Pteridine reductase mechanism correlates pterin metabolism with drug resistance in trypanosomatid parasites
Graduate School of Biomedical Sciences;
Life Sciences | Medicine and Health Sciences
Pteridine reductase (PTR1) is a short-chain reductase (SDR) responsible for the salvage of pterins in parasitic trypanosomatids. PTR1 catalyzes the NADPH-dependent two-step reduction of oxidized pterins to the active tetrahydro-forms and reduces susceptibility to antifolates by alleviating dihydrofolate reductase (DHFR) inhibition. Crystal structures of PTR1 complexed with cofactor and 7,8-dihydrobiopterin (DHB) or methotrexate (MTX) delineate the enzyme mechanism, broad spectrum of activity and inhibition by substrate or an antifolate. PTR1 applies two distinct reductive mechanisms to substrates bound in one orientation. The first reduction uses the generic SDR mechanism, whereas the second shares similarities with the mechanism proposed for DHFR. Both DHB and MTX form extensive hydrogen bonding networks with NADP(H) but differ in the orientation of the pteridine.
DOI of Published Version
Nat Struct Biol. 2001 Jun;8(6):521-5. Link to article on publisher's site
Nature structural biology
Gourley DG, Schuttelkopf AW, Leonard GA, Luba J, Hardy LW, Beverley SM, Hunter WN. (2001). Pteridine reductase mechanism correlates pterin metabolism with drug resistance in trypanosomatid parasites. Morningside Graduate School of Biomedical Sciences Student Publications. https://doi.org/10.1038/88584. Retrieved from https://escholarship.umassmed.edu/gsbs_sp/406