Structure and reactivity of Trypanosoma brucei pteridine reductase: Inhibition by the archetypal antifolate methotrexate

Molecular Microbiology

Volumn 61, Issue 6, 2006, Pages 1457-1468

  Dawson, Alice ^a   Gibellini, Federica ^a   Sienkiewicz, Natasha ^a   Tulloch, Lindsay B ^a   Fyfe, Paul K ^a   McLuskey, Karen ^a,b   Fairlamb, Alan H ^a   Hunter, William N ^a  

^a UNIVERSITY OF DUNDEE   (United Kingdom)

^b UNIVERSITY OF GLASGOW   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CARBOXYL GROUP; CYSTEINE; CYSTEINE PROTEINASE; DIHYDROFOLATE REDUCTASE; FOLIC ACID ANTAGONIST; FOLIC ACID DERIVATIVE; HISTIDINE; METHOTREXATE; NICOTINAMIDE; NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; OXIDOREDUCTASE; PROTEIN SUBUNIT; PROTOZOAL PROTEIN; PTERIDINE; PTERIN DERIVATIVE; PTR1 ENZYME; RECOMBINANT PROTEIN; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; UNCLASSIFIED DRUG;

AMINO ACID SEQUENCE; ARTICLE; BINDING SITE; CATALYSIS; CONTROLLED STUDY; DRUG BINDING; DRUG INHIBITION; DRUG STRUCTURE; ENZYME ACTIVITY; HYDROGEN BOND; LEISHMANIA MAJOR; NONHUMAN; PARASITE DEVELOPMENT; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN BINDING; PROTEIN DETERMINATION; PROTEIN FUNCTION; PROTEIN INTERACTION; PROTEIN STRUCTURE; TRYPANOSOMA BRUCEI; TRYPANOSOMIASIS;

AMINO ACID SEQUENCE; ANIMALS; BINDING SITES; CATALYTIC DOMAIN; CRYSTALLOGRAPHY, X-RAY; FOLIC ACID ANTAGONISTS; METHOTREXATE; MOLECULAR SEQUENCE DATA; OXIDOREDUCTASES; PROTEIN CONFORMATION; PROTOZOAN PROTEINS; TRYPANOSOMA BRUCEI BRUCEI;

LEISHMANIA MAJOR; PROTOZOA; TRYPANOSOMA BRUCEI; TRYPANOSOMATIDAE;

EID: 33748486972     PISSN: 0950382X     EISSN: 13652958     Source Type: Journal    
DOI: 10.1111/j.1365-2958.2006.05332.x     Document Type: Article

References (40)

