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Identification
HMDB Protein ID HMDBP00790
Secondary Accession Numbers
  • 6070
  • HMDBP04883
Name Dihydrofolate reductase
Synonyms Not Available
Gene Name DHFR
Protein Type Enzyme
Biological Properties
General Function Involved in dihydrofolate reductase activity
Specific Function Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.
Pathways
  • Dopa-responsive dystonia
  • Folate biosynthesis
  • Folate malabsorption, hereditary
  • Folate Metabolism
  • Hyperphenylalaniemia due to guanosine triphosphate cyclohydrolase deficiency
  • Hyperphenylalaninemia due to 6-pyruvoyltetrahydropterin synthase deficiency (ptps)
  • Hyperphenylalaninemia due to dhpr-deficiency
  • Methotrexate Action Pathway
  • Methylenetetrahydrofolate Reductase Deficiency (MTHFRD)
  • One carbon pool by folate
  • Pterine Biosynthesis
  • Segawa syndrome
  • Sepiapterin reductase deficiency
  • tetrahydrofolate biosynthesis
Reactions
Tetrahydrofolic acid + NADP → Dihydrofolic acid + NADPH details
Tetrahydrofolic acid + NAD → Dihydrofolic acid + NADH + Hydrogen Ion details
Tetrahydrofolic acid + NAD → Folic acid + NADH + Hydrogen Ion details
Tetrahydrofolic acid + NADP → Dihydrofolic acid + NADPH + Hydrogen Ion details
Tetrahydrofolic acid + NADP → Folic acid + NADPH + Hydrogen Ion details
Dihydrofolic acid + NAD → Folic acid + NADH + Hydrogen Ion details
Dihydrofolic acid + NADP → Folic acid + NADPH + Hydrogen Ion details
GO Classification
Biological Process
nucleotide biosynthetic process
response to methotrexate
regulation of transcription involved in G1/S phase of mitotic cell cycle
folic acid metabolic process
tetrahydrofolate metabolic process
nitric oxide metabolic process
one-carbon metabolic process
glycine biosynthetic process
tetrahydrofolate biosynthetic process
regulation of nitric-oxide synthase activity
Cellular Component
cytosol
nucleoplasm
Function
binding
nucleotide binding
catalytic activity
oxidoreductase activity, acting on the ch-nh group of donors
nadp or nadph binding
oxidoreductase activity, acting on the ch-nh group of donors, nad or nadp as acceptor
oxidoreductase activity
dihydrofolate reductase activity
Molecular Function
NADP binding
drug binding
dihydrofolate reductase activity
mRNA binding
Process
metabolic process
nitrogen compound metabolic process
cellular nitrogen compound metabolic process
nucleobase, nucleoside, nucleotide and nucleic acid metabolic process
nucleobase, nucleoside and nucleotide metabolic process
nucleoside phosphate metabolic process
nucleotide metabolic process
nucleotide biosynthetic process
cellular metabolic process
serine family amino acid metabolic process
glycine metabolic process
oxidation reduction
cellular amino acid and derivative metabolic process
glycine biosynthetic process
cellular amino acid metabolic process
Cellular Location Not Available
Gene Properties
Chromosome Location 5
Locus 5q11.2-q13.2
SNPs DHFR
Gene Sequence
>564 bp
ATGGTTGGTTCGCTAAACTGCATCGTCGCTGTGTCCCAGAACATGGGCATCGGCAAGAAC
GGGGACCTGCCCTGGCCACCGCTCAGGAATGAATTCAGATATTTCCAGAGAATGACCACA
ACCTCTTCAGTAGAAGGTAAACAGAATCTGGTGATTATGGGTAAGAAGACCTGGTTCTCC
ATTCCTGAGAAGAATCGACCTTTAAAGGGTAGAATTAATTTAGTTCTCAGCAGAGAACTC
