BMRB

Biological Magnetic Resonance Data Bank


A Repository for Data from NMR Spectroscopy on Proteins, Peptides, Nucleic Acids, and other Biomolecules 		Member of WWPDB

Selected DHFR Bibliography
Introduction Catalytic Action Sequence Details BMRB and PDB entries Bibliography

Early Studies

  1. Futterman, S. (1957) Enzymatic reduction of folic acid and dihydrofolic acid to tetrahydrofolic acid. J. Biol. Chem. 228: 1031-8.
  2. Osborn, MJ, Huennekens, FM (1958) Enzymatic reduction of dihydroflic acid. J. Biol. Chem. 233: 969-74.
  3. Zakrzewski, SF, Nichol, CA (1958) On the enzyme reduction of folic acid by a purified hydrogenase. Biochim. Biophys. Acta. 27: 425-6.

NMR Publications

  1. Abali EE, Skacel NE, Celikkaya H, Hsieh YC. (2008) Chapter 9 regulation of human dihydrofolate reductase activity and expression. Vitam. Horm. 79: 267-92.
  2. Adane L, Bharatam PV. (2008) Modelling and informatics in the analysis of P. falciparum DHFR enzyme inhibitors. Curr. Med. Chem. 15(16): 1552-69
  3. Assaraf YG. (2007) Molecular basis of antifolate resistance. Cancer Metastasis Rev. 26(1): 153-81.
  4. Bevan AW, Roberts GC, Feeney J, Kuyper L. (1985) 1H and 15N NMR studies of protonation and hydrogen-bonding in the binding of trimethoprim to dihydrofolate reductase. Eur. Biophys. J. 11(4): 211-8
  5. Birdsall B, Andrews J, Ostler G, Tendler SJ, Feeney J, Roberts GC, Davies RW, Cheung HT. (1989) NMR studies of differences in the conformations and dynamics of ligand complexes formed with mutant dihydrofolate reductases. Biochemistry 28(3): 1353-62.
  6. Birdsall B, Arnold JR, Jimenez-Barbero J, Frenkiel TA, Bauer CJ, Tendler SJ, Carr MD, Thomas JA, Roberts GC, Feeney J. (1990) The 1H-NMR assignments of the aromatic resonances in complexes of Lactobacillus casei dihydrofolate reductase and the origins of their chemical shifts. Eur. J. Biochem. 191(3): 659-68.
  7. Birdsall B, Bevan AW, Pascual C, Roberts GC, Feeney J, Gronenborn A, Clore GM. (1984) Multinuclear NMR characterization of two coexisting conformational states of the Lactobacillus casei dihydrofolate reductase-trimethoprim-NADP+ complex. Biochemistry 23(20): 4733-42.
  8. Birdsall B, De Graw J, Feeney J, Hammond S, Searle MS, Roberts GC, Colwell WT, Crase J. (1987) 15N and 1H NMR evidence for multiple conformations of the complex of dihydrofolate reductase with its substrate, folate. FEBS Lett. 217(1): 106-10.
  9. Birdsall B, Feeney J, Griffiths DV, Hammond S, Kimber B, King RW, Roberts GC, Searle M. (1984) The combined use of selective deuteration and double resonance experiments in assigning the 1H resonances of valine and tyrosine residues of dihydrofolate reductase. FEBS Lett. 175(2): 364-8.
  10. Birdsall B, Feeney J, Pascual C, Roberts GC, Kompis I, Then RL, Muller K, Kroehn A. (1984) A 1H NMR study of the interactions and conformations of rationally designed brodimoprim analogues in complexes with Lactobacillus casei dihydrofolate reductase. J. Med. Chem. 27(12): 1672-6.
  11. Birdsall B, Gronenborn A, Clore GM, Roberts GC, Feeney J, Burgen AS. (1981) 13C NMR evidence for three slowly interconverting conformations of the dihydrofolate reductase-NADP+-folate complex. Biochem. Biophys. Res. Commun. 101(4): 1139-44.
  12. Birdsall B, Polshakov VI, Feeney J. (2000) NMR studies of ligand carboxylate group interactions with arginine residues in complexes of Lactobacillus casei dihydrofolate reductase with substrates and substrate analogues. Biochemistry 39(32): 9819-25.
  13. Birdsall B, Roberts GC, Feeney J, Burgen AS. (1977) 31P NMR studies of the binding of adenosine-2'-phosphate to Lactobacillus casei dihydrofolate reductase. FEBS Lett. 80(2): 313-6.
