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Version 2.5
Creation Date 2005-06-13 13:24:05
Update Date 2009-06-23 18:06:07
Primary Accession Number DB00440
Secondary Accession Number
  • APRD00103
Name Trimethoprim
Drug Type
  • Approved
  • Small Molecule
Description A pyrimidine inhibitor of dihydrofolate reductase, it is an antibacterial related to pyrimethamine. The interference with folic acid metabolism may cause a depression of hematopoiesis. It is potentiated by sulfonamides and the trimethoprim-sulfamethoxazole combination is the form most often used. It is sometimes used alone as an antimalarial. trimethoprim resistance has been reported. [PubChem]
Synonyms Not Available
Brand Names
  1. Abacin
  2. Abaprim
  3. Alprim
  4. Apo-Sulfatrim
  5. Bactin
  6. Bactramin
  7. Bactrim
  8. Bactrim DS
  9. Bactrim Pediatric
  10. Baktar
  11. Chemotrim
  12. Co-Trimoxazole
  13. Comox
  14. Cotrim
  15. Cotrim D.S.
  16. Drylin
  17. Eusaprim
  18. Fectrim
  19. Gantaprim
  20. Gantrim
  21. Idotrim
  22. Imexim
  23. Instalac
  24. Ipral
  25. Kepinol
  26. Laratrim
  27. Lidaprim
  28. Linaris
  29. Methoprim
  30. Microtrim
  31. Monoprim
  32. Monotrim
  33. Monotrimin
  34. Nopil
  35. Oraprim
  36. Priloprim
  37. Primosept
  38. Primsol
  39. Proloprim
  40. Septra
  41. Septra DS
  42. Septra Grape
  43. Septrin
  44. Sigaprim
  45. Sulfamethoprim
  46. Sulfamethoprim-DS
  47. Sulfamethoxazole & Trimethoprim
  48. Sulfatrim
  49. Sulfatrim Pediatric
  50. Sulfatrim-DS
  51. Sulfatrim-SS
  52. Sulfotrim
  53. Sulmeprim
  54. Sulmeprim Pediatric
  55. Sulprim
  56. Sumetrolim
  57. Supracombin
  58. Suprim
  59. Syraprim
  60. Teleprim
  61. Thiocuran
  62. Tiempe
  63. Tmp-Ratiopharm
  64. Trigonyl
  65. Trimanyl
  66. Trimesulf
  67. Trimeth/Sulfa
  68. Trimethioprim
  69. Trimethopriom
  70. Trimetoprim
  71. Trimexazole
  72. Trimogal
  73. Trimopan
  74. Trimpex
  75. Trimpex 200
  76. Triprim
  77. Unitrim
  78. Uretrim
  79. Uro-Septra
  80. Uroplus
  81. Uroplus DS
  82. Uroplus SS
  83. Wellcoprim
Brand Mixtures Not Available
Chemical IUPAC Name 5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine
Chemical Formula C14H18N4O3
Chemical Structure Structure
CAS Registry Number 738-70-5
InChI Identifier InChI=1/C14H18N4O3/c1-19-10-5-8(6-11(20-2)12(10)21-3)4-9-7-17-14(16)18-13(9)15/h5-7H,4H2,1-3H3,(H4,15,16,17,18)/f/h15-16H2
InChI Key IEDVJHCEMCRBQM-CLRGVMNRCM
KEGG Drug D00145 Link Image
KEGG Compound C01965 Link Image
PubChem Compound 5578 Link Image
PubChem Substance 156267 Link Image
ChEBI ID 9731 Link Image
PharmGKB ID PA451788 Link Image
HET ID Not Available
GenBank ID Not Available
Drug ID Number [DIN] 02243116 Link Image
RxList Link http://www.rxlist.com/cgi/generic2/trimeth.htm Link Image
PDRhealth Link Not Available
Wikipedia Link http://en.wikipedia.org/wiki/Trimethoprim Link Image
FDA Label
Material Safety Data Sheet (MSDS)
Synthesis Reference Hook, U.S. Pat. 3,049,544 (1962)
Average Molecular Weight 290.3177
Monoisotopic Molecular Weight 290.1379
State Solid
Melting Point 199 - 203 oC
Experimental Water Solubility 12.1 mg/mL Source: PhysProp
Predicted Water Solubility 6.15e-01 mg/mL Calculated using ALOGPS
Experimental LogP/Hydrophobicity 0.6 Source: PhysProp
Predicted LogP 1.26 Calculated using ALOGPS
Experimental LogS -2.86 [ADME Research, USCD]
Predicted LogS -2.67 Calculated using ALOGPS
Experimental Caco2 Permeability Not Available
pKa/Isoelectric Point Not Available
Mass Spectrum Not Available
MOL File Show Link Image | Download Link Image
SDF File Show Link Image | Download Link Image
PDB File Show Link Image | Download Link Image
2D Structure
3D Structure
Experimental PDB ID Not Available
Isomeric SMILES COC1=CC(CC2=CN=C(N)N=C2N)=CC(OC)=C1OC
Canonical SMILES COC1=CC(CC2=CN=C(N)N=C2N)=CC(OC)=C1OC
Drug Category
  • Anti-Infective Agents, Urinary
  • Anti-Infectives
  • Antimalarials
  • Folic Acid Antagonists
ATC Codes
AHFS Codes
  • 08:36.00
Indication For the treatment of initial episodes of uncomplicated urinary tract infections
Pharmacology Trimethoprim, a synthetic antiinfective agent, is used to treat and prevent urinary tract infections, diarrhea, and, when combined with either sulfamethoxazole or dapsone, Pneumocystis carinii infections.
