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Literature summary extracted from

  • Sienkiewicz, N.; Jaros?awski, S.; Wyllie, S.; Fairlamb, A.H.
    Chemical and genetic validation of dihydrofolate reductase-thymidylate synthase as a drug target in African trypanosomes (2008), Mol. Microbiol., 69, 520-533.
    View publication on PubMedView publication on EuropePMC

Application

EC Number Application Comment Organism
1.5.1.3 medicine Double knock-out lines of bifunctional dihydrofolate reductase-thymidylate synthase are unable to infect mice, whereas the virulence of single knock-out lines is similar to wild-type Trypanosoma brucei

Protein Variants

EC Number Protein Variants Comment Organism
1.5.1.3 additional information growth of a single knock-out line of bifunctional dihydrofolate reductase-thymidylate synthase is identical to wild-type cells. Double knock-out cells have an absolute requirement for thymidine. Removal of thymidine from the medium triggers growth arrest in S phase, associated with gross morphological changes, followed by cell death after 60 h. Double knock-out lines are unable to infect mice, whereas the virulence of single knock-out lines is similar to wild-type. Double knock-out trypanosomes show reduced sensitivity to trimetrexate or raltitrexed. Pteridine reductase is not able to compensate for loss of dihydrofolate activity Trypanosoma brucei

Inhibitors

EC Number Inhibitors Comment Organism Structure
1.5.1.3 (2S)-2-[(5-{methyl[(2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl]amino}thiophen-2-yl)formamido]pentanedioic acid in low-folate medium, up to 300-fold increase of inhibitory activity Trypanosoma brucei
1.5.1.3 methotrexate in low-folate medium, up to 300-fold increase of inhibitory activity Trypanosoma brucei
1.5.1.3 pyrimethamine no increase in inhibitory activity in low-folate medium Trypanosoma brucei
1.5.1.3 trimetrexate no increase in inhibitory activity in low-folate medium Trypanosoma brucei
2.1.1.45 2'-deoxy-5-fluorouridine 5'-phosphate
-
 Trypanosoma brucei
2.1.1.45 pemetrexed
-
 Trypanosoma brucei
2.1.1.45 raltitrexed
-
 Trypanosoma brucei

Organism

EC Number Organism UniProt Comment Textmining
1.5.1.3 Trypanosoma brucei
-
 bifunctional dihydrofolate reductase-thymidylate synthase
-
2.1.1.45 Trypanosoma brucei
-
-
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2.1.1.45 5,10-methylenetetrahydrofolate + dUMP
-
 Trypanosoma brucei dihydrofolate + dTMP
-
 ?

Synonyms

EC Number Synonyms Comment Organism
2.1.1.45 DHFR–TS
-
 Trypanosoma brucei
2.1.1.45 dihydrofolate reductase-thymidylate synthase bifunctional enzyme Trypanosoma brucei

Cofactor

EC Number Cofactor Comment Organism Structure
2.1.1.45 N5,N10-methylenetetrahydrofolate
-
 Trypanosoma brucei

General Information

EC Number General Information Comment Organism
2.1.1.45 malfunction growth of single-knockout lines of dihydrofolate reductase-thymidylate synthase in vitro are identical to wild type cells, whereas double-knockout lines of dihydrofolate reductase-thymidylate synthase have an absolute requirement for thymidine Trypanosoma brucei
2.1.1.45 physiological function DHFR–TS is essential for parasite survival Trypanosoma brucei