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Reaction Mechanism and Substrate Specificity of Iso-orotate Decarboxylase: A Combined Theoretical and Experimental Study
Stockholm University, Faculty of Science, Department of Organic Chemistry.
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Number of Authors: 112018 (English)In: Frontiers in Chemistry, E-ISSN 2296-2646, Vol. 6, article id 608Article in journal (Refereed) Published
Abstract [en]

The C-C bond cleavage catalyzed by metal-dependent iso-orotate decarboxylase (IDCase) from the thymidine salvage pathway is of interest for the elucidation of a (hypothetical) DNA demethylation pathway. IDCase appears also as a promising candidate for the synthetic regioselective carboxylation of N-heteroaromatics. Herein, we report a joint experimental-theoretical study to gain insights into the metal identity, reaction mechanism, and substrate specificity of IDCase. In contrast to previous assumptions, the enzyme is demonstrated by ICPMS/MS measurements to contain a catalytically relevant Mn(2+)rather than Zn2+. Quantum chemical calculations revealed that decarboxylation of the natural substrate (5-carboxyuracil) proceeds via a (reverse) electrophilic aromatic substitution with formation of CO2. The occurrence of previously proposed tetrahedral carboxylate intermediates with concomitant formation of HCO3- could be ruled out on the basis of prohibitively high energy barriers. In contrast to related o-benzoic acid decarboxylases, such as y-resorcylate decarboxylase and 5-carboxyvanillate decarboxylase, which exhibit a relaxed substrate tolerance for phenolic acids, IDCase shows high substrate fidelity. Structural and energy comparisons suggest that this is caused by a unique hydrogen bonding of the heterocyclic natural substrate (5-carboxyuracil) to the surrounding residues. Analysis of calculated energies also shows that the reverse carboxylation of uracil is impeded by a strongly disfavored uphill reaction.

Place, publisher, year, edition, pages
2018. Vol. 6, article id 608
Keywords [en]
computational chemistry, biocatalysis, iso-orotate decarboxylase, reaction mechanism, substrate specificity, metal identity
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-163671DOI: 10.3389/fchem.2018.00608ISI: 000453844900001OAI: oai:DiVA.org:su-163671DiVA, id: diva2:1280380
Available from: 2019-01-18 Created: 2019-01-18 Last updated: 2019-01-18Bibliographically approved

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