Mechanism of Action Trimethoprim binds to bacterial dihydrofolate reductase, subsequently interfering with the uptake of p-aminobenzoic acid (PABA) into folic acid. As folic acid is a coenzyme responsible for the transport of one-carbon fragments from one molecule to another, it is an essential component of bacterial development. Sulfonamides inhibit bacterial dihydrofolate synthetase, the enzyme immediately preceding dihydrofolate reductase, and therefore act synergistically with trimethoprim.
Absorption Not Available
Toxicity LD50=4850 (orally in mice)
Protein Binding Approximately 45%
Biotransformation Not Available
Half Life 8-10 hours
Dosage Forms
Form Route
Tablet Oral
Patient Information Not Available
Contraindications Show Link Image
Interactions Show Link Image
Drug Interactions
Drug Interaction
Capecitabine The strong CYP2C9 inhibitor, Capecitabine, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Capecitabine is initiated, discontinued or dose changed.
Delavirdine The strong CYP2C9 inhibitor, Delavirdine, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Delavirdine is initiated, discontinued or dose changed.
Dofetilide Trimethoprim may significantly reduced the clearance of Dofetilide. Trimethoprim is a cation transport inhibitor and may interfere with renal excretion of Dofetilide. Concomitant use is contraindicated.
Floxuridine The strong CYP2C9 inhibitor, Floxuridine, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Floxuridine is initiated, discontinued or dose changed.
Fluconazole The strong CYP2C9 inhibitor, Fluconazole, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Fluconazole is initiated, discontinued or dose changed.
Fluorouracil The strong CYP2C9 inhibitor, Fluorouracil, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Fluorouracil is initiated, discontinued or dose changed.
Flurbiprofen The strong CYP2C9 inhibitor, Flurbiprofen, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Flurbiprofen is initiated, discontinued or dose changed.
Gemfibrozil The strong CYP2C9 inhibitor, Gemfibrozil, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Gemfibrozil is initiated, discontinued or dose changed.
Ibuprofen The strong CYP2C9 inhibitor, Ibuprofen, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Ibuprofen is initiated, discontinued or dose changed.
Indomethacin The strong CYP2C9 inhibitor, Indomethacine, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Indomethacine is initiated, discontinued or dose changed.
Ketoconazole The strong CYP2C9 inhibitor, Ketoconazole, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Ketoconazole is initiated, discontinued or dose changed.
Leucovorin The efficacy of Trimethoprim may be reduced by Leucovorin (folinic acid). The antibiotic, Trimethoprim, acts by blocking bacterial folic acid metabolism. Leucovorin may reduce the efficacy of Trimethoprim by providing an alternate source of folic acid. The therapeutic effect of Trimethoprim should be closely monitored.
Mefenamic acid The strong CYP2C9 inhibitor, Mefenamic acid, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Mefenamic acid is initiated, discontinued or dose changed.
Methotrexate Trimethoprim may increase the adverse/toxic effects of Methotrexate (e.g. bone marrow suppression). Concomitant use should be avoided or closely monitored for Methotrexate toxicity.
Miconazole The strong CYP2C9 inhibitor, Miconazole, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Miconazole is initiated, discontinued or dose changed.
Nicardipine The strong CYP2C9 inhibitor, Nicardipine, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Nicardipine is initiated, discontinued or dose changed.
Piroxicam The strong CYP2C9 inhibitor, Piroxicam, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Piroxicam is initiated, discontinued or dose changed.
