title: Structural diversity and plasticity associated with nucleotides targeting orotidine monophosphate decarboxylase.
abstract: Orotidine monophosphate decarboxylase (ODCase) generally accepts pyrimidine-based mononucleotides as ligands, but other nucleotides are also known to bind to this enzyme. We investigated the kinetic properties of eight common and endogenous nucleotides with ODCases from three species: Methanobacterium thermoautotrophicum, Plasmodium falciparum, and Homo sapiens. UMP and XMP exhibited higher affinities as compared to the other nucleotides tested. The product of ODCase catalyzed decarboxylation, UMP, displayed inhibition constants (K(i)) of 330 microM against the Mt enzyme and of 210 and 220 microM against the Pf and Hs ODCases, respectively. The K(i) values for XMP were 130 microM and 43 microM, respectively, for Mt and Pf ODCases. Interestingly, XMP's affinity for human ODCase (K(i) = 0.71 microM) is comparable and even slightly better than that of the substrate OMP. Binding of various nucleotides and their structural features in the context of ODCase inhibition and inhibitor design are discussed.
authors.affiliation: Center for Molecular Design and Preformulations, Toronto General Research Institute, Toronto General Hospital, Toronto, ON, Canada.
authors.forename: Ewa
authors.initials: E
authors.lastname: Poduch
authors.forename: Lianhu
authors.initials: L
authors.lastname: Wei
authors.forename: Emil F
authors.initials: EF
authors.lastname: Pai
authors.forename: Lakshmi P
authors.initials: LP
authors.lastname: Kotra
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D006801:Humans; D007700:Kinetics; D008024:Ligands; D017014:Methanobacterium / Q000201:enzymology; D008958:Models, Molecular; D009964:Orotidine-5'-Phosphate Decarboxylase / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000201:enzymology; D011485:Protein Binding; D011487:Protein Conformation; D011685:Purine Nucleotides / Q000737:chemistry*; D011742:Pyrimidine Nucleotides / Q000737:chemistry*; D013045:Species Specificity
chemical_list: D008024:Ligands; D011685:Purine Nucleotides; D011742:Pyrimidine Nucleotides; D009964:Orotidine-5'-Phosphate Decarboxylase