Orotidine-5'-monophosphate decarboxylase (ODCase) catalyzes the committed step in the biosynthesis of pyrimidine nucleotides, and thus is an important enzyme.  With its high catalytic efficiency and an elusive mechanism, ODCase has been a target of extensive study. Inhibitors of ODCase may be of potential medicinal interest as leads in the development of anti-viral and anti-cancer drugs.The focus of this project is the synthesis and biochemical study of nucleotides with uric acid as the base.  Uric acid is deprotonated under physiological conditions and is highly polarized.  Nucleotides with a negative charge at the pyrimidine moiety (such as uric acid derivatives) should be potent inhibitors of ODCase.  The synthesis starts with guanosine, which will be protected on the ribose moiety.  Bromination followed by hydrolysis will yield an 8-oxoguanosine derivative, which can be de-aminated to yield protected uric acid nucleoside.  Deprotection followed by phosphorylation will yield the target nucleotide. The binding constant will be compared to that of xanthosine monophosphate, which is reported to be a potent inhibitor of ODCase.

Elucidating the enzyme of orotidine-5'-monophosphate decarboxylase (ODCase)

248th National Meeting (2014)

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