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Gene Review

folA  -  dihydrofolate reductase

Escherichia coli CFT073

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Disease relevance of folA


High impact information on folA


Chemical compound and disease context of folA


Biological context of folA


Anatomical context of folA

  • Transfected E. coli folA dhfr could complement the lack of endogenous DHFR in Chinese hamster ovary (CHO) cells lacking a functional dhfr gene [20].
  • Ricin A chain can transport unfolded dihydrofolate reductase into the cytosol [21].
  • Here we show that removal of as few as 4 amino-terminal residues from the subunit IV presequence (which had been attached to the cytosolic protein dihydrofolate reductase) blocks import of the protein into mitochondria and proteolytic removal of the presequence by the soluble matrix protease [22].
  • A 29 base pair fragment of its ribosome binding site containing the initiation triplet, the Shine-Dalgarno sequence (S-D), 10 nucleotides (nt) upstream and 6 nt downstream of these central elements was cloned into a vector to control the expression of the mouse dihydrofolate reductase gene (dhfr) [23].
  • Mouse fibroblast NIH3T3 cells infected with DC/SV6S31 GPT are more resistant to MTX than cells infected with DC/SV6S31, which carries the Serine 31 DHFR and the neomycin resistance gene cDNA [24].

Associations of folA with chemical compounds


Other interactions of folA


Analytical, diagnostic and therapeutic context of folA


  1. Peptide fragment studies on the folding elements of dihydrofolate reductase from Escherichia coli. Arai, M., Iwakura, M. Proteins (2006) [Pubmed]
  2. Identification and cloning of the Mycobacterium avium folA gene, required for dihydrofolate reductase activity. Zywno-van Ginkel, S., Dooley, T.P., Suling, W.J., Barrow, W.W. FEMS Microbiol. Lett. (1997) [Pubmed]
  3. Nucleotide sequence reveals overlap between T4 phage genes encoding dihydrofolate reductase and thymidylate synthase. Purohit, S., Mathews, C.K. J. Biol. Chem. (1984) [Pubmed]
  4. Hydride transfer reaction catalyzed by hyperthermophilic dihydrofolate reductase is dominated by quantum mechanical tunneling and is promoted by both inter- and intramonomeric correlated motions. Pang, J., Pu, J., Gao, J., Truhlar, D.G., Allemann, R.K. J. Am. Chem. Soc. (2006) [Pubmed]
  5. Bacteriophage T4 baseplate components. II. Binding and location of bacteriophage-induced dihydrofolate reductase. Kozloff, L.M., Crosby, L.K., Lute, M., Hall, D.H. J. Virol. (1975) [Pubmed]
  6. Antibacterial synergism: a proposal for chemotherapeutic potentiation between trimethoprim and sulfamethoxazole. Poe, M. Science (1976) [Pubmed]
  7. Exploring the functional robustness of an enzyme by in vitro evolution. Martinez, M.A., Pezo, V., Marlière, P., Wain-Hobson, S. EMBO J. (1996) [Pubmed]
  8. The downstream box: an efficient and independent translation initiation signal in Escherichia coli. Sprengart, M.L., Fuchs, E., Porter, A.G. EMBO J. (1996) [Pubmed]
  9. Neutron diffraction studies of Escherichia coli dihydrofolate reductase complexed with methotrexate. Bennett, B., Langan, P., Coates, L., Mustyakimov, M., Schoenborn, B., Howell, E.E., Dealwis, C. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  10. Stopped-flow NMR spectroscopy: real-time unfolding studies of 6-19F-tryptophan-labeled Escherichia coli dihydrofolate reductase. Hoeltzli, S.D., Frieden, C. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  11. Protein fragments as probes in the study of protein folding mechanisms: differential effects of dihydrofolate reductase fragments on the refolding of the intact protein. Hall, J.G., Frieden, C. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  12. Role of aspartate 27 in the binding of methotrexate to dihydrofolate reductase from Escherichia coli. Appleman, J.R., Howell, E.E., Kraut, J., Kühl, M., Blakley, R.L. J. Biol. Chem. (1988) [Pubmed]
  13. Crystal structure of a novel trimethoprim-resistant dihydrofolate reductase specified in Escherichia coli by R-plasmid R67. Matthews, D.A., Smith, S.L., Baccanari, D.P., Burchall, J.J., Oatley, S.J., Kraut, J. Biochemistry (1986) [Pubmed]
  14. Determination by Raman spectroscopy of the pKa of N5 of dihydrofolate bound to dihydrofolate reductase: mechanistic implications. Chen, Y.Q., Kraut, J., Blakley, R.L., Callender, R. Biochemistry (1994) [Pubmed]
