First three-dimensional structure of toxoplasma gondii thymidylate synthase-dihydrofolate reductase: Insights for catalysis, interdomain interactions, and substrate channeling

Biochemistry

Volumn 52, Issue 41, 2013, Pages 7305-7317

  Sharma, Hitesh ^a   Landau, Mark J ^a   Vargo, Melissa A ^a   Spasov, Krasimir A ^a   Anderson, Karen S ^a  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DIHYDROFOLATE REDUCTASE; INTER-DOMAIN INTERACTIONS; KINETIC CHARACTERIZATION; SITE DIRECTED MUTAGENESIS; STEADY-STATE KINETICS; SUBSTRATE CHANNELINGS; THREE-DIMENSIONAL STRUCTURE; THYMIDYLATE SYNTHASE;

CATALYSIS; ENZYME ACTIVITY; KINETIC THEORY; KINETICS; THREE DIMENSIONAL;

ENZYME INHIBITION;

ANTIPARASITIC AGENT; DIHYDROFOLATE REDUCTASE; DIHYDROFOLIC ACID; HOMODIMER; MONOMER; THYMIDYLATE SYNTHASE;

ARTICLE; CATALYSIS; CROSSING OVER; ENZYME ACTIVE SITE; ENZYME ACTIVITY; ENZYME KINETICS; ENZYME STRUCTURE; ENZYME SUBSTRATE; MUTATIONAL ANALYSIS; NONHUMAN; PRIORITY JOURNAL; PROTEIN INTERACTION; SITE DIRECTED MUTAGENESIS; STEADY STATE; SURFACE PROPERTY; TOXOPLASMA GONDII;

BINDING SITES; CATALYSIS; CATALYTIC DOMAIN; FOLIC ACID; IMAGING, THREE-DIMENSIONAL; KINETICS; MODELS, MOLECULAR; MULTIENZYME COMPLEXES; PROTEIN STRUCTURE, SECONDARY; PROTOZOAN PROTEINS; SUBSTRATE SPECIFICITY; TETRAHYDROFOLATE DEHYDROGENASE; THYMIDYLATE SYNTHASE; TOXOPLASMA;

EID: 84886067208     PISSN: 00062960     EISSN: 15204995     Source Type: Journal    
DOI: 10.1021/bi400576t     Document Type: Article

References (51)

