Trypanosoma cruzi Pteridine Reductase

Protozoan parasite Trypanosoma cruzi is the causative agent for Chagas’ disease that affects 16-18 million people including 300,000 US immigrants and causes 50,000 deaths annually. Available drugs are ineffective against the intracellular stage of the parasite and show toxic side effects. There is an urgent need for new drugs.

Pteridines (folates and pterins) are essential for the trypanosomes and the parasite must salvage them from the host. Salvaged pteridines undergo two step reductions, first to dihydro- and then to tetrahydropteridines. Pteridine reductase 1 (PTR1) is the only enzyme capable of reducing biopterin and is therefore, an essential enzyme in the parasite. Thus PTR1 offers a novel chemotherapeutic target in T. cruzi. Additionally, PTR1 confers resistance to antifolates, inhibitors of the major folate-reducing enzyme dihydrofolatereductase (DHFR). A potent inhibitor of PTR1 would therefore enhance the success of antifolate therapy as well.

Crystal structures of T. cruzi pteridine reductase in complex with dihydrofolate and cofactor, and methotrexate and cofactor revealed the mechanism of biochemical action of the protein and provide the framework for structure-based drug design.

Currently our laboratory is studying the DHFR and PTR enzymes of T. cruzi for structure-based design of specific inhibitors of these enzymes. For this purpose, we have determined the crystal structure of substrate and inhibitor complexes of T. cruzi PTR at high resolution.