Structural diversity and plasticity associated with nucleotides targeting orotidine monophosphate decarboxylase

Journal of Medicinal Chemistry
Ewa PoduchLakshmi P Kotra

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.

References

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Citations

Mar 23, 2011·Journal of Medicinal Chemistry·Melissa LewisLakshmi P Kotra
Sep 21, 2012·Journal of Medicinal Chemistry·Meena K PurohitLakshmi P Kotra
Jan 29, 2014·Future Medicinal Chemistry·Sourabh Mundra, Lakshmi P Kotra
Jun 11, 2015·Journal of Genetics and Genomics = Yi Chuan Xue Bao·Masahiro FujihashiLakshmi P Kotra
Mar 6, 2009·Journal of Medicinal Chemistry·Angelica M BelloLakshmi P Kotra
Feb 16, 2013·Journal of Medicinal Chemistry·Ian E CrandallLakshmi P Kotra
Oct 25, 2013·Journal of the American Chemical Society·Masahiro FujihashiKunio Miki

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