The Enzymatic Decarboxylation Mechanism of 5‑Carboxy Uracil: A Comprehensive Quantum Chemical Study

Dynamic regulation of DNA methylation
is an important process for
the control of gene expression in mammals. It is believed that in
the demethylation pathway of 5-methyl cytosine, the intermediate 5-carboxy
cytosine (5caC) can be actively decarboxylated alongside
the substitution in the base excision repair. For the active decarboxylation
of 5caC, a decarboxylase has not been identified so far.
Due to the similar chemistry of the decarboxylation of 5-carboxy uracil
(5caU) to uracil (U) in the pyrimidine salvage
pathway catalyzed by the iso-orotate decarboxylase (IDCase), the study
of this reaction might give valuable insights into the active 5caC decarboxylation process. In this work, we employ quantum
chemical and molecular mechanic calculations and find that the catalytic
mechanism of IDCase proceeds via a direct decarboxylation mechanism.
Detailed investigations on the reaction coordinate reveal that it
is a one-step mechanism with concerted proton transfer and C–C
bond opening.