1. Sharma, M. and Chauhan, P. M. (2012) Dihydrofolate reductase as a therapeutic target for infectious diseases: opportunities and challenges Future Med. Chem. 4, 1335-1365
2. Gangjee, A., Jain, H. D., and Kurup, S. (2007) Recent advances in classical and non-classical antifolates as antitumor and antiopportunistic infection agents: part I Anti-Cancer Agents Med. Chem. 7, 524-542
3. Hardy, L. W., Finer-Moore, J. S., Montfort, W. R., Jones, M. O., Santi, D. V., and Stroud, R. M. (1987) Atomic structure of thymidylate synthase: target for rational drug design Science 235, 448-455
4. Schiffer, C. A., Clifton, I. J., Davisson, V. J., Santi, D. V., and Stroud, R. M. (1995) Crystal structure of human thymidylate synthase: a structural mechanism for guiding substrates into the active site Biochemistry 34, 16279-16287
5. Fierke, C. A., Johnson, K. A., and Benkovic, S. J. (1987) Construction and evaluation of the kinetic scheme associated with dihydrofolate reductase from Escherichia coli Biochemistry 26, 4085-4092
6. 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
7. O'Neil, R. H., Lilien, R. H., Donald, B. R., Stroud, R. M., and Anderson, A. C. (2003) Phylogenetic classification of protozoa based on the structure of the linker domain in the bifunctional enzyme, dihydrofolate reductase- thymidylate synthase J. Biol. Chem. 278, 52980-52987
8. Senkovich, O., Schormann, N., and Chattopadhyay, D. (2009) Structures of dihydrofolate reductase-thymidylate synthase of Trypanosoma cruzi in the folate-free state and in complex with two antifolate drugs, trimetrexate and methotrexate Acta Crystallogr., Sect. D: Biol. Crystallogr. 65, 704-716
9. Begley, D. W., Edwards, T. E., Raymond, A. C., Smith, E. R., Hartley, R. C., Abendroth, J., Sankaran, B., Lorimer, D. D., Myler, P. J., Staker, B. L., and Stewart, L. J. (2011) Inhibitor-bound complexes of dihydrofolate reductase-thymidylate synthase from Babesia bovis Acta Crystallogr., Sect. F: Struct. Biol. Cryst. Commun. 67, 1070-1077
10. Yuvaniyama, J., Chitnumsub, P., Kamchonwongpaisan, S., Vanichtanankul, J., Sirawaraporn, W., Taylor, P., Walkinshaw, M. D., and Yuthavong, Y. (2003) Insights into antifolate resistance from malarial DHFR-TS structures Nat. Struct. Biol. 10, 357-365
11. Anderson, K. S. (1999) Fundamental mechanisms of substrate channeling Methods Enzymol. 308, 111-145
12. Meek, T. D., Garvey, E. P., and Santi, D. V. (1985) Purification and characterization of the bifunctional thymidylate synthetase-dihydrofolate reductase from methotrexate-resistant Leishmania tropica Biochemistry 24, 678-686
13. Trujillo, M., Duncan, R., and Santi, D. V. (1997) Construction of a homodimeric dihydrofolate reductase-thymidylate synthase bifunctional enzyme Protein Eng. 10, 567-573
14. Roos, D. S. (1993) Primary structure of the dihydrofolate reductase-thymidylate synthase gene from Toxoplasma gondii J. Biol. Chem. 268, 6269-6280
15. Brophy, V. H., Vasquez, J., Nelson, R. G., Forney, J. R., Rosowsky, A., and Sibley, C. H. (2000) Identification of Cryptosporidium parvum dihydrofolate reductase inhibitors by complementation in Saccharomyces cerevisiae Antimicrob. Agents Chemother. 44, 1019-1028
16. O'Neil, R. H., Lilien, R. H., Donald, B. R., Stroud, R. M., and Anderson, A. C. (2003) The crystal structure of dihydrofolate reductase-thymidylate synthase from Cryptosporidium hominis reveals a novel architecture for the bifunctional enzyme J Eukaryot Microbiol 50 Suppl, 555-556
17. Blakley, R. L. (1960) Crystalline Dihydropteroylglutamic Acid Nature 188, 231-232
18. Martucci, W. E., Udier-Blagovic, M., Atreya, C., Babatunde, O., Vargo, M. A., Jorgensen, W. L., and Anderson, K. S. (2009) Novel non-active site inhibitor of Cryptosporidium hominis TS-DHFR identified by a virtual screen Bioorg. Med. Chem. Lett. 19, 418-423
