TY - JOUR
T1 - Pteridine reductase mechanism correlates pterin metabolism with drug resistance in trypanosomatid parasites
AU - Gourley, David G.
AU - Schüttelkopf, Alexander W.
AU - Leonard, Gordon A.
AU - Luba, James
AU - Hardy, Larry W.
AU - Beverley, Stephen M.
AU - Hunter, William N.
N1 - Funding Information:
We thank C. Bond, C. Frieden, D. Hall and A. Mehlert for discussions, and Daresbury and ESRF for support. Funded by the Wellcome Trust, BBSRC and N.I.H. grants.
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0035014839&partnerID=8YFLogxK
U2 - 10.1038/88584
DO - 10.1038/88584
M3 - Article
C2 - 11373620
AN - SCOPUS:0035014839
VL - 8
SP - 521
EP - 525
JO - Nature Structural Biology
JF - Nature Structural Biology
SN - 1072-8368
IS - 6
ER -