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

David G. Gourley; Alexander W. Schüttelkopf; Gordon A. Leonard; James Luba; Larry W. Hardy; Stephen M. Beverley; William N. Hunter

doi:10.1038/88584

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

David G. Gourley, Alexander W. Schüttelkopf, Gordon A. Leonard, James Luba, Larry W. Hardy, Stephen M. Beverley, William N. Hunter

Research output: Contribution to journal › Article

87 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	521-525
Number of pages	5
Journal	Nature Structural Biology
Volume	8
Issue number	6
DOIs	https://doi.org/10.1038/88584
State	Published - Jun 21 2001

Access to Document

10.1038/88584

Link to publication in Scopus

Fingerprint Dive into the research topics of 'Pteridine reductase mechanism correlates pterin metabolism with drug resistance in trypanosomatid parasites'. Together they form a unique fingerprint.

Cite this

Gourley, D. G., Schüttelkopf, A. W., Leonard, G. A., Luba, J., Hardy, L. W., Beverley, S. M., & Hunter, W. N. (2001). Pteridine reductase mechanism correlates pterin metabolism with drug resistance in trypanosomatid parasites. Nature Structural Biology, 8(6), 521-525. https://doi.org/10.1038/88584

@article{948bbcaa5d964b1c94e0e8932deede90,

title = "Pteridine reductase mechanism correlates pterin metabolism with drug resistance in trypanosomatid parasites",

abstract = "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.",

author = "Gourley, {David G.} and Sch{\"u}ttelkopf, {Alexander W.} and Leonard, {Gordon A.} and James Luba and Hardy, {Larry W.} and Beverley, {Stephen M.} and Hunter, {William N.}",

year = "2001",

month = jun,

day = "21",

doi = "10.1038/88584",

language = "English",

volume = "8",

pages = "521--525",

journal = "Nature Structural Biology",

issn = "1072-8368",

number = "6",

}

Pteridine reductase mechanism correlates pterin metabolism with drug resistance in trypanosomatid parasites. / Gourley, David G.; Schüttelkopf, Alexander W.; Leonard, Gordon A.; Luba, James; Hardy, Larry W.; Beverley, Stephen M.; Hunter, William N.

In: Nature Structural Biology, Vol. 8, No. 6, 21.06.2001, p. 521-525.

Research output: Contribution to journal › Article

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.

PY - 2001/6/21

Y1 - 2001/6/21

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 -