19. Grumont, R., Sirawaraporn, W., and Santi, D. V. (1988) Heterologous expression of the bifunctional thymidylate synthase-dihydrofolate reductase from Leishmania major Biochemistry 27, 3776-3784
20. Matthews, D. A., Alden, R. A., Bolin, J. T., Freer, S. T., Hamlin, R., Xuong, N., Kraut, J., Poe, M., Williams, M., and Hoogsteen, K. (1977) Dihydrofolate reductase: x-ray structure of the binary complex with methotrexate Science 197, 452-455
21. Atreya, C. E. and Anderson, K. S. (2004) Kinetic characterization of bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) from Cryptosporidium hominis: a paradigm shift for ts activity and channeling behavior J. Biol. Chem. 279, 18314-18322
22. Otwinowski, Z. and Minor, W. (1997) Processing of X-ray Diffraction Data Collected in Oscillation Mode Methods Enzymol Macromol Crystallogr 276, 307-326
23. (1994) The CCP4 suite: Programs for protein crystallography, Acta Crystallogr., Sect. D: Biol. Crystallogr. 50, 760-763.
24. Strong, M., Sawaya, M. R., Wang, S., Phillips, M., Cascio, D., and Eisenberg, D. (2006) Toward the structural genomics of complexes: crystal structure of a PE/PPE protein complex from Mycobacterium tuberculosis Proc. Natl. Acad. Sci. U. S. A. 103, 8060-8065
25. Storoni, L. C., McCoy, A. J., and Read, R. J. (2004) Likelihood-enhanced fast rotation functions Acta Crystallogr., Sect. D: Biol. Crystallogr. 60, 432-438
26. Cody, V. and Pace, J. (2011) Structural analysis of Pneumocystis carinii and human DHFR complexes with NADPH and a series of five potent 6-[5′-(omega-carboxyalkoxy)benzyl]pyrido[2,3-d]pyrimidine derivatives Acta Crystallogr., Sect. D: Biol. Crystallogr. 67, 1-7
27. Emsley, P. and Cowtan, K. (2004) Coot: model-building tools for molecular graphics Acta Crystallogr., Sect. D: Biol. Crystallogr. 60, 2126-2132
28. DeLano, W. L. (2002) The PyMol Molecular Graphics System (DeLano Scientific, Palo Alto, CA).
29. 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
30. Doan, L. T., Martucci, W. E., Vargo, M. A., Atreya, C. E., and Anderson, K. S. (2007) Nonconserved residues Ala287 and Ser290 of the Cryptosporidium hominis thymidylate synthase domain facilitate its rapid rate of catalysis Biochemistry 46, 8379-8391
31. Johnson, E. F., Hinz, W., Atreya, C. E., Maley, F., and Anderson, K. S. (2002) Mechanistic characterization of Toxoplasma gondii thymidylate synthase (TS-DHFR)-dihydrofolate reductase. Evidence for a TS intermediate and TS half-sites reactivity J. Biol. Chem. 277, 43126-43136
32. Liang, P. H. and Anderson, K. S. (1998) Substrate channeling and domain-domain interactions in bifunctional thymidylate synthase-dihydrofolate reductase Biochemistry 37, 12195-12205
33. Trujillo, M., Donald, R. G., Roos, D. S., Greene, P. J., and Santi, D. V. (1996) Heterologous expression and characterization of the bifunctional dihydrofolate reductase-thymidylate synthase enzyme of Toxoplasma gondii Biochemistry 35, 6366-6374
34. Dasgupta, T. Kinetic Characterization of the Malarial Drug Target, Thymidylate Synthase-Dihydrofolate Reductase: Implications for Novel Antifolate Design. 2008, Dissertation, 40-48, Yale University School of Medicine, New Haven, CT.
35. Martucci, W. E., Vargo, M. A., and Anderson, K. S. (2008) Explaining an unusually fast parasitic enzyme: folate tail-binding residues dictate substrate positioning and catalysis in Cryptosporidium hominis thymidylate synthase Biochemistry 47, 8902-8911
36. Atreya, C. E., Johnson, E. F., Williamson, J., Chang, S. Y., Liang, P. H., and Anderson, K. S. (2003) Probing electrostatic channeling in protozoal bifunctional thymidylate synthase-dihydrofolate reductase using site-directed mutagenesis J. Biol. Chem. 278, 28901-28911