1. Beck, J.T., and Ullman, B. (1990) Nutritional requirements of wild-type and folate deficient Leishmania donovani for pterins and folates. Mol Biochem Parasitol 43: 221-230.
2. Bello, A.R., Nare, B., Freedman, D., Hardy, L.W., and Beverley, S.M. (1994) PTR1: a reductase mediating salvage of oxidized pteridines and methotrexate resistance in the protozoan parasite Leishmania major. Proc Natl Acad Sci USA 91: 11442-11446.
3. Blakley, R.L. (1995) Eukaryotic dihydrofolate reductase. Adv Enzymol Relat Areas Mol Biol 70: 23-102.
4. Charlton, P.A., Young, D.W., Birdsall, B.W., Feeney, J., and Roberts, G.C.K. (1985) Stereochemistry of reduction of the vitamin folic-acid by dihydrofolate-reductase. J Chem Soc Perkin Trans 191: 1349-1353.
5. Collaborative Computational Project, Number, 4. (1994) The CCP4 suite: programs for protein crystallography. Acta Crystallogr D Biol Crystallogr 50: 760-763.
6. Copeland, R.A. (2000) Enzymes, a Practical Introduction to Structure, Mechanism and Data Analysis, 2nd edn. New York: Wiley-VCH.
7. Cruickshank, D.W.J. (1999) Remarks about protein structure precision. Acta Crystallogr D Biol Crystallogr 55: 583-601.
8. DeLano, W.L. (2002) The PyMOL Molecular Graphics System. San Carlos, CA: DeLano Scientific.
9. Duax, W.L., Pletnev, V., Addlagatta, A., Bruenn, J., and Weeks, C.M. (2003) Rational proteomics I. Fingerprint identification and cofactor specificity in the short-chain oxidoreductase (SCOR) enzyme family. Proteins 53: 931-943.
10. Emsley, P., and Cowtan, K. (2004) Coot: model-building tools for molecular graphics. Acta Crystallogr Biol Crystallogr D60: 2126-2132.
11. Erlanson, D.A., Wells, J.A., and Braisted, A.C. (2004) Tethering: fragment-based drug discovery. Annu Rev Biophys Biomol Struct 33: 199-223.
12. Fairlamb, A.H. (2003) Chemotherapy of human African trypanosomiasis: current and future prospects. Trends Parasitol 11: 488-494.
13. Gilman, A.G., Rall, T.W., and Nies, S. (eds) (1990) The Pharmaceutical Basis of Therapeutics. Taylor P, 8th edn. New York: Pergammon Press.
14. Gouet, P., Courcelle, E., Stuart, D.I., and Metoz, F. (1999) ESPript: analysis of multiple sequence alignments in PostScript. Bioinformatics 15: 305-308.
15. Gourley, D.G., Schüttelkopf, A.W., Leonard, G.A., Luba, J., Hardy, L.W., Beverley, S.M., and Hunter, W.N. (2001) Pteridine reductase mechanism correlates pterin metabolism with drug resistance in trypanosomatid parasites. Nat Struct Biol 8: 521-525.
16. Hardy, L.W., Matthews, W., Nare, B., and Beverley, S.M. (1997) Biochemical and genetic tests for inhibitors of Leishmania pteridine pathways. Exp Parasitol 87: 157-169.
17. Jaffe, J.J., McCormack, J.J., Jr, and Gutteridge, W.E. (1969) Dihydrofolate reductases within the genus Trypanosoma. Exp Parasitol 25: 311-318.
18. Kidder, G., and Dutta, B. (1958) The growth and nutrition of Crithidia fasiculata. J Gen Microbiol 18: 621-638.
19. Knighton, D.R., Kan, C.C., Howland, E., Janson, C.A., Hostomska, Z., Welsh, K.M., and Matthews, D.A. (1994) Structure of and kinetic channelling in bifunctional dihydrofolate reductase-thymidylate synthase. Nat Struct Biol 1: 186-194.
20. Kompis, I.M., Islam, K., and Then, R.L. (2005) DNA and RNA synthesis: antifolates. Chem Rev 105: 593-620.
21. Leonard, G.A., McAuley-Hecht, K., Brown, T., and Hunter, W.N. (1995) Do C-HO hydrogen bonds contribute to the stability of nucleic acid base pairs? Acta Crystallogr D Biol Crystallogr 51: 136-139.
22. Luba, J., Nare, B., Liang, P.H., Anderson. K.S., Beverley, S.M., and Hardy, L.W. (1998) Leishmania major pteridine reductase 1 belongs to the short chain dehydrogenase family: stereochemical and kinetic evidence. Biochemistry 37: 4093-4104.
23. McLuskey, K., Gibellini, F., Carvalho, P., Avery, M.A., and Hunter, W.N. (2004) Inhibition of Leishmania major pteridine reductase by 2,4,6-triaminoquinazoline: structure of the NADPH ternary complex. Acta Crystallogr D Biol Crystallogr 60: 1780-1785.
24. Matthews, D.A., Bolin, J.T., Burridge, J.M., Filman, D.J., Volz, K.W., and Kraut, J. (1985) Dihydrofolate reductase. The stereochemistry of inhibitor selectivity. J Biol Chem 260: 392-399.
25. Morrison, J.F. (1969) Kinetics of the reversible inhibition of enzyme-catalysed reactions by tight-binding inhibitors. Biochim Biophys Acta 185: 269-286.
26. Murshudov, G.N., Vagin, A.A., and Dodson, E.J. (1997) Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr D Biol Crystallogr 53: 240-255.
27. Nare, B., Lua, J., Hardy, L.W., and Beverley, S. (1997a) New approaches to Leishmania chemotherapy: pteridine reductase 1 (PTR1) as a target and modulator of antifolate sensitivity. Parasitology 114: S101-S110.
28. Nare, B., Hardy, L.W., and Beverley, S.M. (1997b) The roles of pteridine reductase 1 and dihydrofolate reductase-thymidylate synthase in pteridine metabolism in the protozoan parasite Leishmania major. J Biol Chem 272: 13883-13891.
29. Olliaro, P.L., and Taylor, W.R. (2003) Antimalarial compounds: from bench to bedside. J Exp Biol 206: 3753-3759.
30. Oppermann, U., Filling, C., Hult, M., Shafqat, N., Wu, X., Lindh, M., et al. (2003) Short-chain dehydrogenases/reductases (SDR): the 2002 update. Chem Biol Interact 143-144: 247-253.
31. Otwinowski, Z., and Minor, W. (1997) Processing of X-ray diffraction data collected in oscillation mode. Method Enzymol 276: 307-326.
32. Robello, C., Navarro, P., Castanys, S., and Gamarro, F. (1997) A pteridine reductase gene ptr1 contiguous to a P-glycoprotein confers resistance to antifolates in Trypanosoma cruzi. Mol Biochem Parasitol 90: 525-535.
33. Sawaya, M.R., and Kraut, J. (1997) Loop and subdomain movements in the mechanism of Escherichia coli dihydrofolate reductase: crystallographic evidence. Biochemistry 36: 586-603.
34. Schnell, J.R., Dyson, H.J., and Wright, P.E. (2004) Structure, dynamics, and catalytic function of dihydrofolate reductase. Annu Rev Biophys Biomol Struct 33: 119-140.
35. Schormann, N., Pal, B., Senkovich, O., Carson, M., Howard, A., Smith, C., et al. (2005) Crystal structure of Trypanosoma cruzi pteridine reductase 2 in complex with a substrate and an inhibitor. J Struct Biol 152: 64-75.
36. Schüttelkopf, A.W., Hardy, L.W., Beverley, S.M., and Hunter, W.N. (2005) Structures of Leishmania major pteridine reductase complexes reveal the active site features important for ligand binding and to guide inhibitor design. J Mol Biol 352: 105-116.
37. Sirawaraporn, W., Sertsrivanich, R., Booth, R.G., Hansch, C., Neal, R.A., and Santi, D.V. (1988) Selective inhibition of Leishmania growth by 5-benzy-2,4-diaminopyrimidines. Mol Biochem Parasitol 31: 79-86.
38. Tyndall, J.D., Nall, T., and Fairlie, D.P. (2005) Proteases universally recognize beta strands in their active sites. Chem Rev 105: 973-999.
39. Vagin, A., and Teplyakov, A. (2000) An approach to multicopy search in molecular replacement. Acta Crystallogr D Biol Crystallogr D56: 1622-1624.
40. Zhao, H., Bray, T., Ouellette, M., Zhao, M., Ferre, R.A., Matthews, D., et al. (2003) Structure of pteridine reductase (PTR1) from Leishmania tarentolae. Acta Crystallogr D Biol Crystallogr 59: 1539-1544.