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DHFR  -  dihydrofolate reductase

Gallus gallus

 
 
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Disease relevance of DHFR

 

High impact information on DHFR

 

Chemical compound and disease context of DHFR

  • 2,4-Diamino-5-[[1,2-dihydro-2,4-dimethyl-3-fluoro-2-(fluoromethyl)-8- methoxy-6(1H)quinolyl]methyl]pyrimidine had an apparent Ki value for E. coli DHFR 13 times lower than that of the control, trimethoprim (1), and was 1 order of magnitude more selective for the bacterial enzyme [6].
  • As with the mammalian isozymes, N. gonorrhoeae DHFR contains an active site phenylalanine replacing Leu-28 of E. coli DHFR, thus creating a more hydrophobic pocket [1].
  • Although the 3,4-dimethoxy analogue 19 was 10-fold less inhibitory to E. coli DHFR than 1, it was 3-4 times more potent on the vertebrate isozymes, whereas the diethyl congener 10 followed 19 in its E. coli DHFR binding but was less active on rat and chicken DHFR [7].
  • The positive electrostatic potential at the entrance of the ligand binding site in E. coli DHFR is shown to be a direct consequence of the presence of three positively charged residues at positions 32, 52, and 57--residues which have also been shown recently to contribute significantly to electronic polarization of the ligand folate [8].
  • The binding of Cibacron blue F3GA to dihydrofolate reductase (EC 1.5.1.3) from chicken liver an amethopterin-resistant Lactobacillus casei has been studied by difference spectroscopy [9].
 

Biological context of DHFR

  • The above results indicate that the activation of DHFR in dilute denaturants is accompanied by a loosening up of its compact structure especially at or near the active site, suggesting that the flexibility at its active site is essential for the full expression of its catalytic activity [10].
  • Enzyme kinetics of 7, 8a and 8b with chicken DHFR confirmed our predictions that they are substrates, with apparent K(m) values of 3.8, 0.08, and 0.65 mM, and apparent V(max) values of 0.47, 2.27, and 0.30 nmol L(-1) min(-1) (for enzyme concentration 0.122 micro M), respectively [11].
  • Energy transfer phenomenon suggests that the specific interaction of Eu3+ with Trp24 located in a loop at the active site of DHFR is responsible for the strong inhibition [12].
  • Furthermore, the results suggest that for the dhfr gene and possibly for other genes in mice as well, the potential termination consensus sequence can exist as part of a long interspersed repetitive DNA element [13].
  • Computer-aided drug design: a free energy perturbation study on the binding of methyl-substituted pterins and N5-deazapterins to dihydrofolate reductase [14].
 

Anatomical context of DHFR

 

Associations of DHFR with chemical compounds

  • The sequences obtained are unique when compared with the known sequence of DHFR and thus allow the points of proteolytic cleavage identified for the urea- and GuHCl-activated enzyme to be at or near the active site [10].
  • The space group and unit cell are isomorphous with the previously reported structure of chicken liver DHFR complexed with NADPH and phenyltriazine [Volz, K. W., Matthews, D. A., Alden, R. A., Freer, S. T., Hansch, C., Kaufman, B. T., & Kraut, J. (1982) J. Biol. Chem. 257, 2528-2536] [17].
  • Crystal structure of chicken liver dihydrofolate reductase complexed with NADP+ and biopterin [17].
  • Activation of chicken liver dihydrofolate reductase by urea and guanidine hydrochloride is accompanied by conformational change at the active site [10].
  • The 2.2-A crystal structure of chicken liver dihydrofolate reductase (EC 1.5.1.3, DHFR) has been solved as a ternary complex with NADP+ and biopterin (a poor substrate) [17].
 

Other interactions of DHFR

  • Ligand-induced conformational changes of GroEL alone and with bound rhodanese, citrate synthase, or dihydrofolate reductase were studied by limited proteolysis [18].
  • A number of rare conformers are detected under pressure for a variety of proteins such as the Ras-binding domain of RalGDS, beta-lactoglobulin, dihydrofolate reductase, ubiquitin, apomyoglobin, p13(MTCP1), and prion, which disclose a rich world of protein structure between basically folded and globally unfolded states [19].
 