37. Dasgupta, T. and Anderson, K. S. (2008) Probing the role of parasite-specific, distant structural regions on communication and catalysis in the bifunctional thymidylate synthase-dihydrofolate reductase from Plasmodium falciparum Biochemistry 47, 1336-1345
38. Elcock, A. H., Potter, M. J., Matthews, D. A., Knighton, D. R., and McCammon, J. A. (1996) Electrostatic channeling in the bifunctional enzyme dihydrofolate reductase-thymidylate synthase J. Mol. Biol. 262, 370-374
39. Franca, T. C., Medeiros, A. L., dos Santos, E. C., Santos-Filho, O. A., and Figueroa-Villar, J. D. (2004) A complete model of the Plasmodium falciparum bifunctional enzyme dihydrofolate reductase-thymidylate synthase. A model to design new antimalarials J Braz. Chem. Soc. 15, 450-454
40. Sussman, J. L., Harel, M., Frolow, F., Oefner, C., Goldman, A., Toker, L., and Silman, I. (1991) Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein Science 253, 872-879
41. Tan, R. C., Truong, T. N., McCammon, J. A., and Sussman, J. L. (1993) Acetylcholinesterase: electrostatic steering increases the rate of ligand binding Biochemistry 32, 401-403
42. Hyde, J. E. (2008) Fine targeting of purine salvage in Cryptosporidium parasites Trends Parasitol. 24, 336-339
43. Hyde, J. E., Dittrich, S., Wang, P., Sims, P. F., de Crecy-Lagard, V., and Hanson, A. D. (2008) Plasmodium falciparum: a paradigm for alternative folate biosynthesis in diverse microorganisms? Trends Parasitol. 24, 502-508
44. Pelphrey, P. M., Popov, V. M., Joska, T. M., Beierlein, J. M., Bolstad, E. S., Fillingham, Y. A., Wright, D. L., and Anderson, A. C. (2007) Highly efficient ligands for dihydrofolate reductase from Cryptosporidium hominis and Toxoplasma gondii inspired by structural analysis J. Med. Chem. 50, 940-950
45. Gangjee, A., Li, W., Kisliuk, R. L., Cody, V., Pace, J., Piraino, J., and Makin, J. (2009) Design, synthesis, and X-ray crystal structure of classical and nonclassical 2-amino-4-oxo-5-substituted-6-ethylthieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors and as potential antitumor agents J. Med. Chem. 52, 4892-4902
46. Gangjee, A., Jain, H. D., Queener, S. F., and Kisliuk, R. L. (2008) The effect of 5-alkyl modification on the biological activity of pyrrolo[2,3-d]pyrimidine containing classical and nonclassical antifolates as inhibitors of dihydrofolate reductase and as antitumor and/or antiopportunistic infection agents J. Med. Chem. 51, 4589-4600
47. Gangjee, A., Li, W., Yang, J., and Kisliuk, R. L. (2008) Design, synthesis, and biological evaluation of classical and nonclassical 2-amino-4-oxo-5-substituted-6-methylpyrrolo[3,2-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors J. Med. Chem. 51, 68-76
48. Sharma, H., Yang, J., Zaware, N., Devambatla, R. K. V., Queener, S. F., Anderson, K. S., and Gangjee, A. Discovery of potent and selective inhibitors of Toxoplasma gondii thymidylate synthase-dihydrofolate reductase as a novel class of TS inhibitors for opportunistic infections. ACS Med. Chem. Lett. 2013, In press
49. Atreya, C. E., Johnson, E. F., Irwin, J. J., Dow, A., Massimine, K. M., Coppens, I., Stempliuk, V., Beverley, S., Joiner, K. A., Shoichet, B. K., and Anderson, K. S. (2003) A molecular docking strategy identifies Eosin B as a non-active site inhibitor of protozoal bifunctional thymidylate synthase-dihydrofolate reductase J. Biol. Chem. 278, 14092-14100
50. Landau, M. J., Sharma, H., and Anderson, K. S. (2013) Selective peptide inhibitors of bifunctional thymidylate synthase-dihydrofolate reductase from Toxoplasma gondii provide insights into domain-domain communication and allosteric regulation Protein Sci. 22, 1161-1173
51. Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., and Ferrin, T. E. (2004) UCSF Chimera - a visualization system for exploratory research and analysis J. Comput. Chem. 25, 1605-1612