Literature summary for 1.5.1.3 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.

Search for more literature for 1.5.1.3

Application

Application	Comment	Organism
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

Protein Variants	Comment	Organism
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

Inhibitors	Comment	Organism	Structure
(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
methotrexate	in low-folate medium, up to 300-fold increase of inhibitory activity	Trypanosoma brucei
pyrimethamine	no increase in inhibitory activity in low-folate medium	Trypanosoma brucei
trimetrexate	no increase in inhibitory activity in low-folate medium	Trypanosoma brucei

Organism

Organism	UniProt	Comment	Textmining
Trypanosoma brucei	-	bifunctional dihydrofolate reductase-thymidylate synthase	-

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Release 2023.1 (January 2023)