AAGGAACCTCCACAAGGAGCTCATTTTCTTTCCAGAAGTCTAGATGATGCCTTAAAACTT
ACTGAACAACCAGAATTAGCAAATAAAGTAGACATGGTCTGGATAGTTGGTGGCAGTTCT
GTTTATAAGGAAGCCATGAATCACCCAGGCCATCTTAAACTATTTGTGACAAGGATCATG
CAAGACTTTGAAAGTGACACGTTTTTTCCAGAAATTGATTTGGAGAAATATAAACTTCTG
CCAGAATACCCAGGTGTTCTCTCTGATGTCCAGGAGGAGAAAGGCATTAAGTACAAATTT
GAAGTATATGAGAAGAATGATTAA
Protein Properties
Number of Residues 187
Molecular Weight 21452.61
Theoretical pI 7.42
Pfam Domain Function
Signals Not Available
Transmembrane Regions Not Available
Protein Sequence
>Dihydrofolate reductase
MVGSLNCIVAVSQNMGIGKNGDLPWPPLRNEFRYFQRMTTTSSVEGKQNLVIMGKKTWFS
IPEKNRPLKGRINLVLSRELKEPPQGAHFLSRSLDDALKLTEQPELANKVDMVWIVGGSS
VYKEAMNHPGHLKLFVTRIMQDFESDTFFPEIDLEKYKLLPEYPGVLSDVQEEKGIKYKF
EVYEKND
GenBank ID Protein 182724
UniProtKB/Swiss-Prot ID P00374
UniProtKB/Swiss-Prot Entry Name DYR_HUMAN
PDB IDs
GenBank Gene ID J00140
GeneCard ID DHFR
GenAtlas ID DHFR
HGNC ID HGNC:2861
References
General References
  1. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [PubMed:15489334 ]
  2. Chen MJ, Shimada T, Moulton AD, Cline A, Humphries RK, Maizel J, Nienhuis AW: The functional human dihydrofolate reductase gene. J Biol Chem. 1984 Mar 25;259(6):3933-43. [PubMed:6323448 ]
  3. Masters JN, Attardi G: The nucleotide sequence of the cDNA coding for the human dihydrofolic acid reductase. Gene. 1983 Jan-Feb;21(1-2):59-63. [PubMed:6687716 ]
  4. Yang JK, Masters JN, Attardi G: Human dihydrofolate reductase gene organization. Extensive conservation of the G + C-rich 5' non-coding sequence and strong intron size divergence from homologous mammalian genes. J Mol Biol. 1984 Jun 25;176(2):169-87. [PubMed:6235374 ]
  5. Oefner C, D'Arcy A, Winkler FK: Crystal structure of human dihydrofolate reductase complexed with folate. Eur J Biochem. 1988 Jun 1;174(2):377-85. [PubMed:3383852 ]
  6. Davies JF 2nd, Delcamp TJ, Prendergast NJ, Ashford VA, Freisheim JH, Kraut J: Crystal structures of recombinant human dihydrofolate reductase complexed with folate and 5-deazafolate. Biochemistry. 1990 Oct 9;29(40):9467-79. [PubMed:2248959 ]
  7. Stockman BJ, Nirmala NR, Wagner G, Delcamp TJ, DeYarman MT, Freisheim JH: Sequence-specific 1H and 15N resonance assignments for human dihydrofolate reductase in solution. Biochemistry. 1992 Jan 14;31(1):218-29. [PubMed:1731871 ]
  8. Lewis WS, Cody V, Galitsky N, Luft JR, Pangborn W, Chunduru SK, Spencer HT, Appleman JR, Blakley RL: Methotrexate-resistant variants of human dihydrofolate reductase with substitutions of leucine 22. Kinetics, crystallography, and potential as selectable markers. J Biol Chem. 1995 Mar 10;270(10):5057-64. [PubMed:7890613 ]
  9. Cody V, Galitsky N, Luft JR, Pangborn W, Rosowsky A, Blakley RL: Comparison of two independent crystal structures of human dihydrofolate reductase ternary complexes reduced with nicotinamide adenine dinucleotide phosphate and the very tight-binding inhibitor PT523. Biochemistry. 1997 Nov 11;36(45):13897-903. [PubMed:9374868 ]
  10. Gangjee A, Vidwans AP, Vasudevan A, Queener SF, Kisliuk RL, Cody V, Li R, Galitsky N, Luft JR, Pangborn W: Structure-based design and synthesis of lipophilic 2,4-diamino-6-substituted quinazolines and their evaluation as inhibitors of dihydrofolate reductases and potential antitumor agents. J Med Chem. 1998 Aug 27;41(18):3426-34. [PubMed:9719595 ]