  15. Binding sites in Escherichia coli dihydrofolate reductase communicate by modulating the conformational ensemble. Pan, H., Lee, J.C., Hilser, V.J. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  16. Refolding of Escherichia coli dihydrofolate reductase: sequential formation of substrate binding sites. Frieden, C. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  17. Simulating pseudogene evolution in vitro: determining the true number of mutations in a lineage. Vartanian, J.P., Henry, M., Wain-Hobson, S. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  18. Dihydrofolate reductase of the extremely halophilic archaebacterium Halobacterium volcanii. The enzyme and its coding gene. Zusman, T., Rosenshine, I., Boehm, G., Jaenicke, R., Leskiw, B., Mevarech, M. J. Biol. Chem. (1989) [Pubmed]
  19. Cloning, expression, and characterization of Cryptococcus neoformans dihydrofolate reductase. Sirawaraporn, W., Cao, M., Santi, D.V., Edman, J.C. J. Biol. Chem. (1993) [Pubmed]
  20. Use of the Escherichia coli chromosomal DHFR gene as selection marker in mammalian cells. Asselbergs, F.A., Widmer, R. J. Biotechnol. (1995) [Pubmed]
  21. Ricin A chain can transport unfolded dihydrofolate reductase into the cytosol. Beaumelle, B., Taupiac, M.P., Lord, J.M., Roberts, L.M. J. Biol. Chem. (1997) [Pubmed]
  22. Amino-terminal deletions in the presequence of an imported mitochondrial protein block the targeting function and proteolytic cleavage of the presequence at the carboxy terminus. Hurt, E.C., Allison, D.S., Müller, U., Schatz, G. J. Biol. Chem. (1987) [Pubmed]
  23. An unstructured mRNA region and a 5' hairpin represent important elements of the E. coli translation initiation signal determined by using the bacteriophage T7 gene 1 translation start site. Helke, A., Geisen, R.M., Vollmer, M., Sprengart, M.L., Fuchs, E. Nucleic Acids Res. (1993) [Pubmed]
  24. Purine salvage rescue by xanthine-guanine phosphoribosyltransferase (XGPRT) potentiates methotrexate resistance conferred by transfer of a mutated dihydrofolate reductase gene. Mineishi, S., Nakahara, S., Takebe, N., Zhao, S.C., Banerjee, D., Bertino, J.R. Cancer Gene Ther. (1998) [Pubmed]
  25. Correlated motion and the effect of distal mutations in dihydrofolate reductase. Rod, T.H., Radkiewicz, J.L., Brooks, C.L. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  26. Vibrational structure of dihydrofolate bound to R67 dihydrofolate reductase. Deng, H., Callender, R., Howell, E. J. Biol. Chem. (2001) [Pubmed]
  27. Inhibition of thymidylate synthetase and dihydrofolate reductase by naturally occurring oligoglutamate derivatives of folic acid. Friedkin, M., Plante, L.T., Crawford, E.J., Crumm, M. J. Biol. Chem. (1975) [Pubmed]
  28. Identification of an uncleavable targeting signal in the 70-kilodalton spinach chloroplast outer envelope membrane protein. Wu, C., Ko, K. J. Biol. Chem. (1993) [Pubmed]
  29. Construction of a fol mutant strain of Escherichia coli for use in dihydrofolate reductase mutagenesis experiments. Ahrweiler, P.M., Frieden, C. J. Bacteriol. (1988) [Pubmed]
  30. Dihydrofolate influences the activity of Escherichia coli dihydrofolate reductase synthesised de novo. Mouat, M.F. Int. J. Biochem. Cell Biol. (2000) [Pubmed]
  31. Conditional dihydrofolate reductase deficiency due to transposon Tn5tac1 insertion downstream from the folA gene in Escherichia coli. Neuwald, A.F., Krishnan, B.R., Ahrweiler, P.M., Frieden, C., Berg, D.E. Gene (1993) [Pubmed]
  32. Chemically induced dimerization of dihydrofolate reductase by a homobifunctional dimer of methotrexate. Kopytek, S.J., Standaert, R.F., Dyer, J.C., Hu, J.C. Chem. Biol. (2000) [Pubmed]
  33. Probing the functional role of phenylalanine-31 of Escherichia coli dihydrofolate reductase by site-directed mutagenesis. Chen, J.T., Taira, K., Tu, C.P., Benkovic, S.J. Biochemistry (1987) [Pubmed]
  34. An expedient and facile one-step synthesis of a biguanide library by microwave irradiation coupled with simple product filtration. Inhibitors of dihydrofolate reductase. Mayer, S., Daigle, D.M., Brown, E.D., Khatri, J., Organ, M.G. Journal of combinatorial chemistry. (2004) [Pubmed]
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