Pteridine reductase mechanism correlates pterin metabolism with drug resistance in trypanosomatid parasites
Pteridine reductase mechanism correlates pterin metabolism with drug resistance in trypanosomatid parasites
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DOI：
10.1038/88584
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发表时间：
2001-06-01
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影响因子：
--
通讯作者：
Hunter, WN
中科院分区：
文献类型：
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作者：
Gourley, DG;Schüttelkopf, AW;Hunter, WN
蝶啶还原酶（Pteridine reductase，PTR 1）是一种短链还原酶（Short-chain reductase，SDR），在寄生锥虫体内参与蝶呤类化合物的拯救，催化氧化蝶呤类化合物还原为活性四氢形式，并通过减轻二氢叶酸还原酶（dihydrofolate reductase，DHFR）的抑制作用降低抗叶酸剂的敏感性。8-二氢生物蝶呤（DHB）或甲氨蝶呤（MTX）描述了酶的机制，广谱活性和抑制底物或抗叶酸剂。PTR 1将两种不同的还原机制应用于在一个方向上结合的底物。第一个减少使用通用的SDR机制，而第二个共享的DHFR拟议的机制相似。DHB和MTX均与NADP（H）形成广泛的氢键网络，但蝶啶的取向不同。
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.