  14. Birdsall B, Tendler SJ, Arnold JR, Feeney J, Griffin RJ, Carr MD, Thomas JA, Roberts GC, Stevens MF. (1990) NMR studies of multiple conformations in complexes of Lactobacillus casei dihydrofolate reductase with analogues of pyrimethamine. Biochemistry 29(41): 9660-7.
  15. Boehr DD, Dyson HJ, Wright PE. (2008) Conformational relaxation following hydride transfer plays a limiting role in dihydrofolate reductase catalysis. Biochemistry 47(35): 9227-33.
  16. Bolstad ES, Anderson AC. (2008) In pursuit of virtual lead optimization: The role of the receptor structure and ensembles in accurate docking. Proteins 73(3): 566-580.
  17. Boroujerdi, Arezue F. B., Young, John K. (2007) NMR assignments of the binary hvDHFR1:folate complex Protein Sci. 16(8): 1783-7.
  18. Burgen AS, Dann J, Feeney J, Roberts GC, Yuferov V. (1974) Proceedings: NMR studies of the binding of substrate analogues to L. casei dihydrofolate reductase. Br. J. Pharmacol. 51(1): 126P-127P.
  19. Carr MD, Birdsall B, Frenkiel TA, Bauer CJ, Jimenez-Barbero J, Polshakov VI, McCormick JE, Roberts GC, Feeney J. (1991) Dihydrofolate reductase: sequential resonance assignments using 2D and 3D NMR and secondary structure determination in solution. Biochemistry 30(25): 6330-41.
  20. Chen J, Dima RI, Thirumalai D. (2007) Allosteric communication in dihydrofolate reductase: signaling network and pathways for closed to occluded transition and back. J Mol Biol. 374(1): 250-66.
  21. Cheung HT, Birdsall B, Feeney J. (1992) 13C NMR studies of complexes of Escherichia coli dihydrofolate reductase formed with methotrexate and with folic acid. FEBS Lett. 312(2-3): 147-51.
  22. Cheung HT, Birdsall B, Frenkiel TA, Chau DD, Feeney J. (1993) 13C NMR determination of the tautomeric and ionization states of folate in its complexes with Lactobacillus casei dihydrofolate reductase. Biochemistry 2(27): 6846-54.
  23. Cheung HT, Searle MS, Feeney J, Birdsall B, Roberts GC, Kompis I, Hammond SJ. (1986) Trimethoprim binding to Lactobacillus casei dihydrofolate reductase: a 13C NMR study using selectively 13C-enriched trimethoprim. Biochemistry 25(8): 1925-31.
  24. Chopra S, Lynch R, Kim SH, Jackson M, Howell EE. (2006) Effects of temperature and viscosity on R67 dihydrofolate reductase catalysis. Biochemistry 45(21): 6596-605.
  25. Eriksen J, Mwankusye S, Mduma S, Veiga MI, Kitua A, Tomson G, Petzold MG, Swedberg G, Gustafsson LL, Warsame M. (2008) Antimalarial resistance and DHFR/DHPS genotypes of Plasmodium falciparum three years after introduction of sulfadoxine-pyrimethamine and amodiaquine in rural Tanzania. Trans. R. Soc. Trop. Med. Hyg. 102(2): 137-42.
  26. Falzone CJ, Benkovic SJ, Wright PE. (1990) Partial 1H NMR assignments of the Escherichia coli dihydrofolate reductase complex with folate: evidence for a unique conformation of bound folate. Biochemistry 29(41): 9667-77.
  27. Feeney J. (2000) NMR Studies of Ligand Binding to Dihydrofolate Reductase. Angew. Chem. Int. Ed. Engl. 39(2): 290-312.
  28. Feeney J. (1990) NMR studies of interactions of ligands with dihydrofolate reductase. Biochem. Pharmacol. 40(1):141-52.
  29. Feeney J, Birdsall B, Roberts GC, Burgen AS. (1975) 31P NMR studies of NADPH and NADP+ binding to L. casei dihydrofolate reductase. Nature 257(5527): 564-6.
  30. Gargaro AR, Frenkiel TA, Nieto PM, Birdsall B, Polshakov VI, Morgan WD, Feeney J. (1996) NMR detection of arginine-ligand interactions in complexes of Lactobacillus casei dihydrofolate reductase. Eur. J. Biochem. 238(2): 435-9.
  31. Gargaro AR, Soteriou A, Frenkiel TA, Bauer CJ, Birdsall B, Polshakov VI, Barsukov IL, Roberts GC, Feeney J. (1998) The solution structure of the complex of Lactobacillus casei dihydrofolate reductase with methotrexate. J. Mol. Biol. 277(1): 119-34.