Procainamide Trimethoprim may reduce the clearance of Procainamide. Alternative treatments should be considered. If Trimethoprim is initiated or the dose is increased, monitor for increased toxicity of Procainamide (e.g. QTc intervals, EKG, serum drug concentrations). If Trimethoprim is discontinued or the dose decreased, monitor for reduced effects of Procainamide.
Sulfadiazine The strong CYP2C9 inhibitor, Sulfadiazine, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Sulfadiazine is initiated, discontinued or dose changed.
Sulfisoxazole The strong CYP2C9 inhibitor, Sulfisoxazole, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Sulfisoxazole is initiated, discontinued or dose changed.
Tolbutamide The strong CYP2C9 inhibitor, Tolbutamide, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Tolbutamide is initiated, discontinued or dose changed.
sitaxentan The strong CYP2C9 inhibitor, Sitaxsentan, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Sitaxsentan is initiated, discontinued or dose changed.
Food Interactions
  • Do not take calcium, aluminium, magnesium or iron supplements within 2 hours of taking this medication.
  • Take on empty stomach: 1 hour before or 2 hours after meals.
  • Take with a full glass of water.
Pathways Not Available
General References
  1. Johnson JR, Manges AR, O'Bryan TT, Riley LW: A disseminated multidrug-resistant clonal group of uropathogenic Escherichia coli in pyelonephritis. Lancet. 2002 Jun 29;359(9325):2249-51. [PubMed Link Image]
  2. Felmingham D, Reinert RR, Hirakata Y, Rodloff A: Increasing prevalence of antimicrobial resistance among isolates of Streptococcus pneumoniae from the PROTEKT surveillance study, and compatative in vitro activity of the ketolide, telithromycin. J Antimicrob Chemother. 2002 Sep;50 Suppl S1:25-37. [PubMed Link Image]
  3. Bean DC, Livermore DM, Papa I, Hall LM: Resistance among Escherichia coli to sulphonamides and other antimicrobials now little used in man. J Antimicrob Chemother. 2005 Nov;56(5):962-4. Epub 2005 Sep 8. [PubMed Link Image]
  4. Brumfitt W, Hamilton-Miller JM: Limitations of and indications for the use of co-trimoxazole. J Chemother. 1994 Feb;6(1):3-11. [PubMed Link Image]
  5. Brumfitt W, Hamilton-Miller JM: Reassessment of the rationale for the combinations of sulphonamides with diaminopyrimidines. J Chemother. 1993 Dec;5(6):465-9. [PubMed Link Image]
  6. Drugs.com Link Image
  7. Wikipedia Link Image
  8. RxList Link Image
Organisms Affected
  • Gram negative and gram positive bacteria
Phase 1 Metabolizing Enzymes
  1. Cytochrome P450 2C8 (CYP2C8)
Targets
  1. FolC bifunctional protein [Includes: Folylpolyglutamate synthase
  2. Dihydrofolate reductase
  3. Bifunctional dihydrofolate reductase-thymidylate synthase
Phase 1 Metabolizing Enzyme 1 [top]
Enzyme 1 Name Cytochrome P450 2C8 (CYP2C8)
Enzyme 1 Gene Name CYP2C8
Enzyme 1 SwissProt ID P10632 Link Image
Enzyme 1 SNPs SNPJam Report Link Image
Enzyme 1 Protein Sequence >sp|P10632|CP2C8_HUMAN Cytochrome P450 2C8 (EC 1.14.14.1) 
MEPFVVLVLCLSFMLLFSLWRQSCRRRKLPPGPTPLPIIGNMLQIDVKDICKSFTNFSKV
YGPVFTVYFGMNPIVVFHGYEAVKEALIDNGEEFSGRGNSPISQRITKGLGIISSNGKRW
KEIRRFSLTTLRNFGMGKRSIEDRVQEEAHCLVEELRKTKASPCDPTFILGCAPCNVICS
