Orotidine Monophosphate Decarboxylase – A Fascinating Workhorse Enzyme with Therapeutic Potential

Masahiro Fujihashi; Jagjeet S. Mnpotra; Ram Kumar Mishra; Emil F. Pai; Lakshmi P. Kotra

doi:10.1016/j.jgg.2015.04.005

Volume 42 Issue 5

May 2015

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Article Navigation > Journal of Genetics and Genomics > 2015 > 42(5): 221-234

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Orotidine Monophosphate Decarboxylase – A Fascinating Workhorse Enzyme with Therapeutic Potential

doi: 10.1016/j.jgg.2015.04.005

a
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto, 606-8502, Japan
b
Department of Chemistry & Biochemistry, The University of North Carolina at Greensboro, Greensboro, NC, 27412, USA
c
Department of Biochemistry, University of Toronto, Toronto, Ontario, M5S 1A8, Canada
d
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 1L7, Canada
e
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada
f
Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, M5G 1L7, Canada
g
Center for Molecular Design and Preformulations, and Toronto General Research Institute, University Health Network, Toronto, Ontario, M5G 1L7, Canada
h
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, M5S 3M2, Canada

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Corresponding author: E-mail address: lkotra@uhnres.utoronto.ca (Lakshmi P. Kotra)
Received Date: 2014-12-26
Accepted Date: 2015-04-15
Rev Recd Date: 2015-04-13

Available Online: 2015-05-16

Publish Date: 2015-05-20

Abstract

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.
- Pyrimidine biosynthesis,
- Orotidine monophosphate decarboxylase,
- Ligand-enzyme interactions,
- Antimalarial agents

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References(83)

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