  32. Gerothanassis IP, Barrie PJ, Birdsall B, Feeney J. (1994) 31P-NMR studies of NADPH, NADP+ and the complex of NADPH and methotrexate with Lactobacillus casei dihydrofolate reductase in the solid state. Eur. J. Biochem. 226(1): 211-8.
  33. Gerothanassis IP, Barrie PJ, Birdsall B, Feeney J. (1996) 31P solid-state NMR measurements used to detect interactions between NADPH and water and to determine the ionisation state of NADPH in a protein-ligand complex subjected to low-level hydration. Eur. J. Biochem. 235(1-2): 262-6.
  34. Gerothanassis IP, Birdsall B, Bauer CJ, Feeney J. (1992) 31P-NMR assignment and conformational study of NADPH bound to Lactobacillus casei dihydrofolate reductase based on two-dimensional 1H-31P-heteronuclear and 1H-detected 1H-31P-shift-correlation experiments. Eur. J. Biochem. 204(1): 173-7.
  35. Gerothanassis IP, Birdsall B, Bauer CJ, Frenkiel TA, Feeney J. (1992) Nuclear magnetic resonance detection of bound water molecules in the active site of Lactobacillus casei dihydrofolate reductase in aqueous solution. J. Mol. Biol. 226(2): 549-54.
  36. Gerothanassis IP, Birdsall B, Feeney J. (1991) Hydrogen bonding effects on 31P NMR shielding in the pyrophosphate group of NADPH bound to L. casei dihydrofolate reductase. FEBS Lett. 291(1): 21-3.
  37. Hammond SJ, Birdsall B, Feeney J, Searle MS, Roberts GC, Cheung HT. (1987) Structural comparisons of complexes of methotrexate analogues with Lactobacillus casei dihydrofolate reductase by two-dimensional 1H NMR at 500 MHz. Biochemistry 26(26): 8585-90.
  38. Hammond SJ, Birdsall B, Searle MS, Roberts GC, Feeney J. (1986) Dihydrofolate reductase. 1H resonance assignments and coenzyme-induced conformational changes. J. Mol. Biol. 188(1): 81-97.
  39. Hata K, Kono R, Fujisawa M, Kitahara R, Kamatari YO, Akasaka K, Xu Y. (2004) High pressure nmr study of dihydrofolate reductase from a deep-sea bacterium Moritella profunda. Cell. Mol. Biol. 50(4): 311-6.
  40. Hoeltzli SD, Frieden C. (1995) Free in PMC Stopped-flow NMR spectroscopy: real-time unfolding studies of 6-19F-tryptophan-labeled Escherichia coli dihydrofolate reductase. Proc. Natl. Acad. Sci. U. S. A. 92(20): 9318-22.
  41. Hoeltzli SD, Frieden C. (1996) Real-time refolding studies of 6-19F-tryptophan labeled Escherichia coli dihydrofolate reductase using stopped-flow NMR spectroscopy. Biochemistry 35(51): 16843-51.
  42. Hoeltzli SD, Frieden C. (1998) Refolding of [6-19F]tryptophan-labeled Escherichia coli dihydrofolate reductase in the presence of ligand: a stopped-flow NMR spectroscopy study. Biochemistry 37(1): 387-98.
  43. Hoeltzli SD, Frieden C. (1994) 19F NMR spectroscopy of [6-19F]tryptophan-labeled Escherichia coli dihydrofolate reductase: equilibrium folding and ligand binding studies. Biochemistry 33(18): 5502-9.
  44. Horst R, Fenton WA, Englander SW, Wüthrich K, Horwich AL. (2007) Folding trajectories of human dihydrofolate reductase inside the GroEL GroES chaperonin cavity and free in solution. Proc. Natl. Acad. Sci. U.S.A. 104(52): 20788-92.
  45. Huang FY, Yang QX, Huang TH. (1991) 15N NMR studies of the conformation of E. coli dihydrofolate reductase in complex with folate or methotrexate. FEBS Lett. 289(2): 231-4.
  46. Huang FY, Yang QX, Huang TH, Gelbaum L, Kuyper LF. (1991) The conformations of trimethoprim/E. coli dihydrofolate reductase complexes. A 15N and 31P NMR study. FEBS Lett. 283(1): 44-6.
  47. Jayalakshmi V, Krishna NR. (2005) Determination of the conformation of trimethoprim in the binding pocket of bovine dihydrofolate reductase from a STD-NMR intensity-restrained CORCEMA-ST optimization. J. Am. Chem. Soc. 127(40): 14080-4.
  48. Johnson JM, Meiering EM, Wright JE, Pardo J, Rosowsky A, Wagner G. (1997) NMR solution structure of the antitumor compound PT523 and NADPH in the ternary complex with human dihydrofolate reductase. Biochemistry 36(15): 4399-411.
