Identification
Name:Dihydrofolate reductase
Synonyms:Not Available
Gene Name:folA
Enzyme Class:
Biological Properties
General Function:Involved in dihydrofolate reductase activity
Specific Function:Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis
Cellular Location:Not Available
SMPDB Pathways:
KEGG Pathways:
KEGG Reactions:
1.0Thumb+1.0Thumb+1.0Thumb1.0Thumb+1.0Thumb
1.0Thumb+1.0Thumb1.0Thumb+1.0Thumb+1.0Thumb
1.0Thumb+2.0Thumb1.0Thumb+2.0Thumb+2.0Thumb
1.0Thumb+1.0Thumb1.0Thumb+1.0Thumb+1.0Thumb
1.0Thumb+2.0Thumb1.0Thumb+2.0Thumb+2.0Thumb
1.0Thumb+1.0Thumb1.0Thumb+1.0Thumb+1.0Thumb
1.0Thumb+1.0Thumb1.0Thumb+1.0Thumb+1.0Thumb
SMPDB Reactions:
1.0Thumb+1.0Thumb+1.0Dihydrofolic acid1.0Thumb+1.0NADPH+1.0Thumb+1.0Thumb
1.0Dihydrofolic acid + 1.0NADP + 1.0Dihydrofolic acid → 1.0Folic acid + 1.0NADPH + 1.0Hydrogen ion + 1.0NADPH
ReactionCard
1.0Thumb+1.0NADPH+1.0Thumb+1.0Dihydrofolic acid+1.0Thumb1.0Tetrahydrofolic acid+1.0Thumb+1.0Thumb
1.0Dihydrofolic acid + 1.0NADPH + 1.0Hydrogen ion + 1.0Dihydrofolic acid + 1.0NADPH → 1.0Tetrahydrofolic acid + 1.0NADP + 1.0Tetrahydrofolic acid
ReactionCard
1.07,8-dihydrofolate monoglutamate+1.0Thumb+1.0NADPH+1.0Thumb+1.0Thumb1.0Thumb+1.0Tetrahydrofolic acid+1.0Thumb
1.07,8-dihydrofolate monoglutamate + 1.0Hydrogen ion + 1.0NADPH + 1.0Dihydrofolic acid + 1.0NADPH → 1.0NADP + 1.0Tetrahydrofolic acid + 1.0Tetrahydrofolic acid
ReactionCard
1.0Thumb+2.0NADPH+2.0Thumb+2.0Thumb1.0Tetrahydrofolic acid+2.0Thumb+1.0Thumb
1.0Folic acid + 2.0NADPH + 2.0Hydrogen ion + 2.0NADPH → 1.0Tetrahydrofolic acid + 2.0NADP + 1.0Tetrahydrofolic acid
ReactionCard
EcoCyc Reactions:
1.0Thumb+1.0Thumb+1.0Thumb1.0Thumb+1.0Thumb
1.0Thumb+1.0Thumb1.0Thumb+1.0Thumb+1.0Thumb
Complex Reactions:
1.0Thumb+1.0Thumb1.0Thumb+1.0Thumb
Metabolites:
ECMDB IDNameView
ECMDB01056Dihydrofolic acidMetaboCard
ECMDB00121Folic acidMetaboCard
ECMDB21225Hydrogen ionMetaboCard
ECMDB00902NADMetaboCard
ECMDB01487NADHMetaboCard
ECMDB00217NADPMetaboCard
ECMDB04111NADPHMetaboCard
ECMDB01846Tetrahydrofolic acidMetaboCard
GO Classification:
Function
binding
catalytic activity
dihydrofolate reductase activity
NADP or NADPH binding
nucleotide binding
oxidoreductase activity
oxidoreductase activity, acting on the CH-NH group of donors
oxidoreductase activity, acting on the CH-NH group of donors, NAD or NADP as acceptor
Process
cellular amino acid and derivative metabolic process
cellular amino acid metabolic process
cellular metabolic process
cellular nitrogen compound metabolic process
glycine biosynthetic process
glycine metabolic process
metabolic process
nitrogen compound metabolic process
nucleobase, nucleoside and nucleotide metabolic process
nucleobase, nucleoside, nucleotide and nucleic acid metabolic process
nucleoside phosphate metabolic process
nucleotide biosynthetic process
