Pteridine reductase (PTR1) is a potential target for drug development against parasitic Trypanosoma and Leishmania species, protozoa that are responsible for a range of serious diseases found in tropical and subtropical parts of the world. As part of a structure-based approach to inhibitor development, specifically targeting Leishmania species, well ordered crystals of L. donovani PTR1 were sou...

Ciliapterin, a new unconjugated pteridine, has been isolated from the ciliated protozoan, Tefrahymena pyriformis. It has been determined by alkaline permanganate oxidation to be a 2-amino-4-hydroxy-6-substituted pteridine and by acid hydrolytic treatment to possess no labile bonds (such as glycosidic or phosphoester). The substitution at position 6 is dihydroxypropyl, as shown by the identifica...

In the title compound, C(10)H(10)N(4)O(4)·0.5H(2)O, the two rings of the pteridine system are nearly coplanar [dihedral angle = 4.25 (9)°]. The atoms of the carboxyl group are also coplanar with the pteridine unit [r.m.s. deviation from the mean plane of the pteridine skeleton = 0.092 (2) Å]. In the crystal, the presence of the water molecule of crystallization (O atom site symmetry 2) leads to...

We have tested the hypothesis that 2,4-diamino-6-hydroxymethyl-pteridine (DAP), 2,4-diaminopteroic acid (DAPA), and 2,4 diamino-N10-methyl-pteroic acid (DAMPA) could be converted into aminopterin (from DAP and DAPA) and methotrexate (from DAMPA), both of which are potent inhibitors of dihydrofolate reductase, a proven drug target for Plasmodium falciparum. DAP, DAPA, and DAMPA inhibited parasit...

The newborn screening for phenylketonuria (PKU) has become a common practice in many countries. The success of this type of mass screening is the result of the reliability of the Guthrie test in the identification of high blood phenylalanine levels. Recently, new syndromes other than PKU have been recognized that give high blood phenylalanine levels. These syndromes are referred to as “atypical...

In the protozoan parasite Leishmania, drug resistance can be a complex phenomenon. Several metabolic pathways and membrane transporters are implicated in the resistance phenotype. To monitor the expression of these genes, we generated custom DNA microarrays with PCR fragments corresponding to 44 genes involved with drug resistance. Transcript profiling of arsenite and antimony resistant mutants...

The phenotypes of single- (SKO) and double-knockout (DKO) lines of dihydrofolate reductase-thymidylate synthase (DHFR-TS) of bloodstream Trypanosoma brucei were evaluated in vitro and in vivo. Growth of SKO in vitro is identical to wild-type (WT) cells, whereas DKO has an absolute requirement for thymidine. Removal of thymidine from the medium triggers growth arrest in S phase, associated with ...

R67 dihydrofolate reductase (DHFR) is a novel enzyme that confers resistance to the antibiotic trimethoprim. The crystal structure of R67 DHFR displays a toroidal structure with a central active-site pore. This homotetrameric protein exhibits 222 symmetry, with only a few residues from each chain contributing to the active site, so related sites must be used to bind both substrate (dihydrofolat...