Dihydrofolate reductase

NameDihydrofolate reductase
Synonyms
  • 1.5.1.3
  • tmrA
Gene NamefolA
OrganismEscherichia coli (strain K12)
Amino acid sequence
>lcl|BSEQ0019220|Dihydrofolate reductase
MISLIAALAVDRVIGMENAMPWNLPADLAWFKRNTLNKPVIMGRHTWESIGRPLPGRKNI
ILSSQPGTDDRVTWVKSVDEAIAACGDVPEIMVIGGGRVYEQFLPKAQKLYLTHIDAEVE
GDTHFPDYEPDDWESVFSEFHDADAQNSHSYCFEILERR
Number of residuesNone
Molecular Weight17999.21
Theoretical pI4.61
GO Classification
Functions
  • NADP binding
  • dihydrofolate reductase activity
Processes
  • response to drug
  • response to antibiotic
  • response to methotrexate
  • one-carbon metabolic process
  • tetrahydrofolate biosynthetic process
  • glycine biosynthetic process
  • nucleotide biosynthetic process
Components
  • cytosol
General FunctionNadp binding
Specific FunctionKey enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.
Transmembrane Regions
GenBank Protein ID
UniProtKB IDP0ABQ4
UniProtKB Entry Name
Cellular LocationNone
Gene sequence
>lcl|BSEQ0019221|Dihydrofolate reductase (folA)
ATGATCAGTCTGATTGCGGCGTTAGCGGTAGATCGCGTTATCGGCATGGAAAACGCCATG
CCGTGGAACCTGCCTGCCGATCTCGCCTGGTTTAAACGCAACACCTTAAATAAACCCGTG
ATTATGGGCCGCCATACCTGGGAATCAATCGGTCGTCCGTTGCCAGGACGCAAAAATATT
ATCCTCAGCAGTCAACCGGGTACGGACGATCGCGTAACGTGGGTGAAGTCGGTGGATGAA
GCCATCGCGGCGTGTGGTGACGTACCAGAAATCATGGTGATTGGCGGCGGTCGCGTTTAT
GAACAGTTCTTGCCAAAAGCGCAAAAACTGTATCTGACGCATATCGACGCAGAAGTGGAA
GGCGACACCCATTTCCCGGATTACGAGCCGGATGACTGGGAATCGGTATTCAGCGAATTC
CACGATGCTGATGCGCAGAACTCTCACAGCTATTGCTTTGAGATTCTGGAGCGGCGGTAA
GenBank Gene ID
GeneCard IDNone
GenAtlas ID
HGNC ID
Chromosome LocationNone
LocusNone
References
  1. Stone D, Phillips AW, Burchall JJ: The amino-acid sequence of the dihydrofolate reductase of a trimethoprim-resistant strain of Escherichia coli. Eur J Biochem. 1977 Feb;72(3):613-24. [320005 ]
  2. Bennett CD, Rodkey JA, Sondey JM, Hirschmann R: Dihydrofolate reductase: the amino acid sequence of the enzyme from a methotrexate-resistant mutant of Escherichia coli. Biochemistry. 1978 Apr 4;17(7):1328-37. [350268 ]
  3. Smith DR, Calvo JM: Nucleotide sequence of the E coli gene coding for dihydrofolate reductase. Nucleic Acids Res. 1980 May 24;8(10):2255-74. [6159575 ]
  4. Baccanari DP, Stone D, Kuyper L: Effect of a single amino acid substitution on Escherichia coli dihydrofolate reductase catalysis and ligand binding. J Biol Chem. 1981 Feb 25;256(4):1738-47. [7007370 ]
  5. Flensburg J, Skold O: Massive overproduction of dihydrofolate reductase in bacteria as a response to the use of trimethoprim. Eur J Biochem. 1987 Feb 2;162(3):473-6. [3549289 ]
  6. Yura T, Mori H, Nagai H, Nagata T, Ishihama A, Fujita N, Isono K, Mizobuchi K, Nakata A: Systematic sequencing of the Escherichia coli genome: analysis of the 0-2.4 min region. Nucleic Acids Res. 1992 Jul 11;20(13):3305-8. [1630901 ]
