Mol. Microbiol. 68, 37-50
15. Hassan, H. F., and Coombs, G. H. (1986) A comparative study of the purine- and pyrimidine-metabolising enzymes of a range of trypanosomatids. Comp. Biochem. Physiol. B. 84, 219-223
16. Shi, W., Schramm, V. L., and Almo, S. C. (1999) Nucleoside hydrolase from Leishmania major. Cloning, expression, catalytic properties, transition state inhibitors, and the 2.5-A crystal structure. J. Biol. Chem. 274, 21114-21120
17. Schumacher, M. A., Bashor, C. J., Song, M. H., Otsu, K., Zhu, S., Parry, R. J., Ullman, B., and Brennan, R. G. (2002) The structural mechanism of GTP stabilized oligomerization and catalytic activation of the Toxoplasma gondii uracil phosphoribosyltransferase. Proc. Natl. Acad. Sci. U.S.A. 99, 78-83
18. Carter, D., Donald, R. G., Roos, D., and Ullman, B. (1997) Expression, purification, and characterization of uracil phosphoribosyltransferase from Toxoplasma gondii. Mol. Biochem. Parasitol. 87, 137-144
19. Natalini, P., Ruggieri, S., Santarelli, I., Vita, A., and Magni, G. (1979) Baker's yeast UMP:pyrophosphate phosphoribosyltransferase. Purification, enzymatic and kinetic properties. J. Biol. Chem. 254, 1558-1563
20. Mikus, J., and Steverding, D. (2000) A simple colorimetric method to screen drug cytotoxicity against Leishmania using the dye Alamar Blue. Parasitol. Int. 48, 265-269
21. Schumacher, M. A., Carter, D., Scott, D. M., Roos, D. S., Ullman, B., and Brennan, R. G. (1998) Crystal structures of Toxoplasma gondii uracil phosphoribosyltransferase reveal the atomic basis of pyrimidine discrimination and prodrug binding. EMBO J. 17, 3219-3232
22. Berriman, M., Ghedin, E., Hertz-Fowler, C., Blandin, G., Renauld, H., Bartholomeu, D. C., Lennard, N. J., Caler, E., Hamlin, N. E., Haas, B., Böhme, U., Hannick, L., Aslett, M. A., Shallom, J., Marcello, L., Hou, L., Wickstead, B., Alsmark, U. C., Arrowsmith, C., Atkin, R. J., Barron, A. J., Bringaud, F., Brooks, K., Carrington, M., Cherevach, I., Chillingworth, T. J., Churcher, C., Clark, L. N., Corton, C. H., Cronin, A., Davies, R. M., Doggett, J., Djikeng, A., Feldblyum, T., Field, M. C., Fraser, A., Goodhead, I., Hance, Z., Harper, D., Harris, B. R., Hauser, H., Hostetler, J., Ivens, A., Jagels, K., Johnson, D., Johnson, J., Jones, K., Kerhornou, A. X., Koo, H., Larke, N., Landfear, S., Larkin, C., Leech, V., Line, A., Lord, A., Macleod, A., Mooney, P. J., Moule, S., Martin, D. M., Morgan, G. W., Mungall, K., Norbertczak, H., Ormond, D., Pai, G., Peacock, C. S., Peterson, J., Quail, M. A., Rabbinowitsch, E., Rajandream, M. A., Reitter, C., Salzberg, S. L., Sanders, M., Schobel, S., Sharp, S., Simmonds, M., Simpson, A. J., Tallon, L., Turner, C. M., Tait, A., Tivey, A. R., Van Aken, S., Walker, D., Wanless, D., Wang, S., White, B., White, O., Whitehead, S., Woodward, J., Wortman, J., Adams, M. D., Embley, T. M., Gull, K., Ullu, E., Barry, J. D., Fairlamb, A. H., Opperdoes, F., Barrell, B. G., Donelson, J. E., Hall, N., Fraser, C. M., Melville, S. E., and El-Sayed, N. M. (2005) The genome of the African trypanosome Trypanosoma brucei. Science 309, 416-422
