Protozoan parasites of the trypanosomatid genus Leishmania are pteridine auxotrophs, and have evolved an elaborate and versatile pteridine salvage network capable of accumulating and reducing pteridines. This includes biopterin and folate transporters (BT1 and FT1), pteridine reductase (PTR1), and dihydrofolate reductase-thymidylate synthase (DHFR-TS). Notably, PTR1 is a novel alternative pteri...

Leishmania and other trypanosomatid protozoa require reduced pteridines (pterins and folates) for growth, suggesting that inhibition of these pathways could be targeted for effective chemotherapy. This goal has not yet been realized, indicating that pteridine metabolism may be unusual in this lower eukaryote. We have investigated this possibility using both wild type and laboratory-selected ant...

Trypanosomatid protozoans depend upon exogenous sources of pteridines (pterins or folates) for growth. A broad spectrum pteridine reductase (PTR1) was recently identified in Leishmania major, whose sequence places it in the short chain alcohol dehydrogenase protein family although its enzymatic activities resemble dihydrofolate reductases. The properties of PTR1 suggested a role in essential pt...

drosylation reaction and may account for the observed inhibition when crude sepia extracts are tested at high concentrations. The K, for sepia pteridine in the hydrosylation reaction is 3 to 4 X 10e6 M. On a molar basis it is approximately 25 times more active than tetrahydrofolate. The maximal rate of tyrosine formation at saturating levels of cofactor is about the same for sepia pteridinc and...

The enzyme pteridine reductase 1 (PTR1) is a potential target for new compounds to treat human African trypanosomiasis. A virtual screening campaign for fragments inhibiting PTR1 was carried out. Two novel chemical series were identified containing aminobenzothiazole and aminobenzimidazole scaffolds, respectively. One of the hits (2-amino-6-chloro-benzimidazole) was subjected to crystal structu...

A critical step in the infectious cycle of Leishmania is the differentiation of parasites within the sand fly vector to the highly infective metacyclic promastigote stage. Here, we establish tetrahydrobiopterin (H4B) levels as an important factor controlling the extent of metacyclogenesis. H4B levels decline substantially during normal development, and genetic or nutritional manipulations showe...

background : leishmaniasis is an endemic disease in 88 countries. reports on leishmania drug resistance are growing in number. the mechanism of unresponsiveness against glucantime in iranian cutaneous leishmaniasis has not yet been characterized. to begin the first step in finding an anti- leishmania chemotherapy, we prepared recombinant l. major ptr1 enzyme and characterized its activity by en...

background: pteridine metabolic pathway is unusual features of leishmania , which is necessary for the growth of parasite. leishmania has evolved a complex and versatile pteridine salvage network which has the ability of scavenging a wide area of the conjugated and unconjugated pteridines espe-cially folate and biopterin. in this study, we focus on the inhibition of ptr1 gene expression. method...

Background: Currently, there are no effective vaccines against leishmaniasis, and treatment using pentavalent antimonial drugs is occasionally effective and often toxic for patients. The PTR1 enzyme, which causes antifolate drug resistance in Leishmania parasites encoded by gene pteridine reductase 1 (ptr1). Since Leishmania lacks pteridine and folate metabolism, it cannot synthesize the pterid...

Keywords: DHFR-inhibiting activity, pteridine, furo[3,2-g]pteridine, molecular docking, QSAR-analysis