title: Orotidine Monophosphate Decarboxylase--A Fascinating Workhorse Enzyme with Therapeutic Potential.
abstract: Orotidine 5'-monophosphate decarboxylase (ODCase) is known as one of the most proficient enzymes. The enzyme catalyzes the last reaction step of the de novo pyrimidine biosynthesis, the conversion from orotidine 5'-monophosphate (OMP) to uridine 5'-monophosphate. The enzyme is found in all three domains of life, Bacteria, Eukarya and Archaea. Multiple sequence alignment of 750 putative ODCase sequences resulted in five distinct groups. While the universally conserved DxKxxDx motif is present in all the groups, depending on the groups, several characteristic motifs and residues can be identified. Over 200 crystal structures of ODCases have been determined so far. The structures, together with biochemical assays and computational studies, elucidated that ODCase utilized both transition state stabilization and substrate distortion to accelerate the decarboxylation of its natural substrate. Stabilization of the vinyl anion intermediate by a conserved lysine residue at the catalytic site is considered the largest contributing factor to catalysis, while bending of the carboxyl group from the plane of the aromatic pyrimidine ring of OMP accounts for substrate distortion. A number of crystal structures of ODCases complexed with potential drug candidate molecules have also been determined, including with 6-iodo-uridine, a potential antimalarial agent.
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto, 606-8502, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fujihashi
authors.affiliation: Department of Chemistry & Biochemistry, The University of North Carolina at Greensboro, Greensboro, NC, 27412, USA.
authors.forename: Jagjeet S
authors.initials: JS
authors.lastname: Mnpotra
authors.affiliation: Center for Molecular Design and Preformulations, and Toronto General Research Institute, University Health Network, Toronto, Ontario, M5G 1L7, Canada.
authors.forename: Ram Kumar
authors.initials: RK
authors.lastname: Mishra
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, Ontario, M5S 1A8, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, M5G 1L7, Canada.
authors.forename: Emil F
authors.initials: EF
authors.lastname: Pai
authors.affiliation: Center for Molecular Design and Preformulations, and Toronto General Research Institute, University Health Network, Toronto, Ontario, M5G 1L7, Canada; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, M5S 3M2, Canada. Electronic address: lkotra@uhnres.utoronto.ca.
authors.forename: Lakshmi P
authors.initials: LP
authors.lastname: Kotra
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009964:Orotidine-5'-Phosphate Decarboxylase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D013045:Species Specificity
chemical_list: D004791:Enzyme Inhibitors; D009964:Orotidine-5'-Phosphate Decarboxylase
keywords: Antimalarial agents; Ligand-enzyme interactions; Orotidine monophosphate decarboxylase; Pyrimidine biosynthesis