  7. Blattner FR, Plunkett G 3rd, Bloch CA, Perna NT, Burland V, Riley M, Collado-Vides J, Glasner JD, Rode CK, Mayhew GF, Gregor J, Davis NW, Kirkpatrick HA, Goeden MA, Rose DJ, Mau B, Shao Y: The complete genome sequence of Escherichia coli K-12. Science. 1997 Sep 5;277(5331):1453-62. [9278503 ]
  8. Hayashi K, Morooka N, Yamamoto Y, Fujita K, Isono K, Choi S, Ohtsubo E, Baba T, Wanner BL, Mori H, Horiuchi T: Highly accurate genome sequences of Escherichia coli K-12 strains MG1655 and W3110. Mol Syst Biol. 2006;2:2006.0007. Epub 2006 Feb 21. [16738553 ]
  9. VanBogelen RA, Abshire KZ, Moldover B, Olson ER, Neidhardt FC: Escherichia coli proteome analysis using the gene-protein database. Electrophoresis. 1997 Aug;18(8):1243-51. [9298644 ]
  10. Filman DJ, Bolin JT, Matthews DA, Kraut J: 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. 1982 Nov 25;257(22):13663-72. [6815179 ]
  11. Bystroff C, Oatley SJ, Kraut J: 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. 1990 Apr 3;29(13):3263-77. [2185835 ]
  12. Bystroff C, Kraut J: Crystal structure of unliganded Escherichia coli dihydrofolate reductase. Ligand-induced conformational changes and cooperativity in binding. Biochemistry. 1991 Feb 26;30(8):2227-39. [1998681 ]
  13. Reyes VM, Sawaya MR, Brown KA, Kraut J: Isomorphous crystal structures of Escherichia coli dihydrofolate reductase complexed with folate, 5-deazafolate, and 5,10-dideazatetrahydrofolate: mechanistic implications. Biochemistry. 1995 Feb 28;34(8):2710-23. [7873554 ]
  14. Lee H, Reyes VM, Kraut J: Crystal structures of Escherichia coli dihydrofolate reductase complexed with 5-formyltetrahydrofolate (folinic acid) in two space groups: evidence for enolization of pteridine O4. Biochemistry. 1996 Jun 4;35(22):7012-20. [8679526 ]
  15. Sawaya MR, Kraut J: Loop and subdomain movements in the mechanism of Escherichia coli dihydrofolate reductase: crystallographic evidence. Biochemistry. 1997 Jan 21;36(3):586-603. [9012674 ]
  16. Iwakura M, Maki K, Takahashi H, Takenawa T, Yokota A, Katayanagi K, Kamiyama T, Gekko K: Evolutional design of a hyperactive cysteine- and methionine-free mutant of Escherichia coli dihydrofolate reductase. J Biol Chem. 2006 May 12;281(19):13234-46. Epub 2006 Mar 1. [16510443 ]
  17. Summerfield RL, Daigle DM, Mayer S, Mallik D, Hughes DW, Jackson SG, Sulek M, Organ MG, Brown ED, Junop MS: 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. 2006 Nov 30;49(24):6977-86. [17125251 ]
  18. Bennett B, Langan P, Coates L, Mustyakimov M, Schoenborn B, Howell EE, Dealwis C: Neutron diffraction studies of Escherichia coli dihydrofolate reductase complexed with methotrexate. Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18493-8. Epub 2006 Nov 27. [17130456 ]
  19. Bennett BC, Wan Q, Ahmad MF, Langan P, Dealwis CG: X-ray structure of the ternary MTX.NADPH complex of the anthrax dihydrofolate reductase: a pharmacophore for dual-site inhibitor design. J Struct Biol. 2009 May;166(2):162-71. [19374017 ]

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