Canduri Fernanda, dos Santos Denis Marangoni, Silva Rafael Guimarães, Mendes Maria Anita, Basso Luiz Augusto, Palma Mário Sérgio, de Azevedo Walter Filgueira, Santos Diógenes Santiago
Departamento de Física, UNESP, São José do Rio Preto, SP 15054-000, Brazil.
Biochem Biophys Res Commun. 2004 Jan 23;313(4):907-14. doi: 10.1016/j.bbrc.2003.11.179.
Human purine nucleoside phosphorylase (PNP) is a ubiquitous enzyme which plays a key role in the purine salvage pathway, and PNP deficiency in humans leads to an impairment of T-cell function, usually with no apparent effect on B-cell function. PNP is highly specific for 6-oxopurine nucleosides and exhibits negligible activity for 6-aminopurine nucleosides. The catalytic efficiency for inosine is 350,000-fold greater than for adenosine. Adenine nucleosides and nucleotides are deaminated by adenosine deaminase and AMP deaminase to their corresponding inosine derivatives which, in turn, may be further degraded. Here we report the crystal structures of human PNP in complex with inosine and 2('),3(')-dideoxyinosine, refined to 2.8A resolution using synchrotron radiation. The present structures provide explanation for ligand binding, refine the purine-binding site, and can be used for future inhibitor design.
人嘌呤核苷磷酸化酶（PNP）是一种普遍存在的酶，在嘌呤补救途径中起关键作用，人类PNP缺乏会导致T细胞功能受损，通常对B细胞功能无明显影响。PNP对6-氧嘌呤核苷具有高度特异性，对6-氨基嘌呤核苷的活性可忽略不计。对肌苷的催化效率比对腺苷高350,000倍。腺嘌呤核苷和核苷酸被腺苷脱氨酶和AMP脱氨酶脱氨生成相应的肌苷衍生物，这些衍生物进而可能被进一步降解。在此，我们报道了人PNP与肌苷和2('),3(')-二脱氧肌苷复合物的晶体结构，利用同步辐射将其精修至2.8埃分辨率。目前的结构为配体结合提供了解释，完善了嘌呤结合位点，可用于未来的抑制剂设计。