VVFQKRFDYKDQNFLTLMKRFNENFRILNSPWIQVCNNFPLLIDCFPGTHNKVLKNVALT
RSYIREKVKEHQASLDVNNPRDFIDCFLIKMEQEKDNQKSEFNIENLVGTVADLFVAGTE
TTSTTLRYGLLLLLKHPEVTAKVQEEIDHVIGRHRSPCMQDRSHMPYTDAVVHEIQRYSD
LVPTGVPHAVTTDTKFRNYLIPKGTTIMALLTSVLHDDKEFPNPNIFDPGHFLDKNGNFK
KSDYFMPFSAGKRICAGEGLARMELFLFLTTILQNFNLKSVDDLKNLNTTAVTKGIVSLP
PSYQICFIPV
Drug Target 1 [top]
Target 1 ID 137
Target 1 Name FolC bifunctional protein [Includes: Folylpolyglutamate synthase
Target 1 Synonyms
  1. EC 6.3.2.17
  2. FPGS
  3. Folylpoly-gamma-glutamate synthetase
  4. Tetrahydrofolate synthase
Target 1 Gene Name folC
Target 1 Protein Sequence >FolC bifunctional protein [Includes: Folylpolyglutamate synthase 
MIIKRTPQAASPLASWLSYLENLHSKTIDLGLERVSLVAARLGVLKPAPFVFTVAGTNGK
GTTCRTLESILMAAGYKVGVYSSPHLVRYTERVRVQGQELPESAHTASFAEIESARGDIS
LTYFEYGTLSALWLFKQAQLDVVILEVGLGGRLDATNIVDADVAVVTSIALDHTDWLGPD
RESIGREKAGIFRSEKPAIVGEPEMPSTIADVAQEKGALLQRRGVEWNYSVTDHDWAFSD
AHGTLENLPLPLVPQPNAATALAALRASGLEVSENAIRDGIASAILPGRFQIVSESPRVI
FDVAHNPHAAEYLTGRMKALPKNGRVLAVIGMLHDKDIAGTLAWLKSVVDDWYCAPLEGP
RGATAEQLLEHLGNGKSFDSVAQAWDAAMADAKAEDTVLVCGSFHTVAHVMEVIDARRSG
GK
Target 1 Number of Residues 429
Target 1 Molecular Weight 45406
Target 1 Theoretical pI 5.59
Target 1 GO Classification
Function
binding
nucleotide binding
purine nucleotide binding
adenyl nucleotide binding
ATP binding
catalytic activity
ligase activity
ligase activity, forming carbon-nitrogen bonds
acid-amino acid ligase activity
tetrahydrofolylpolyglutamate synthase activity
Process
biosynthesis
physiological process
metabolism
cellular metabolism
aromatic compound metabolism
folic acid and derivative metabolism
folic acid and derivative biosynthesis
Component
Not Available
Target 1 General Function Coenzyme transport and metabolism
Target 1 Specific Function Conversion of folates to polyglutamate derivatives
Target 1 Pathways
Name SMPDB Link KEGG Link
Folate biosynthesis map00790 Link Image
Target 1 Reactions
  • ATP + 7,8-dihydropteroate + L-glutamate = ADP + phosphate + 7,8-dihydropteroylglutamate
Target 1 Pfam Domain Function
Target 1 Signals
  • None
Target 1 Transmembrane Regions
  • None
Target 1 Essentiality Essential
Target 1 GenBank ID Protein 146020 Link Image
Target 1 UniProtKB/Swiss-Prot ID P08192 Link Image
Target 1 UniProtKB/Swiss-Prot Entry Name FOLC_ECOLI Link Image
Target 1 PDB ID 1W7K Link Image
Target 1 PDB File Show
Target 1 3D Structure
Target 1 Cellular Location Not Available
Target 1 Gene Sequence >1269 bp 
ATGATTATCAAACGCACTCCTCAAGCCGCGTCGCCTCTGGCTTCGTGGCTTTCTTATCTG
GAAAACCTGCACAGTAAAACTATCGATCTCGGCCTTGAGCGCGTGAGCCTGGTCGCGGCG
CGTCTTGGCGTCCTGAAACCAGCGCCATTTGTGTTTACCGTTGCGGGTACGAATGGCAAA
GGCACCACCTGCCGTACGCTGGAGTCGATTCTGATGGCGGCAGGGTACAAAGTGGGCGTC
TACAGTTCGCCTCATCTGGTGCGTTATACCGAGCGCGTACGTGTGCAGGGCCAGGAATTG
CCGGAATCGGCCCACACCGCCTCTTTTGCGGAGATTGAATCGGCACGCGGTGATATTTCC
CTGACCTATTTCGAGTACGGTACGCTGTCGGCGTTGTGGCTGTTCAAGCAGGCACAACTT
GACGTGGTGATTCTGGAAGTAGGGCTGGGCGGTCGTCTGGACGCAACCAATATTGTCGAC
GCCGATGTCGCGGTAGTAACCAGTATTGCGCTGGATCATACCGACTGGCTGGGTCCAGAT
CGCGAAAGTATTGGTCGCGAGAAAGCAGGCATCTTCCGCAGCGAAAAACCGGCAATTGTC
GGTGAGCCGGAAATGCCTTCTACCATTGCTGATGTGGCGCAGGAAAAAGGTGCACTGTTA
CAACGTCGGGGCGTTGAGTGGAACTATTCCGTCACCGATCATGACTGGGCGTTTAGCGAT
GCTCACGGCACGCTGGAAAATCTGCCGTTGCCGCTTGTCCCGCAACCGAATGCCGCAACA
