Trypanosoma brucei pteridine reductase 1 (TbPTR1)

Trypanosoma brucei pteridine reductase 1 (TbPTR1) is a key enzyme in the folate and pteridine metabolism of the protozoan parasite responsible for Human African Trypanosomiasis, also known as Sleeping Sickness [1]. While humans rely exclusively on dihydrofolate reductase (DHFR) to maintain pools of reduced folates, Trypanosoma brucei possesses both DHFR and PTR1, the latter of which can reduce both folates and biopterins [2]. This dual activity allows PTR1 to act as a metabolic bypass, rendering traditional DHFR inhibitors like methotrexate less effective against the parasite unless PTR1 is also inhibited [3]. Consequently, TbPTR1 is considered a high-priority therapeutic target for the development of new anti-trypanosomal drugs to overcome resistance to standard antifolates [4]. Inhibiting TbPTR1 disrupts the synthesis of tetrahydrofolate and tetrahydrobiopterin, leading to a cessation of DNA synthesis and increased oxidative stress within the parasite [5]. Current drug discovery efforts focus on identifying selective TbPTR1 inhibitors that do not cross-react with human DHFR to ensure safety and efficacy [4].

Other names

PTR1Pteridine reductase 1TbPTR1Pteridine-dependent oxidoreductase

Inhibition of the enzyme prevents the reduction of oxidized pteridines and folates to their active tetrahydro forms, which are essential cofactors for thymidylate synthesis and other one-carbon transfer reactions [2, 5].