nucleotide metabolic process
oxidation reduction
serine family amino acid metabolic process
Gene Properties
Blattner:b0048
Gene OrientationClockwise
Centisome Percentage:1.07
Left Sequence End49823
Right Sequence End50302
Gene Sequence:
>480 bp
ATGATCAGTCTGATTGCGGCGTTAGCGGTAGATCGCGTTATCGGCATGGAAAACGCCATG
CCGTGGAACCTGCCTGCCGATCTCGCCTGGTTTAAACGCAACACCTTAAATAAACCCGTG
ATTATGGGCCGCCATACCTGGGAATCAATCGGTCGTCCGTTGCCAGGACGCAAAAATATT
ATCCTCAGCAGTCAACCGGGTACGGACGATCGCGTAACGTGGGTGAAGTCGGTGGATGAA
GCCATCGCGGCGTGTGGTGACGTACCAGAAATCATGGTGATTGGCGGCGGTCGCGTTTAT
GAACAGTTCTTGCCAAAAGCGCAAAAACTGTATCTGACGCATATCGACGCAGAAGTGGAA
GGCGACACCCATTTCCCGGATTACGAGCCGGATGACTGGGAATCGGTATTCAGCGAATTC
CACGATGCTGATGCGCAGAACTCTCACAGCTATTGCTTTGAGATTCTGGAGCGGCGGTAA
Protein Properties
Pfam Domain Function:
Protein Residues:159
Protein Molecular Weight:17999
Protein Theoretical pI:5
PDB File:1DDS
Signaling Regions:
  • None
Transmembrane Regions:
  • None
Protein Sequence:
>Dihydrofolate reductase
MISLIAALAVDRVIGMENAMPWNLPADLAWFKRNTLNKPVIMGRHTWESIGRPLPGRKNI
ILSSQPGTDDRVTWVKSVDEAIAACGDVPEIMVIGGGRVYEQFLPKAQKLYLTHIDAEVE
GDTHFPDYEPDDWESVFSEFHDADAQNSHSYCFEILERR
References
External Links:
ResourceLink
Uniprot ID:P0ABQ4
Uniprot Name:DYR_ECOLI
GenBank Gene ID:AP009048
Genebank Protein ID:21321929
PDB ID:1DDS
Ecogene ID:EG10326
Ecocyc:EG10326
ColiBase:b0048
Kegg Gene:b0048
EchoBASE ID:EB0322
CCDB:DYR_ECOLI
BacMap:16128042
General Reference:
  • Baccanari, D. P., Stone, D., Kuyper, L. (1981). "Effect of a single amino acid substitution on Escherichia coli dihydrofolate reductase catalysis and ligand binding." J Biol Chem 256:1738-1747. Pubmed: 7007370
  • Bennett, B. C., Wan, Q., Ahmad, M. F., Langan, P., Dealwis, C. G. (2009). "X-ray structure of the ternary MTX.NADPH complex of the anthrax dihydrofolate reductase: a pharmacophore for dual-site inhibitor design." J Struct Biol 166:162-171. Pubmed: 19374017
  • Bennett, B., Langan, P., Coates, L., Mustyakimov, M., Schoenborn, B., Howell, E. E., Dealwis, C. (2006). "Neutron diffraction studies of Escherichia coli dihydrofolate reductase complexed with methotrexate." Proc Natl Acad Sci U S A 103:18493-18498. Pubmed: 17130456
  • Bennett, C. D., Rodkey, J. A., Sondey, J. M., Hirschmann, R. (1978). "Dihydrofolate reductase: the amino acid sequence of the enzyme from a methotrexate-resistant mutant of Escherichia coli." Biochemistry 17:1328-1337. Pubmed: 350268
  • Blattner, F. R., Plunkett, G. 3rd, Bloch, C. A., Perna, N. T., Burland, V., Riley, M., Collado-Vides, J., Glasner, J. D., Rode, C. K., Mayhew, G. F., Gregor, J., Davis, N. W., Kirkpatrick, H. A., Goeden, M. A., Rose, D. J., Mau, B., Shao, Y. (1997). "The complete genome sequence of Escherichia coli K-12." Science 277:1453-1462. Pubmed: 9278503