GCGCTGGCGGCACTGCGTGCCAGCGGGCTGGAAGTCAGTGAAAATGCCATTCGCGACGGG
ATTGCCAGCGCAATTTTGCCGGGACGTTTCCAGATTGTGAGCGAGTCGCCACGCGTTATT
TTTGATGTCGCGCATAATCCACATGCGGCGGAATATCTCACCGGGCGTATGAAAGCGCTA
CCGAAAAACGGGCGCATGCTGGCGGTTATCGGTATGCTACATGATAAAGATATTGCCGGA
ACTCTGGCCTGGTTGAAAAGCGTGGTTGATGACTGGTATTGTGCGCCACTGGAAGGGCCG
CGCGGTGCCACGGCAGAACAACTGCTTGAGCATTTGGGTAACGGCAAATCATTTGATAGC
GTTGCGCAGGCATGGGATGCCGCAATGGCGGACGCTAAAGCGGAAGACACCGTGCTGGTG
TGTGGTTCTTTCCACACGGTCGCACATGTCATGGAAGTGATTGACGCGAGGAGAAGCGGT
GGCAAGTAA
Target 1 GenBank Gene ID
Target 1 GeneCard ID Not Available
Target 1 GenAtlas ID Not Available
Target 1 HGNC ID Not Available
Target 1 Chromosome Location Not Available
Target 1 Locus Not Available
Target 1 SNPs SNPJam Report Link Image
Target 1 General References
  1. Kimlova LJ, Pyne C, Keshavjee K, Huy J, Beebakhee G, Bognar AL: Mutagenesis of the folC gene encoding folylpolyglutamate synthetase-dihydrofolate synthetase in Escherichia coli. Arch Biochem Biophys. 1991 Jan;284(1):9-16. [PubMed Link Image]
  2. Nonet ML, Marvel CC, Tolan DR: The hisT-purF region of the Escherichia coli K-12 chromosome. Identification of additional genes of the hisT and purF operons. J Biol Chem. 1987 Sep 5;262(25):12209-17. [PubMed Link Image]
  3. Bognar AL, Osborne C, Shane B: Primary structure of the Escherichia coli folC gene and its folylpolyglutamate synthetase-dihydrofolate synthetase product and regulation of expression by an upstream gene. J Biol Chem. 1987 Sep 5;262(25):12337-43. [PubMed Link Image]
  4. Yamamoto Y, Aiba H, Baba T, Hayashi K, Inada T, Isono K, Itoh T, Kimura S, Kitagawa M, Makino K, Miki T, Mitsuhashi N, Mizobuchi K, Mori H, Nakade S, Nakamura Y, Nashimoto H, Oshima T, Oyama S, Saito N, Sampei G, Satoh Y, Sivasundaram S, Tagami H, Horiuchi T, et al.: Construction of a contiguous 874-kb sequence of the Escherichia coli -K12 genome corresponding to 50.0-68.8 min on the linkage map and analysis of its sequence features. DNA Res. 1997 Apr 28;4(2):91-113. [PubMed Link Image]
  5. 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):1453-74. [PubMed Link Image]
Target 1 Drug References
  1. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed Link Image]
  2. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed Link Image]
  3. Gangjee A, Jain HD, Kurup S: Recent advances in classical and non-classical antifolates as antitumor and antiopportunistic infection agents: part I. Anticancer Agents Med Chem. 2007 Sep;7(5):524-42. [PubMed Link Image]
Drug Target 2 [top]
Target 2 ID 365
Target 2 Name Dihydrofolate reductase
Target 2 Synonyms
  1. EC 1.5.1.3
Target 2 Gene Name DHFR
Target 2 Protein Sequence >Dihydrofolate reductase 
VGSLNCIVAVSQNMGIGKNGDLPWPPLRNEFRYFQRMTTTSSVEGKQNLVIMGKKTWFSI
PEKNRPLKGRINLVLSRELKEPPQGAHFLSRSLDDALKLTEQPELANKVDMVWIVGGSSV
YKEAMNHPGHLKLFVTRIMQDFESDTFFPEIDLEKYKLLPEYPGVLSDVQEEKGIKYKFE
VYEKND
Target 2 Number of Residues 189
Target 2 Molecular Weight 21322
Target 2 Theoretical pI 7.60
Target 2 GO Classification
Function
binding
cofactor binding
coenzyme binding
NADP binding
catalytic activity
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
dihydrofolate reductase activity
Process
nucleobase, nucleoside, nucleotide and nucleic acid metabolism