  49. Jones BE, Matthews CR. (1995) Early intermediates in the folding of dihydrofolate reductase from Escherichia coli detected by hydrogen exchange and NMR. Protein Sci. 4(2): 167-77.
  50. Kimber BJ, Feeney J, Roberts GC, Birdsall B, Griffiths DV, Burgen AS, Sykes BD. (1978) Proximity of two tryptophan residues in dihydrofolate reductase determined by 19f NMR. Nature. 271(5641): 184-5.
  51. Kitahara R, Sareth S, Yamada H, Ohmae E, Gekko K, Akasaka K. (2000) High pressure NMR reveals active-site hinge motion of folate-bound Escherichia coli dihydrofolate reductase. Biochemistry 39(42):12789-95.
  52. Kovalevskaya NV, Smurnyy YD, Polshakov VI, Birdsall B, Bradbury AF, Frenkiel T, Feeney J. (2005) Solution structure of human dihydrofolate reductase in its complex with trimethoprim and NADPH. J. BioMol. NMR. 33(1):69-72.
  53. London RE, Groff JP, Blakley RL. (1979) 13C NMR evidence of the slow exchange of tryptophans in dihydrofolate reductase between stable conformations. Biochem. Biophys. Res. Commun. 86(3):779-86.
  54. London RE, Wageman WE, Blakley RL. (1983) 13C-NMR studies of selectively carboxymethylated [methyl-13C]methionine-labeled bacterial dihydrofolate reductase. FEBS Lett. 160(1-2): 56-60.
  55. Martorell G, Gradwell MJ, Birdsall B, Bauer CJ, Frenkiel TA, Cheung HT, Polshakov VI, Kuyper L, Feeney J. (1994) Solution structure of bound trimethoprim in its complex with Lactobacillus casei dihydrofolate reductase. Biochemistry 33(41): 12416-26.
  56. Mbugi EV, Mutayoba BM, Malisa AL, Balthazary ST, Nyambo TB, Mshinda H. (2006) Drug resistance to sulphadoxine-pyrimethamine in Plasmodium falciparum malaria in Mlimba, Tanzania. Malar. J. 5: 94.
  57. McCollum AM, Basco LK, Tahar R, Udhayakumar V, Escalante AA. (2008) Hitchhiking and selective sweeps of Plasmodium falciparum sulfadoxine and pyrimethamine resistant alleles in a population from central Africa. Antimicrob. Agents Chemother. 52(11):4089-97.
  58. Mockenhaupt FP, Bedu-Addo G, Eggelte TA, Hommerich L, Holmberg V, von Oertzen C, Bienzle U. (2008) Rapid Increase in the Prevalence of Sulfadoxine-Pyrimethamine Resistance among Plasmodium falciparum Isolated from Pregnant Women in Ghana. J. Infect. Dis. 198(10): 1545-1549.
  59. Morgan WD, Birdsall B, Nieto PM, Gargaro AR, Feeney J. (1999) 1H/15N HSQC NMR studies of ligand carboxylate group interactions with arginine residues in complexes of brodimoprim analogues and Lactobacillus casei dihydrofolate reductase. Biochemistry 38(7): 2127-34.
  60. Morgan WD, Birdsall B, Polshakov VI, Sali D, Kompis I, Feeney J. (1995) Solution structure of a brodimoprim analogue in its complex with Lactobacillus casei dihydrofolate reductase. Biochemistry 34(37): 11690-702.
  61. Ndounga M, Tahar R, Basco LK, Casimiro PN, Malonga DA, Ntoumi F. (2007) Therapeutic efficacy of sulfadoxine-pyrimethamine and the prevalence of molecular markers of resistance in under 5-year olds in Brazzaville, Congo. Trop. Med. Int. Health 12(10): 1164-71.
  62. Ochong E, Bell DJ, Johnson DJ, D'Alessandro U, Mulenga M, Muangnoicharoen S, Winstanley PA, Bray PG, Ward SA, Owen A. (2008) Plasmodium falciparum harbouring DHFR I164L are absent in Malawi and Zambia even under antifolate drug pressure. Antimicrob. Agents Chemother. 52(11): 3883-8.
  63. Osborne MJ, Venkitakrishnan RP, Dyson HJ, Wright PE. (2003) Diagnostic chemical shift markers for loop conformation and substrate and cofactor binding in dihydrofolate reductase complexes. Protein Sci. 12(10): 2230-8.
