PURINE NUCLEOSIDE PHOSPHORYLASE - A TARGET FOR DRUG DESIGN
PURINE NUCLEOSIDE PHOSPHORYLASE - A TARGET FOR DRUG DESIGN
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DOI：
10.1002/med.2610130302
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发表时间：
1993-05-01
影响因子：
13.3
通讯作者：
MONTGOMERY, JA
中科院分区：
文献类型：
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作者：
MONTGOMERY, JA
哺乳动物嘌呤核苷磷酸化酶（PNP，嘌呤核苷正磷酸核糖基转移酶，EC 2.4。2.1)催化鸟嘌呤、次黄嘌呤和一些相关核苷同系物的核糖核苷和2 '-脱氧核糖核苷的可逆磷酸解（图1）。腺嘌呤也是哺乳动物酶的底物，但动力学参数是如此不利，以至于这种反应或腺苷的磷酸解在正常细胞代谢中起作用是极不可能的。2相反，PNP快速降解腺苷脱氨酶（ADA）、肌苷和2 '-脱氧肌苷的产物。在除胸腺外的所有人胎儿组织中，PNP的活性均超过ADA。虽然在平衡条件下，分离的酶催化核苷合成，但它通常在完整细胞中以磷酸解方向起作用。PNP在某些组织中与黄嘌呤氧化酶偶联时作为分解代谢酶发挥作用，与次黄嘌呤-鸟嘌呤磷酸核糖转移酶（HGPRT）偶联时作为补救酶发挥作用。由于核糖核苷和2 '-脱氧核糖核苷都被PNP挽救以仅形成核糖核苷酸，所以它与ADA结合可以将2'-脱氧核糖核苷酸的产生限制于它们通过核糖核苷二磷酸还原酶（一种高度调节的酶）的合成。PNP已经从真核和原核细胞中分离，但是尽管哺乳动物酶对6-氧代嘌呤及其类似物具有特异性，来自其他生物体的PNP在其特异性方面有所不同。这篇评论将主要涉及从哺乳动物来源的酶的抑制剂。
Mammalian purine nucleoside phosphorylase (PNP, purine nucleoside orthophosphate ribosyltransferase, EC 2.4. 2.1) catalyzes the reversible phosphorolysis of the ribonucleosides and 2'-deoxyribonucleosides of guanine, hypoxanthine, and a number of related nucleoside congeners (Fig. 1). l Adenine is also a substrate of the mammalian enzyme, but the kinetic parameters are so unfavorable that it is highly unlikely that this reaction or the phosphorolysis of adenosine have a role in normal cellular metabolism. 2 Instead, PNP rapidly degrades the products of adenosine deaminase (ADA), inosine, and 2'-deoxyinosine. The activity of PNP exceeds that of ADA in all human fetal tissues examined except thy mu^.^ Although under equilibrium conditions the isolated enzyme catalyses nucleoside synthesis, it normally acts in the phosphorolytic direction in intact cells. PNP functions as a catabolic enzyme when it is coupled with xanthine oxidase in some tissues, and as a salvage enzyme when it is coupled with hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Since both ribo-and 2'-deoxyribonucleosides are salvaged by PNP to form only ribonucleotides, it may, in conjunction with ADA, limit the production of 2'-deoxyribonucleotides to their synthesis by ribonucleoside diphosphate reductase, a highly regulated enzyme.PNP has been isolated from both eukaryotic and prokaryotic cells, but while the mammalian enzyme is specific for the 6-oxypurines and analogs thereof, PNPs from other organisms vary in their specificity. This review will deal primarily with inhibitors of the enzyme from mammalian sources.