nucleotide metabolism
nucleotide biosynthesis
physiological process
metabolism
cellular metabolism
amino acid and derivative metabolism
amino acid metabolism
serine family amino acid metabolism
glycine metabolism
glycine biosynthesis
Component
Not Available
Target 2 General Function Coenzyme transport and metabolism
Target 2 Specific Function Not Available
Target 2 Pathways
Name SMPDB Link KEGG Link
Folate biosynthesis map00790 Link Image
One carbon pool by folate SMP00053 Link Image map00670 Link Image
Target 2 Reactions
  • 5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
Target 2 Pfam Domain Function
Target 2 Signals
  • None
Target 2 Transmembrane Regions
  • None
Target 2 Essentiality Non-Essential
Target 2 GenBank ID Protein 182724 Link Image
Target 2 UniProtKB/Swiss-Prot ID P00374 Link Image
Target 2 UniProtKB/Swiss-Prot Entry Name DYR_HUMAN Link Image
Target 2 PDB ID 1MVT Link Image
Target 2 PDB File Show
Target 2 3D Structure
Target 2 Cellular Location Not Available
Target 2 Gene Sequence >564 bp 
ATGGTTGGTTCGCTAAACTGCATCGTCGCTGTGTCCCAGAACATGGGCATCGGCAAGAAC
GGGGACCTGCCCTGGCCACCGCTCAGGAATGAATTCAGATATTTCCAGAGAATGACCACA
ACCTCTTCAGTAGAAGGTAAACAGAATCTGGTGATTATGGGTAAGAAGACCTGGTTCTCC
ATTCCTGAGAAGAATCGACCTTTAAAGGGTAGAATTAATTTAGTTCTCAGCAGAGAACTC
AAGGAACCTCCACAAGGAGCTCATTTTCTTTCCAGAAGTCTAGATGATGCCTTAAAACTT
ACTGAACAACCAGAATTAGCAAATAAAGTAGACATGGTCTGGATAGTTGGTGGCAGTTCT
GTTTATAAGGAAGCCATGAATCACCCAGGCCATCTTAAACTATTTGTGACAAGGATCATG
CAAGACTTTGAAAGTGACACGTTTTTTCCAGAAATTGATTTGGAGAAATATAAACTTCTG
CCAGAATACCCAGGTGTTCTCTCTGATGTCCAGGAGGAGAAAGGCATTAAGTACAAATTT
GAAGTATATGAGAAGAATGATTAA
Target 2 GenBank Gene ID
Target 2 GeneCard ID DHFR Link Image
Target 2 GenAtlas ID DHFR Link Image
Target 2 HGNC ID HGNC:2861 Link Image
Target 2 Chromosome Location 5
Target 2 Locus 5q11.2-q13.2
Target 2 SNPs SNPJam Report Link Image
Target 2 General References
  1. 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 Link Image]
  2. 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 Link Image]
  3. 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 Link Image]
  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 Link Image]
  5. 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 Link Image]
  6. 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 Link Image]
  7. 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 Link Image]
Target 2 Drug References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed Link Image]
  2. Laskowska E, Kuczynska-Wisnik D, Bak M, Lipinska B: Trimethoprim induces heat shock proteins and protein aggregation in E. coli cells. Curr Microbiol. 2003 Oct;47(4):286-9. [PubMed Link Image]
  3. Floris-Moore MA, Amodio-Groton MI, Catalano MT: Adverse reactions to trimethoprim/sulfamethoxazole in AIDS. Ann Pharmacother. 2003 Dec;37(12):1810-3. [PubMed Link Image]
  4. Rosowsky A, Fu H, Chan DC, Queener SF: Synthesis of 2,4-diamino-6-[2'-O-(omega-carboxyalkyl)oxydibenz[b,f]azepin-5-yl]methylpt eridines as potent and selective inhibitors of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductase. J Med Chem. 2004 May 6;47(10):2475-85. [PubMed Link Image]