  • Bystroff, C., Kraut, J. (1991). "Crystal structure of unliganded Escherichia coli dihydrofolate reductase. Ligand-induced conformational changes and cooperativity in binding." Biochemistry 30:2227-2239. Pubmed: 1998681
  • Bystroff, C., Oatley, S. J., Kraut, J. (1990). "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." Biochemistry 29:3263-3277. Pubmed: 2185835
  • Filman, D. J., Bolin, J. T., Matthews, D. A., Kraut, J. (1982). "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." J Biol Chem 257:13663-13672. Pubmed: 6815179
  • Flensburg, J., Skold, O. (1987). "Massive overproduction of dihydrofolate reductase in bacteria as a response to the use of trimethoprim." Eur J Biochem 162:473-476. Pubmed: 3549289
  • Hayashi, K., Morooka, N., Yamamoto, Y., Fujita, K., Isono, K., Choi, S., Ohtsubo, E., Baba, T., Wanner, B. L., Mori, H., Horiuchi, T. (2006). "Highly accurate genome sequences of Escherichia coli K-12 strains MG1655 and W3110." Mol Syst Biol 2:2006.0007. Pubmed: 16738553
  • Iwakura, M., Maki, K., Takahashi, H., Takenawa, T., Yokota, A., Katayanagi, K., Kamiyama, T., Gekko, K. (2006). "Evolutional design of a hyperactive cysteine- and methionine-free mutant of Escherichia coli dihydrofolate reductase." J Biol Chem 281:13234-13246. Pubmed: 16510443
  • Lee, H., Reyes, V. M., Kraut, J. (1996). "Crystal structures of Escherichia coli dihydrofolate reductase complexed with 5-formyltetrahydrofolate (folinic acid) in two space groups: evidence for enolization of pteridine O4." Biochemistry 35:7012-7020. Pubmed: 8679526
  • Reyes, V. M., Sawaya, M. R., Brown, K. A., Kraut, J. (1995). "Isomorphous crystal structures of Escherichia coli dihydrofolate reductase complexed with folate, 5-deazafolate, and 5,10-dideazatetrahydrofolate: mechanistic implications." Biochemistry 34:2710-2723. Pubmed: 7873554
  • Sawaya, M. R., Kraut, J. (1997). "Loop and subdomain movements in the mechanism of Escherichia coli dihydrofolate reductase: crystallographic evidence." Biochemistry 36:586-603. Pubmed: 9012674
  • Smith, D. R., Calvo, J. M. (1980). "Nucleotide sequence of the E coli gene coding for dihydrofolate reductase." Nucleic Acids Res 8:2255-2274. Pubmed: 6159575
  • Stone, D., Phillips, A. W., Burchall, J. J. (1977). "The amino-acid sequence of the dihydrofolate reductase of a trimethoprim-resistant strain of Escherichia coli." Eur J Biochem 72:613-624. Pubmed: 320005
  • Summerfield, R. L., Daigle, D. M., Mayer, S., Mallik, D., Hughes, D. W., Jackson, S. G., Sulek, M., Organ, M. G., Brown, E. D., Junop, M. S. (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 49:6977-6986. Pubmed: 17125251
  • Yura, T., Mori, H., Nagai, H., Nagata, T., Ishihama, A., Fujita, N., Isono, K., Mizobuchi, K., Nakata, A. (1992). "Systematic sequencing of the Escherichia coli genome: analysis of the 0-2.4 min region." Nucleic Acids Res 20:3305-3308. Pubmed: 1630901