  11. Klon AE, Heroux A, Ross LJ, Pathak V, Johnson CA, Piper JR, Borhani DW: Atomic structures of human dihydrofolate reductase complexed with NADPH and two lipophilic antifolates at 1.09 a and 1.05 a resolution. J Mol Biol. 2002 Jul 12;320(3):677-93. [PubMed:12096917 ]
  12. Cody V, Galitsky N, Luft JR, Pangborn W, Gangjee A: Analysis of two polymorphic forms of a pyrido[2,3-d]pyrimidine N9-C10 reversed-bridge antifolate binary complex with human dihydrofolate reductase. Acta Crystallogr D Biol Crystallogr. 2003 Apr;59(Pt 4):654-61. Epub 2003 Mar 25. [PubMed:12657784 ]
  13. Cody V, Luft JR, Pangborn W, Gangjee A: Analysis of three crystal structure determinations of a 5-methyl-6-N-methylanilino pyridopyrimidine antifolate complex with human dihydrofolate reductase. Acta Crystallogr D Biol Crystallogr. 2003 Sep;59(Pt 9):1603-9. Epub 2003 Aug 19. [PubMed:12925791 ]
  14. Cody V, Luft JR, Pangborn W, Gangjee A, Queener SF: Structure determination of tetrahydroquinazoline antifolates in complex with human and Pneumocystis carinii dihydrofolate reductase: correlations between enzyme selectivity and stereochemistry. Acta Crystallogr D Biol Crystallogr. 2004 Apr;60(Pt 4):646-55. Epub 2004 Mar 23. [PubMed:15039552 ]
  15. Cody V, Luft JR, Pangborn W: Understanding the role of Leu22 variants in methotrexate resistance: comparison of wild-type and Leu22Arg variant mouse and human dihydrofolate reductase ternary crystal complexes with methotrexate and NADPH. Acta Crystallogr D Biol Crystallogr. 2005 Feb;61(Pt 2):147-55. Epub 2005 Jan 19. [PubMed:15681865 ]
  16. Kovalevskaya NV, Smurnyy YD, Polshakov VI, Birdsall B, Bradbury AF, Frenkiel T, Feeney J: Solution structure of human dihydrofolate reductase in its complex with trimethoprim and NADPH. J Biomol NMR. 2005 Sep;33(1):69-72. [PubMed:16222560 ]
  17. Reynolds RC, Campbell SR, Fairchild RG, Kisliuk RL, Micca PL, Queener SF, Riordan JM, Sedwick WD, Waud WR, Leung AK, Dixon RW, Suling WJ, Borhani DW: Novel boron-containing, nonclassical antifolates: synthesis and preliminary biological and structural evaluation. J Med Chem. 2007 Jul 12;50(14):3283-9. Epub 2007 Jun 15. [PubMed:17569517 ]
  18. Cody V, Pace J, Makin J, Piraino J, Queener SF, Rosowsky A: Correlations of inhibitor kinetics for Pneumocystis jirovecii and human dihydrofolate reductase with structural data for human active site mutant enzyme complexes. Biochemistry. 2009 Mar 3;48(8):1702-11. doi: 10.1021/bi801960h. [PubMed:19196009 ]
  19. Volpato JP, Yachnin BJ, Blanchet J, Guerrero V, Poulin L, Fossati E, Berghuis AM, Pelletier JN: Multiple conformers in active site of human dihydrofolate reductase F31R/Q35E double mutant suggest structural basis for methotrexate resistance. J Biol Chem. 2009 Jul 24;284(30):20079-89. doi: 10.1074/jbc.M109.018010. Epub 2009 May 28. [PubMed:19478082 ]
  20. Gangjee A, Li W, Kisliuk RL, Cody V, Pace J, Piraino J, Makin J: Design, synthesis, and X-ray crystal structure of classical and nonclassical 2-amino-4-oxo-5-substituted-6-ethylthieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors and as potential antitumor agents. J Med Chem. 2009 Aug 13;52(15):4892-902. doi: 10.1021/jm900490a. [PubMed:19719239 ]