  5. Nahimana A, Rabodonirina M, Bille J, Francioli P, Hauser PM: Mutations of Pneumocystis jirovecii dihydrofolate reductase associated with failure of prophylaxis. Antimicrob Agents Chemother. 2004 Nov;48(11):4301-5. [PubMed Link Image]
  6. Barrow EW, Bourne PC, Barrow WW: Functional cloning of Bacillus anthracis dihydrofolate reductase and confirmation of natural resistance to trimethoprim. Antimicrob Agents Chemother. 2004 Dec;48(12):4643-9. [PubMed Link Image]
Drug Target 3 [top]
Target 3 ID 457
Target 3 Name Bifunctional dihydrofolate reductase-thymidylate synthase
Target 3 Synonyms
  1. DHFR-TS
Target 3 Gene Name Not Available
Target 3 Protein Sequence >Bifunctional dihydrofolate reductase-thymidylate synthase 
MEDLSETFDIYAICACCKVLNDDEKVRCFNNKTFKGIGNAGVLPWKCNLIDMKYFSSVTS
YINENNYIRLKWKRDKYMEKHNLKNNVELNTNIISSTNNLQNIVVMGKKSWESIPKKFKP
LQNRINIILSRTLKKEDIVNENNNENNNVIIIKSVDDLFPILKCTKYYKCFIIGGSSVYK
EFLDRNLIKKIYFTRINNSYNCDVLFPEINENLFKITSISDVYYSNNTTLDFIIYSKTKE
INPNEEVPNNTFLGVCDEQNKAFDDEDDYTYFSFNKNKENIKKNSEHAHNFKIYNSIKYK
NHPEYQYLNIIYDIIMHGNKQDDRTGVGVLSKFGYMMKFNLNEYFPLLTTKKLFIRGIIE
ELLWFIRGETNGNTLLEKNVRIWEANGTREFLDNRKLFHREVNDLGPIYGFQWRHFGAEY
TDMHDNYKDKGVDQLKNIINLIKNDPTCRRIILCAWNVKNLDQMALPPCHILCQFYVFDG
KLSCIMYQRSCDLGLGVPFNIASYSIFTYMIAQVCNLQAAEFIHVLGNAHVYNNHIESLK
IQLNRTPYPFPTLKLNPDIKNIEDFTISDFTVQNYVHHDKINMDMAA
Target 3 Number of Residues 596
Target 3 Molecular Weight 68933
Target 3 Theoretical pI 7.89
Target 3 GO Classification
Function
transferase activity
transferase activity, transferring one-carbon groups
methyltransferase activity
5,10-methylenetetrahydrofolate-dependent methyltransferase activity
thymidylate synthase activity
catalytic activity
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
dihydrofolate reductase activity
Process
pyrimidine nucleotide metabolism
pyrimidine nucleotide biosynthesis
pyrimidine nucleoside monophosphate biosynthesis
pyrimidine deoxyribonucleoside monophosphate biosynthesis
dTMP biosynthesis
nucleobase, nucleoside, nucleotide and nucleic acid metabolism
nucleotide metabolism
nucleotide biosynthesis
amino acid and derivative metabolism
amino acid metabolism
serine family amino acid metabolism
glycine metabolism
glycine biosynthesis
physiological process
metabolism
cellular metabolism
one-carbon compound metabolism
Component
Not Available
Target 3 General Function Nucleotide transport and metabolism
Target 3 Specific Function Not Available
Target 3 Pathways
Name SMPDB Link KEGG Link
One carbon pool by folate SMP00053 Link Image map00670 Link Image
Pyrimidine metabolism SMP00046 Link Image map00240 Link Image
Target 3 Reactions
  • 5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
Target 3 Pfam Domain Function
Target 3 Signals
  • None
Target 3 Transmembrane Regions
  • None
Target 3 Essentiality Essential
Target 3 GenBank ID Protein 555825 Link Image
Target 3 UniProtKB/Swiss-Prot ID Q27713 Link Image
Target 3 UniProtKB/Swiss-Prot Entry Name DRTS_PLABA Link Image
Target 3 PDB ID 1J3K Link Image
Target 3 PDB File Show
Target 3 3D Structure
Target 3 Cellular Location Not Available
Target 3 Gene Sequence >1764 bp 
ATGGAAGACTTATCTGAAACATTCGATATATATGCAATATGTGCATGTTGTAAAGTTCTG
AACGATGATGAAAAGGTTAGATGCTTTAATAATAAAACGTTTAAGGGAATTGGAAATGCG
GGGGTGTTACCTTGGAAATGTAATTTAATCGATATGAAATATTTTAGTTCTGTAACATCA
