Pteridine reductase mechanism correlates pterin metabolism with drug resistance in trypanosomatid parasites

Pteridine reductase (PTR1) is a short-chain reductase (SDR) responsible for the salvage of pterins in parasitic trypanosomatids, PTR1 catalyzes the NA DPH-dependent two-step reduction of oxidized pterins to the active tetrahyd ro-forms and reduces susceptibility to antifolates by alleviating dihydrofo late reductase (DHFR) inhibition, Crystal structures of PTR1 complexed with cofactor and 7,8-dihydrobiopterin (DHB) or methotrexate (MTX) delineate th e enzyme mechanism, broad spectrum of activity and inhibition by substrate or an antifolate. PTR1 applies two distinct reductive mechanisms to substra tes bound in one orientation. The first reduction uses the generic SDR mech anism, whereas the second shares similarities with the mechanism proposed f or DHFR. Both DHB and MTX form extensive hydrogen bonding networks with NAD P(H) but differ in the orientation of the pteridine.