Abstract
Babesiosis is a tick-borne disease caused by eukaryotic Babesia parasites which are morphologically similar to Plasmodium falciparum, the causative agent of malaria in humans. Like Plasmodium, different species of Babesia are tuned to infect different mammalian hosts, including rats, dogs, horses and cattle. Most species of Plasmodium and Babesia possess an essential bifunctional enzyme for nucleotide synthesis and folate metabolism: dihydrofolate reductase-thymidylate synthase. Although thymidylate synthase is highly conserved across organisms, the bifunctional form of this enzyme is relatively uncommon in nature. The structural characterization of dihydrofolate reductase-thymidylate synthase in Babesia bovis, the causative agent of babesiosis in livestock cattle, is reported here. The apo state is compared with structures that contain dUMP, NADP and two different antifolate inhibitors: pemetrexed and raltitrexed. The complexes reveal modes of binding similar to that seen in drug-resistant malaria strains and point to the utility of applying structural studies with proven cancer chemotherapies towards infectious disease research.
Highlights
Babesiosis is an infectious disease affecting humans, cattle and other mammals caused by protozoal Babesia piroplasms
We describe the structural features of dihydrofolate reductase-thymidylate synthase from B. bovis (BbDHFR-TS), the causative agent of babesiosis in cattle
This 511-residue, 58.2 kDa bifunctional enzyme consists of a dihydrofolate reductase (DHFR) subunit at the N-terminus and a thymidylate synthase (TS) subunit at the C-terminus connected by a linker (Fig. 2)
Summary
Babesiosis is an infectious disease affecting humans, cattle and other mammals caused by protozoal Babesia piroplasms. Like Plasmodium falciparum, the causative agent of malaria in humans, Babesia species generate asexual merozoites through binary fission of red blood cells (RBCs) after infection. Babesia represents an emerging threat to commercial livestock and an increasing cause for concern in humans, with recent reports of resistance in B. microti to azithromycin– atovaquone drug therapy (Wormser et al, 2010). For these reasons, babesiosis and other tick-borne illnesses have become a priority with the National Institute for Allergy and Infectious Disease (NIAID), prompting research into the development of vaccines and new chemotherapeutics for treatment. Mechanisms of resistance which have already appeared in malaria owing to various environmental pressures may
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