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Gene Review

folA  -  dihydrofolate reductase

Escherichia coli str. K-12 substr. MG1655

Synonyms: ECK0049, JW0047, tmrA
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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

  • The presecretory protein preprocecropinA (which comprises 64 amino acid residues) as well as a synthetic hybrid between preprocecropinA and dihydrofolate reductase (which comprises 252 amino acid residues) are processed by and transported into mammalian microsomes [18].
  • A fusion between the N-terminal 15 amino acid residues of beta-subunit and the mouse cytosolic protein dihydrofolate reductase (DHFR) was transcribed and translated in vitro and found to be transported into isolated yeast mitochondria [19].
  • Two novel analogues of aminopterin with a single fluorine substitution in the 2' (compound 8) or in the 3' (compound 9) position of the p-aminobenzoyl group were synthesized and evaluated as inhibitors of dihydrofolate reductase from two bacterial species and from human HeLa cells [20].
  • Translation of this recombinant mRNA in the Escherichia coli cell-free system resulted in the synthesis of DHFR, which was two orders of magnitude higher than that in the case of translation of the control DHFR mRNA [21].
  • Purified DNA from Chinese hamster ovary (CHO) cells was reacted in vitro with the active metabolites N-acetoxy-IQ or N-acetoxy-MelQx, and the adduct levels in the 5' dihydrofolate reductase (DHFR) gene and downstream region were quantitated by Southern hybridization [22].

Associations of folA with chemical compounds


Other interactions of folA


Analytical, diagnostic and therapeutic context of folA

  • The refolded DHFR was purified by methotrexate-Sepharose affinity chromatography to give the homogeneous enzyme [29].
  • Immunoprecipitation and chemical cross-linking experiments revealed that SCE70-DHFR is targeted to the same complex as SCE70 in the chloroplast envelope [30].
  • The purified DHFR migrates as a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis with apparent mass of approximately 30 kDa, and gel filtration showed that the protein is a monomer [29].
  • The complete amino acid sequence of dihydrofolate reductase from an amethopterin-resistant strain of Lactobacillus casei has been determined by sequence analysis of peptides produced by cleavage with cyanogen bromide, trypsin, staphylococcal protease, and myxobacter protease [31].
  • The stopped-flow circular dichroism (CD) measurements show that the CD spectra at the early stages of folding are similar among the mutants and the wild-type DHFR, indicating that the presence of the complete set of folding elements is sufficient to preserve the early folding events [32].