TATATAAATGAAAATAATTATATAAGATTGAAATGGAAAAGAGATAAATATATGGAAAAA
CATAATTTAAAAAATAATGTAGAACTAAATACTAATATAATTTCTTCAACTAATAATTTA
CAAAATATTGTAGTAATGGGAAAAAAAAGTTGGGAAAGTATTCCCAAAAAATTTAAACCT
TTACAAAATCGAATAAACATTATTTTGTCTAGAACTTTGAAAAAAGAAGATATTGTAAAC
GAAAATAATAATGAAAATAATAATGTTATTATAATTAAAAGTGTAGATGATTTATTTCCT
ATTTTAAAATGCACAAAATATTACAAATGTTTTATTATAGGGGGTTCGTCTGTTTATAAA
GAATTTTTAGATCGTAATTTAATAAAAAAAATATATTTTACAAGAATAAATAATTCTTAT
AATTGTGATGTTTTATTCCCAGAAATAAACGAAAATTTGTTTAAAATAACTTCAATAAGT
GATGTATATTATAGTAACAACACAACTTTAGATTTTATAATTTATAGTAAGACAAAAGAA
ATAAATCCAAATGAGGAAGTACCTAATAATACATTTTTAGGTGTATGTGATGAACAAAAT
AAAGCCTTTGATGATGAAGACGATTATACATATTTCAGTTTCAATAAAAATAAAGAAAAT
ATTAAAAAAAATTCTGAACATGCTCATAATTTTAAAATATATAATAGCATAAAATATAAA
AATCATCCTGAATATCAATATTTAAATATTATATATGATATAATAATGCATGGAAATAAA
CAAGATGATAGAACAGGTGTTGGTGTGTTAAGTAAATTTGGATATATGATGAAATTTAAT
TTAAATGAATATTTTCCATTATTAACAACAAAAAAATTATTTATAAGAGGTATTATCGAA
GAATTATTGTGGTTTATAAGAGGGGAAACAAATGGAAATACTTTGTTAGAAAAAAACGTA
AGAATATGGGAAGCTAATGGAACAAGGGAATTTTTAGATAATAGAAAATTATTTCATAGA
GAAGTTAATGATCTCGGTCCAATTTATGGATTTCAATGGAGGCATTTTGGTGCTGAATAT
ACAGATATGCATGATAATTATAAAGACAAAGGAGTTGATCAATTAAAAAATATTATAAAT
TTAATTAAAAATGATCCTACTTGTAGACGAATTATTTTGTGTGCATGGAATGTAAAAAAT
TTAGATCAAATGGCATTACCTCCTTGTCATATTTTATGTCAATTTTATGTTTTTGACGGA
AAATTATCATGTATTATGTATCAAAGATCTTGTGATTTAGGGCTTGGGGTTCCATTCAAT
ATTGCTTCCTATTCTATATTTACATATATGATAGCACAAGTATGTAACTTACAGGCAGCT
GAATTTATACATGTATTGGGTAATGCTCATGTTTATAATAATCATATTGAAAGCTTAAAG
ATTCAGTTAAATAGAACTCCTTACCCTTTTCCTACTCTTAAATTAAATCCTGACATTAAA
AATATCGAGGATTTTACAATTTCTGATTTTACTGTTCAAAATTATGTTCATCACGATAAA
ATAAATATGGATATGGCAGCTTAA
Target 3 GenBank Gene ID
Target 3 GeneCard ID Not Available
Target 3 GenAtlas ID Not Available
Target 3 HGNC ID Not Available
Target 3 Chromosome Location Not Available
Target 3 Locus Not Available
Target 3 SNPs Not Available
Target 3 General References
  1. van Dijk MR, McConkey GA, Vinkenoog R, Waters AP, Janse CJ: Mechanisms of pyrimethamine resistance in two different strains of Plasmodium berghei. Mol Biochem Parasitol. 1994 Nov;68(1):167-71. [PubMed Link Image]
  2. Cheng Q, Saul A: The dihydrofolate reductase domain of rodent malarias: point mutations and pyrimethamine resistance. Mol Biochem Parasitol. 1994 Jun;65(2):361-3. [PubMed Link Image]
Target 3 Drug References
  1. Rosowsky A, Papoulis AT, Forsch RA, Queener SF: Synthesis and antiparasitic and antitumor activity of 2, 4-diamino-6-(arylmethyl)-5,6,7,8-tetrahydroquinazoline analogues of piritrexim. J Med Chem. 1999 Mar 25;42(6):1007-17. [PubMed Link Image]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed Link Image]
  3. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed Link Image]
  4. Gamarro F, Yu PL, Zhao J, Edman U, Greene PJ, Santi D: Trypanosoma brucei dihydrofolate reductase-thymidylate synthase: gene isolation and expression and characterization of the enzyme. Mol Biochem Parasitol. 1995 Jun;72(1-2):11-22. [PubMed Link Image]
  5. Reche P, Arrebola R, Santi DV, Gonzalez-Pacanowska D, Ruiz-Perez LM: Expression and characterization of the Trypanosoma cruzi dihydrofolate reductase domain. Mol Biochem Parasitol. 1996 Feb-Mar;76(1-2):175-85. [PubMed Link Image]

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.