The crystal structure of Leishmania major N(5),N(10)-methylenetetrahydrofolate dehydrogenase/cyclohydrolase and assessment of a potential drug target.
Bottom Line: Here, we present the 2.7 Å resolution crystal structure of the bifunctional apo-DHCH from L. major, which is a potential drug target.Sequence alignments show that the cytosolic enzymes found in trypanosomatids share a high level of identity of approximately 60%.Additionally, residues that interact and participate in catalysis in the human homologue are conserved amongst trypanosomatid sequences and this may complicate attempts to derive potent, parasite specific DHCH inhibitors.
Affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.Show MeSH
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Mentions: Folate and derivatives are essential cofactors in the biosynthesis of thymidine, purines, glycine, methionine, initiator fMet-tRNA and also in the metabolism of histidine and serine (Fig. 1a) . It is not surprising that enzymes involved in folate-dependent pathways, e.g. dihydrofolate reductase (DHFR), are important antimicrobial and anticancer drug targets [7,8]. Trypanosomatids are auxotrophic for folates and pterins  and reliant on uptake and salvage mechanisms to maintain the required level of these important compounds. Inhibition of DHFR should, in principle, provide a route to treat trypanosomatid infections. However, the presence of a pteridine reductase (PTR1) able to reduce dihydrofolate (DHF) to tetrahydrofolate (THF), i.e. catalyze the same reaction as DHFR, helps to compromise the use of such inhibitors . Promising PTR1 inhibitors have been identified [11–15] in support of a strategy to develop a combination treatment with known DHFR inhibitors to cut-off the supply of reduced pterins/folates. The use of drug combinations might also serve to alleviate the development of drug resistance [13,15]. Here, we turn our attention onto enzymes that maintain the required levels of N10-formyltetrahydrofolate, a key intermediate supporting protein synthesis.
Affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.