  64. Ostler G, Soteriou A, Moody CM, Khan JA, Birdsall B, Carr MD, Young DW, Feeney J. (1993) Stereospecific assignments of the leucine methyl resonances in the 1H NMR spectrum of Lactobacillus casei dihydrofolate reductase. FEBS Lett. 318(2): 177-80.
  65. Pitcher WH 3rd, DeRose EF, Mueller GA, Howell EE, London RE. (2003) NMR studies of the interaction of a type II dihydrofolate reductase with pyridine nucleotides reveal unexpected phosphatase and reductase activity. Biochemistry 42(38): 11150-60.
  66. Poe M, Greenfield NJ, Williams MN, Hoogsteen K. (1973) Proton NMR studies of E. coli MB 1428 dihydrofolate reductase. Ann. N. Y. Acad. Sci. 222:722-3.
  67. Polshakov VI, Birdsall B, Frenkiel TA, Gargaro AR, Feeney J. (1999) Structure and dynamics in solution of the complex of Lactobacillus casei dihydrofolate reductase with the new lipophilic antifolate drug trimetrexate. Protein Sci. 8(3): 467-81.
  68. Polshakov VI, Smirnov EG, Birdsall B, Kelly G, Feeney J. (2002) NMR-based solution structure of the complex of Lactobacillus casei dihydrofolate reductase with trimethoprim and NADPH. J. BioMol. NMR. 24(1): 67-70.
  69. Saito-Nakano Y, Tanabe K, Kamei K, Iwagami M, Komaki-Yasuda K, Kawazu S, Kano S, Ohmae H, Endo T. (2008) Genetic evidence for Plasmodium falciparum resistance to chloroquine and pyrimethamine in Indochina and the Western Pacific between 1984 and 1998. Am. J. Trop. Med. Hyg. 79(4): 613-9.
  70. Soteriou A, Carr MD, Frenkiel TA, McCormick JE, Bauer CJ, Sali D, Birdsall B, Feeney J. (1993) 3D 13C/1H NMR-based assignments for side-chain resonances of Lactobacillus casei dihydrofolate reductase. Evidence for similarities between the solution and crystal structures of the enzyme. J. BioMol. NMR. 3(5): 535-46.
  71. Stockman BJ, Nirmala NR, Wagner G, Delcamp TJ, DeYarman MT, Freisheim JH. (1991) Methotrexate binds in a non-productive orientation to human dihydrofolate reductase in solution, based on NMR spectroscopy. FEBS Lett. 283(2): 267-9.
  72. Stockman BJ, Nirmala NR, Wagner G, Delcamp TJ, DeYarman MT, Freisheim JH. (1992) Sequence-specific 1H and 15N resonance assignments for human dihydrofolate reductase in solution. Biochemistry 31(1): 218-29.
  73. Summerfield RL, Daigle DM, Mayer S, Mallik D, Hughes DW, Jackson SG, Sulek M, Organ MG, Brown ED, Junop MS. (2006) A 2.13 A structure of E. coli dihydrofolate reductase bound to a novel competitive inhibitor reveals a new binding surface involving the M20 loop region. J. Med. Chem. 49(24): 6977-86.
  74. Tendler SJ, Griffin RJ, Birdsall B, Stevens MF, Roberts GC, Feeney J. (1988) Direct 19F NMR observation of the conformational selection of optically active rotamers of the antifolate compound fluoronitropyrimethamine bound to the enzyme dihydrofolate reductase. FEBS Lett. 240(1-2): 201-4.
  75. Thomas JA, Arnold JR, Basran J, Andrews J, Roberts GC, Birdsall B, Feeney J. (1994) Effects of substitution of Thr63 by alanine on the structure and function of Lactobacillus casei dihydrofolate reductase. Protein. Eng. 7(6): 783-92.
  76. Venkitakrishnan RP, Zaborowski E, McElheny D, Benkovic SJ, Dyson HJ, Wright PE. (2004) Conformational changes in the active site loops of dihydrofolate reductase during the catalytic cycle. Biochemistry 43(51):16046-55.
  77. Volpato JP, Fossati E, Pelletier JN. (2007) Increasing methotrexate resistance by combination of active-site mutations in human dihydrofolate reductase. J. Mol. Biol. 373(3): 599-611.
  78. Yang QX, Huang FY, Huang TH, Gelbaum L. (1993) Free in PMC The effect of hydration on the dynamics of trimethoprim bound to dihydrofolate reductase. A deuterium NMR study. Biophys. J. 64(4): 1361-5.
  79. Yang QX, Huang FY, Lin TH, Gelbaum L, Howell EE, Huang TH. (1996) Dynamics of trimethoprim bound to dihydrofolate reductase--a deuterium NMR study. Solid State Nucl. Magn. Reson. 7(3): 193-201.