23. El-Sayed, N. M., Myler, P. J., Bartholomeu, D. C., Nilsson, D., Aggarwal, G., Tran, A. N., Ghedin, E., Worthey, E. A., Delcher, A. L., Blandin, G., Westenberger, S. J., Caler, E., Cerqueira, G. C., Branche, C., Haas, B., Anupama, A., Arner, E., Aslund, L., Attipoe, P., Bontempi, E., Bringaud, F., Burton, P., Cadag, E., Campbell, D. A., Carrington, M., Crabtree, J., Darban, H., da Silveira, J. F., de Jong, P., Edwards, K., Englund, P. T., Fazelina, G., Feldblyum, T., Ferella, M., Frasch, A. C., Gull, K., Horn, D., Hou, L., Huang, Y., Kindlund, E., Klingbeil, M., Kluge, S., Koo, H., Lacerda, D., Levin, M. J., Lorenzi, H., Louie, T., Machado, C. R., McCulloch, R., McKenna, A., Mizuno, Y., Mottram, J. C., Nelson, S., Ochaya, S., Osoegawa, K., Pai, G., Parsons, M., Pentony, M., Pettersson, U., Pop, M., Ramirez, J. L., Rinta, J., Robertson, L., Salzberg, S. L., Sanchez, D. O., Seyler, A., Sharma, R., Shetty, J., Simpson, A. J., Sisk, E., Tammi, M. T., Tarleton, R., Teixeira, S., Van Aken, S., Vogt, C., Ward, P. N., Wickstead, B., Wortman, J., White, O., Fraser, C. M., Stuart, K. D., and Andersson, B. (2005) The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease. Science 309, 409-415
24. Hammond, D. J., and Gutteridge, W. E. (1982) UMP synthesis in the kinetoplastida. Biochim. Biophys. Acta 718, 1-10
25. Boitz, J. M., and Ullman, B. (2006) A conditional mutant deficient in hypoxanthine- guanine phosphoribosyltransferase and xanthine phosphoribosyltransferase validates the purine salvage pathway of Leishmania donovani. J. Biol. Chem. 281, 16084-16089
26. Cleary, M. D., Meiering, C. D., Jan, E., Guymon, R., and Boothroyd, J. C. (2005) Biosynthetic labeling of RNA with uracil phosphoribosyltransferase allows cell-specific microarray analysis of mRNA synthesis and decay. Nat. Biotechnol. 23, 232-237
27. Zeiner, G. M., Cleary, M. D., Fouts, A. E., Meiring, C. D., Mocarski, E. S., and Boothroyd, J. C. (2008) RNA analysis by biosynthetic tagging using 4-thiouracil and uracil phosphoribosyltransferase. Methods Mol. Biol. 419, 135-146
28. Pfefferkorn, E. R., and Pfefferkorn, L. C. (1977) Specific labeling of intracellular Toxoplasma gondii with uracil. J. Protozool. 24, 449-453
29. Longley, D. B., Harkin, D. P., and Johnston, P. G. (2003) 5-fluorouracil: mechanisms of action and clinical strategies. Nat. Rev. Cancer 3, 330-338
30. Shoemaker, L. K., Arora, U., and Rocha Lima, C. M. (2004) 5-fluorouracilinduced coronary vasospasm. Cancer Control 11, 46-49
31. Iltzsch, M. H., and Tankersley, K. O. (1994) Structure-activity relationship of ligands of uracil phosphoribosyltransferase from Toxoplasma gondii. Biochem. Pharmacol. 48, 781-792
32. Peters, G. J., Laurensse, E., Leyva, A., Lankelma, J., and Pinedo, H. M. (1986) Sensitivity of human, murine, and rat cells to 5-fluorouracil and 5'-deoxy-5-fluorouridine in relation to drug-metabolizing enzymes. Cancer Res. 46, 20-28