Adenosine binding to low-molecular-weight purine nucleoside phosphorylase: the structural basis for recognition based on its complex with the enzyme from Schistosoma mansoni.
Schistosomes are unable to synthesize purines de novo and depend exclusively on the salvage pathway for their purine requirements. It has been suggested that blockage of this pathway could lead to parasite death. The enzyme purine nucleoside phosphorylase (PNP) is one of its key components and molecules designed to inhibit the low-molecular-weight (LMW) PNPs, which include both the human and schistosome enzymes, are typically analogues of the natural substrates inosine and guanosine. Here, it is shown that adenosine both binds to Schistosoma mansoni PNP and behaves as a weak micromolar inhibitor of inosine phosphorolysis. Furthermore, the first crystal structures of complexes of an LMW PNP with adenosine and adenine are reported, together with those with inosine and hypoxanthine. These are used to propose a structural explanation for the selective binding of adenosine to some LMW PNPs but not to others. The results indicate that transition-state analogues based on adenosine or other 6-amino nucleosides should not be discounted as potential starting points for alternative inhibitors.
Pereira
Humberto M
HM
Instituto de Física de São Carlos, Universidade de São Paulo, Avenida Trabalhador Sãocarlense 400, São Carlos, SP 13560-970, Brazil. hmuniz.pereira@gmail.com
Rezende
Martha M
MM
Castilho
Marcelo Santos
MS
Oliva
Glaucius
G
Garratt
Richard C
RC
D000818:Animals; D003460:Crystallization; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D015801:Helminth Proteins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008968:Molecular Conformation; D008970:Molecular Weight; D011485:Protein Binding; D011684:Purine Nucleosides / Q000737:chemistry* / Q000378:metabolism; D011683:Purine-Nucleoside Phosphorylase / Q000737:chemistry* / Q000378:metabolism; D012550:Schistosoma mansoni / Q000201:enzymology*
D004791:Enzyme Inhibitors; D015801:Helminth Proteins; D011684:Purine Nucleosides; D011683:Purine-Nucleoside Phosphorylase