DT-Web

DB01099 - Flucytosine


Identification
Name Flucytosine
Accession Number DB01099 (APRD00299)
Type small molecule
Description A fluorinated cytosine analog that is used as an antifungal agent. [PubChem]
Structure
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 129.0925
Groups approved
Monoisotopic Weight 129.03383997
Pharmacology
Indication For the treatment (in combination with amphotericin B) of serious infections caused by susceptible strains of Candida (septicemia, endocarditis and urinary system infections) and/or Cryptococcus (meningitis and pulmonary infections).
Mechanism of action Although the exact mode of action is unknown, it has been proposed that flucytosine acts directly on fungal organisms by competitive inhibition of purine and pyrimidine uptake and indirectly by intracellular metabolism to 5-fluorouracil. Flucytosine enters the fungal cell via cytosine permease; thus, flucytosine is metabolized to 5-fluorouracil within fungal organisms. The 5-fluorouracil is extensively incorporated into fungal RNA and inhibits synthesis of both DNA and RNA. The result is unbalanced growth and death of the fungal organism. It also appears to be an inhibitor of fungal thymidylate synthase.
Absorption Rapidly and virtually completely absorbed following oral administration. Bioavailability 78% to 89%.
Protein binding 28-31%
Biotransformation Flucytosine is deaminated, possibly by gut bacteria or by the fungal targets, to 5-fluorouracil, the active metabolite.
Route of elimination Flucytosine is excreted via the kidneys by means of glomerular filtration without significant tubular reabsorption. A small portion of the dose is excreted in the feces.
Toxicity Oral, rat: LD50 = >15 gm/kg.
Affected organisms
  • Yeast and other fungi
Interactions
Drug Interactions Not Available
Food Interactions Not Available

Targets


DNA
Name DNA
Gene Name Not Available
Pharmacological action yes
Actions cross-linking/alkylation
References
  • Osterman DG, DePillis GD, Wu JC, Matsuda A, Santi DV: 5-Fluorocytosine in DNA is a mechanism-based inhibitor of HhaI methylase. Biochemistry. 1988 Jul 12;27(14):5204-10. - Pubmed
  • Waldorf AR, Polak A: Mechanisms of action of 5-fluorocytosine. Antimicrob Agents Chemother. 1983 Jan;23(1):79-85. - Pubmed
  • Wyszynski MW, Gabbara S, Kubareva EA, Romanova EA, Oretskaya TS, Gromova ES, Shabarova ZA, Bhagwat AS: The cysteine conserved among DNA cytosine methylases is required for methyl transfer, but not for specific DNA binding. Nucleic Acids Res. 1993 Jan 25;21(2):295-301. - Pubmed
DTHybrid score Not Available
DNA (cytosine-5)-methyltransferase 1
Name DNA (cytosine-5)-methyltransferase 1
Gene Name DNMT1
Pharmacological action unknown
Actions other
References
  • Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. - Pubmed
  • 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
  • Shieh FK, Reich NO: AdoMet-dependent Methyl-transfer: Glu(119) Is Essential for DNA C5-Cytosine Methyltransferase M.HhaI. J Mol Biol. 2007 Aug 19;. - Pubmed
  • Wyszynski MW, Gabbara S, Kubareva EA, Romanova EA, Oretskaya TS, Gromova ES, Shabarova ZA, Bhagwat AS: The cysteine conserved among DNA cytosine methylases is required for methyl transfer, but not for specific DNA binding. Nucleic Acids Res. 1993 Jan 25;21(2):295-301. - Pubmed
DTHybrid score 1.1316
Thymidylate synthase
Name Thymidylate synthase
Gene Name TMP1
Pharmacological action unknown
Actions inhibitor
References
  • Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. - Pubmed
  • 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
  • Fox BA, Belperron AA, Bzik DJ: Stable transformation of Toxoplasma gondii based on a pyrimethamine resistant trifunctional dihydrofolate reductase-cytosine deaminase-thymidylate synthase gene that confers sensitivity to 5-fluorocytosine. Mol Biochem Parasitol. 1999 Jan 5;98(1):93-103. - Pubmed
  • Rehemtulla A, Hamstra DA, Kievit E, Davis MA, Ng EY, Dornfeld K, Lawrence TS: Extracellular expression of cytosine deaminase results in increased 5-FU production for enhanced enzyme/prodrug therapy. Anticancer Res. 2004 May-Jun;24(3a):1393-9. - Pubmed
  • Wang ZH, Samuels S, Gama Sosa MA, Kolodny EH: 5-Fluorocytosine-mediated apoptosis and DNA damage in glioma cells engineered to express cytosine deaminase and their enhancement with interferon. J Neurooncol. 1998 Feb;36(3):219-29. - Pubmed
DTHybrid score 1.2102

Predictions


Id Partner name Gene Name Score
359 Thymidylate synthase TYMS 1.2102
2626 Thymidylate synthase thyA 1.2102
2729 Thymidylate synthase thyA 1.2102
5352 Thymidylate synthase THYA 1.2102
3611 Cytidine deaminase cdd 0.1528
3707 Cytidine deaminase cdd 0.1528
4211 Cytidine deaminase CDA 0.1528
4773 Deoxycytidine kinase DCK 0.129
6147 Solute carrier family 22 member 3 SLC22A3 0.0201
833 Organic cation/carnitine transporter 1 SLC22A4 0.02
220 Sodium channel protein type 5 subunit alpha SCN5A 0.0199
6144 Solute carrier family 22 member 2 SLC22A2 0.0177
118 Organic cation/carnitine transporter 2 SLC22A5 0.0175
3923 Cholinesterase BCHE 0.0171
6145 Solute carrier family 22 member 1 SLC22A1 0.017
4119 Cytochrome P450 2D6 CYP2D6 0.0124
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