%0 Journal Article
%T Implications of the structure of human uridine phosphorylase 1 on the development of novel inhibitors for improving the therapeutic window of fluoropyrimidine chemotherapy
%A Tarmo P Roosild
%A Samantha Castronovo
%A Michael Fabbiani
%A Giuseppe Pizzorno
%J BMC Structural Biology
%D 2009
%I BioMed Central
%R 10.1186/1472-6807-9-14
%X In this report we present the high resolution structures of human uridine phosphorylase 1 (hUPP1) in ligand-free and BAU-inhibited conformations. The structures confirm the unexpected solution observation that the human enzyme is dimeric in contrast to the hexameric assembly present in microbial UPPs. They also reveal in detail the mechanism by which BAU engages the active site of the protein and subsequently disables the enzyme by locking the protein in a closed conformation. The observed inter-domain motion of the dimeric human enzyme is much greater than that seen in previous UPP structures and may result from the simpler oligomeric organization.The structural details underlying hUPP1's active site and additional surfaces beyond these catalytic residues, which coordinate binding of BAU and other acyclouridine analogues, suggest avenues for future design of more potent inhibitors of this enzyme. Notably, the loop forming the back wall of the substrate binding pocket is conformationally different and substantially less flexible in hUPP1 than in previously studied microbial homologues. These distinctions can be utilized to discover novel inhibitory compounds specifically optimized for efficacy against the human enzyme as a step toward the development of more effective chemotherapeutic regimens that can selectively protect normal tissues with inherently lower UPP activity.Uridine phosphorylase (UPP; EC 2.4.2.3) is a ubiquitous enzyme involved in pyrimidine salvage and maintenance of uridine homeostasis [1-3]. It catalyzes the reversible phosphorolysis of uracil ribosides and analogous compounds to their respective nucleobases and ribose-1-phosphate. The structural mechanisms underlying the catalytic activity of this enzyme have been extensively studied through analysis of E. coli UPP (EcUPP) [4-7] and more recently the S. typhimurium homologue [8]. These structures have shown UPP to belong to the nucleoside phosphorylase (NP) super-family of proteins in the NP-I subs
%U http://www.biomedcentral.com/1472-6807/9/14