Analytical, diagnostic and therapeutic context of DHFR

References

  1. 2,4-Diamino-5-benzylpyrimidines as antibacterial agents. 7. Analysis of the effect of 3,5-dialkyl substituent size and shape on binding to four different dihydrofolate reductase enzymes. Roth, B., Rauckman, B.S., Ferone, R., Baccanari, D.P., Champness, J.N., Hyde, R.M. J. Med. Chem. (1987) [Pubmed]
  2. On the structure selectivity problem in drug design. A comparative study of benzylpyrimidine inhibition of vertebrate and bacterial dihydrofolate reductase via molecular graphics and quantitative structure-activity relationships. Selassie, C.D., Fang, Z.X., Li, R.L., Hansch, C., Debnath, G., Klein, T.E., Langridge, R., Kaufman, B.T. J. Med. Chem. (1989) [Pubmed]
  3. Refined crystal structures of Escherichia coli and chicken liver dihydrofolate reductase containing bound trimethoprim. Matthews, D.A., Bolin, J.T., Burridge, J.M., Filman, D.J., Volz, K.W., Kaufman, B.T., Beddell, C.R., Champness, J.N., Stammers, D.K., Kraut, J. J. Biol. Chem. (1985) [Pubmed]
  4. Interaction of methotrexate, folates, and pyridine nucleotides with dihydrofolate reductase: calorimetric and spectroscopic binding studies. Subramanian, S., Kaufman, B.T. Proc. Natl. Acad. Sci. U.S.A. (1978) [Pubmed]
  5. Interaction of polyglutamyl derivatives of methotrexate, 10-deazaaminopterin, and dihydrofolate with dihydrofolate reductase. Kumar, P., Kisliuk, R.L., Gaumont, Y., Nair, M.G., Baugh, C.M., Kaufman, B.T. Cancer Res. (1986) [Pubmed]
  6. 2,4-Diamino-5-benzylpyrimidines and analogues as antibacterial agents. 12. 1,2-Dihydroquinolylmethyl analogues with high activity and specificity for bacterial dihydrofolate reductase. Johnson, J.V., Rauchman, B.S., Baccanari, D.P., Roth, B. J. Med. Chem. (1989) [Pubmed]
  7. 2,4-Diamino-5-benzylpyrimidines as antibacterial agents. 8. The 3,4,5-triethyl isostere of trimethoprim. A study of specificity. Roth, B., Aig, E. J. Med. Chem. (1987) [Pubmed]
  8. The electrostatic potential of Escherichia coli dihydrofolate reductase. Bajorath, J., Kitson, D.H., Kraut, J., Hagler, A.T. Proteins (1991) [Pubmed]
  9. Dihydrofolate reductases from chicken liver and Lactobacillus casei bind Cibacron blue F3GA in different modes and at different sites. Subramanian, S., Kaufman, B.T. J. Biol. Chem. (1980) [Pubmed]
  10. Activation of chicken liver dihydrofolate reductase by urea and guanidine hydrochloride is accompanied by conformational change at the active site. Fan, Y.X., Ju, M., Zhou, J.M., Tsou, C.L. Biochem. J. (1996) [Pubmed]
  11. Synthesis of quaternised 2-aminopyrimido[4,5-d]pyrimidin-4(3H)-ones and their biological activity with dihydrofolate reductase. Gebauer, M.G., McKinlay, C., Gready, J.E. European journal of medicinal chemistry. (2003) [Pubmed]
  12. Lanthanide ions inhibit the activity of dihydrofolate reductase from chicken liver. Wu, Y. Biometals (2000) [Pubmed]
  13. Structural features of the murine dihydrofolate reductase transcription termination region: identification of a conserved DNA sequence element. Frayne, E.G., Kellems, R.E. Nucleic Acids Res. (1986) [Pubmed]
  14. Computer-aided drug design: a free energy perturbation study on the binding of methyl-substituted pterins and N5-deazapterins to dihydrofolate reductase. Cummins, P.L., Gready, J.E. J. Comput. Aided Mol. Des. (1993) [Pubmed]
  15. Relation between some folate-dependent metabolic pathways and dietary folate content in chicks. Whitehead, C.C., Rennie, J.S. Br. J. Nutr. (1989) [Pubmed]
  16. Dihydrofolate reductase from Eimeria tenella: rationalization of chemotherapeutic efficacy of pyrimethamine. Wang, C.C., Stotish, R.L., Poe, M. J. Protozool. (1975) [Pubmed]
  17. Crystal structure of chicken liver dihydrofolate reductase complexed with NADP+ and biopterin. McTigue, M.A., Davies, J.F., Kaufman, B.T., Kraut, J. Biochemistry (1992) [Pubmed]
  18. Ligand-induced conformational changes of GroEL are dependent on the bound substrate polypeptide. Mendoza, J.A., Campo, G.D. J. Biol. Chem. (1996) [Pubmed]
  19. Highly fluctuating protein structures revealed by variable-pressure nuclear magnetic resonance. Akasaka, K. Biochemistry (2003) [Pubmed]
  20. Determination of the conformation of trimethoprim in the binding pocket of bovine dihydrofolate reductase from a STD-NMR intensity-restrained CORCEMA-ST optimization. Jayalakshmi, V., Krishna, N.R. J. Am. Chem. Soc. (2005) [Pubmed]
  21. Circular dichroism studies in the near UV of ligand binding to chicken liver dihydrofolate reductase. Seng, G., Bolard, J. Biochimie (1983) [Pubmed]
  22. Screening for inhibitors of dihydrofolate reductase using pulsed ultrafiltration mass spectrometry. Nikolic, D., van Breemen, R.B. Comb. Chem. High Throughput Screen. (1998) [Pubmed]
  23. Characterization of chicken liver dihydrofolate reductase after purification by affinity chromatography and isoelectric focusing. Kaufman, B.T., Kemerer, V.F. Arch. Biochem. Biophys. (1977) [Pubmed]
 
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