  1. 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]
  2. Crystal structures of Escherichia coli and Lactobacillus casei dihydrofolate reductase refined at 1.7 A resolution. II. Environment of bound NADPH and implications for catalysis. Filman, D.J., Bolin, J.T., Matthews, D.A., Kraut, J. J. Biol. Chem. (1982) [Pubmed]
  3. Production of cyclic peptides and proteins in vivo. Scott, C.P., Abel-Santos, E., Wall, M., Wahnon, D.C., Benkovic, S.J. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  4. Species-specific irreversible inhibition of Neisseria gonorrhoeae dihydrofolate reductase by a substituted 2,4-diamino-5-benzylpyrimidine. Tansik, R.L., Averett, D.R., Roth, B., Paterson, S.J., Stone, D., Baccanari, D.P. J. Biol. Chem. (1984) [Pubmed]
  5. The structure of the mutant dihydrofolate reductase from Streptococcus faecium. Amino acid sequence of peptide CNBr 7 and complete sequence of the protein. Peterson, D.L., Gleisner, J.M., Blakley, R.L. J. Biol. Chem. (1975) [Pubmed]
  6. Insights into enzyme function from studies on mutants of dihydrofolate reductase. Benkovic, S.J., Fierke, C.A., Naylor, A.M. Science (1988) [Pubmed]
  7. 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]
  8. Impact of distal mutations on the network of coupled motions correlated to hydride transfer in dihydrofolate reductase. Wong, K.F., Selzer, T., Benkovic, S.J., Hammes-Schiffer, S. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  9. Single-molecule and transient kinetics investigation of the interaction of dihydrofolate reductase with NADPH and dihydrofolate. Zhang, Z., Rajagopalan, P.T., Selzer, T., Benkovic, S.J., Hammes, G.G. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  10. 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]
  11. Use of the Escherichia coli chromosomal DHFR gene as selection marker in mammalian cells. Asselbergs, F.A., Widmer, R. J. Biotechnol. (1995) [Pubmed]
  12. Dihydrofolate reductase: the amino acid sequence of the enzyme from a methotrexate-resistant mutant of Escherichia coli. Bennett, C.D., Rodkey, J.A., Sondey, J.M., Hirschmann, R. Biochemistry (1978) [Pubmed]
  13. Crystal structures of Escherichia coli dihydrofolate reductase: the NADP+ holoenzyme and the folate.NADP+ ternary complex. Substrate binding and a model for the transition state. Bystroff, C., Oatley, S.J., Kraut, J. Biochemistry (1990) [Pubmed]
  14. Crystal structure of unliganded Escherichia coli dihydrofolate reductase. Ligand-induced conformational changes and cooperativity in binding. Bystroff, C., Kraut, J. Biochemistry (1991) [Pubmed]
  15. Effect of a single amino acid substitution on Escherichia coli dihydrofolate reductase catalysis and ligand binding. Baccanari, D.P., Stone, D., Kuyper, L. J. Biol. Chem. (1981) [Pubmed]
  16. Conformation coupled enzyme catalysis: single-molecule and transient kinetics investigation of dihydrofolate reductase. Antikainen, N.M., Smiley, R.D., Benkovic, S.J., Hammes, G.G. Biochemistry (2005) [Pubmed]
  17. Regulation of dihydrofolate reductase synthesis in Escherichia coli. Smith, D.R., Calvo, J.M. Mol. Gen. Genet. (1979) [Pubmed]
  18. Structural requirements for transport of preprocecropinA and related presecretory proteins into mammalian microsomes. Schlenstedt, G., Gudmundsson, G.H., Boman, H.G., Zimmermann, R. J. Biol. Chem. (1992) [Pubmed]
  19. Transport of the yeast ATP synthase beta-subunit into mitochondria. Effects of amino acid substitutions on targeting. Walker, M.E., Valentin, E., Reid, G.A. Biochem. J. (1990) [Pubmed]
  20. Novel fluorinated antifolates. Enzyme inhibition and cytotoxicity studies on 2'- and 3'-fluoroaminopterin. Henkin, J., Washtien, W.L. J. Med. Chem. (1983) [Pubmed]
  21. Viral Q beta RNA as a high expression vector for mRNA translation in a cell-free system. Katanaev, V.L., Kurnasov, O.V., Spirin, A.S. FEBS Lett. (1995) [Pubmed]
  22. Quantitation of 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline DNA adducts in specific sequences using alkali or uvrABC excinuclease. Nouso, K., Bohr, V.A., Schut, H.A., Snyderwine, E.G. Mol. Carcinog. (1993) [Pubmed]
  23. CsgD, a regulator of curli and cellulose synthesis, also regulates serine hydroxymethyltransferase synthesis in Escherichia coli K-12. Chirwa, N.T., Herrington, M.B. Microbiology (Reading, Engl.) (2003) [Pubmed]
  24. Growth properties of a folA null mutant of Escherichia coli K12. Herrington, M.B., Chirwa, N.T. Can. J. Microbiol. (1999) [Pubmed]
  25. A mutation in the folA promoter delays adaptation to minimal medium by Escherichia coli K-12. Herrington, M.B., MacRae, T.J., Panagopoulos, D., Wong, S.H. J. Basic Microbiol. (2002) [Pubmed]
  26. Role of Lys-32 residues in R67 dihydrofolate reductase probed by asymmetric mutations. Hicks, S.N., Smiley, R.D., Stinnett, L.G., Minor, K.H., Howell, E.E. J. Biol. Chem. (2004) [Pubmed]
  27. "Catch 222," the effects of symmetry on ligand binding and catalysis in R67 dihydrofolate reductase as determined by mutations at Tyr-69. Stinnett, L.G., Smiley, R.D., Hicks, S.N., Howell, E.E. J. Biol. Chem. (2004) [Pubmed]
  28. Nucleotide sequence of the thymidylate synthase B and dihydrofolate reductase genes contained in one Bacillus subtilis operon. Iwakura, M., Kawata, M., Tsuda, K., Tanaka, T. Gene (1988) [Pubmed]
  29. The dihydrofolate reductase domain of Plasmodium falciparum thymidylate synthase-dihydrofolate reductase. Gene synthesis, expression, and anti-folate-resistant mutants. Sirawaraporn, W., Prapunwattana, P., Sirawaraporn, R., Yuthavong, Y., Santi, D.V. J. Biol. Chem. (1993) [Pubmed]
  30. 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]
  31. Dihydrofolate reductase from amethopterin-resistant Lactobacillus casei. Sequences of the cyanogen bromide peptides and complete sequences of the enzyme. Freisheim, J.H., Bitar, K.G., Reddy, A.V., Blankenship, D.T. J. Biol. Chem. (1978) [Pubmed]
  32. Testing the relationship between foldability and the early folding events of dihydrofolate reductase from Escherichia coli. Arai, M., Maki, K., Takahashi, H., Iwakura, M. J. Mol. Biol. (2003) [Pubmed]
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