Oral Presentation 21st International Conference on Biological Inorganic Chemistry 2025
A Novel Proposal for the Mechanism of Quercetin Dioxygenases (121054)
The quercetin dioxygenases (QDOs) are unusual metalloenzymes in that they display ring-opening dioxygenase activity with several different first-row transition metal ions which do not undergo redox changes during turnover.[i] The QDOs are also unique in that the substrate binds as an η1 flavonolate rather than the η2 bidentate mode seen in all reported model complexes. The flavonol substrates were early examples of excited state intramolecular proton transfer (ESIPT) phenomena, in which photoexcitation causes an H-atom exchange between the adjacent hydroxyl and ketone, generating an oxidopyrylium emissive state. These oxidopyryliums undergo ring-opening dioxygenations analogous to the enzymatic reactions. Our hypothesis is that lability of the divalent metal ion may allow access to a reactive oxidopyrylium intermediate via coordination switching from the oxy to ketone position, which allows reaction with O2. We have found flavonol and thioflavonol derivatives modeling several η1- and η2-coordination modes. Methylation of 3-hydroxythioflavone generates a stable η1 hydroxopyrylium salt, which undergoes rapid ring-opening dioxygenation by deprotonation or photoexcitation. By comparison, η1-methoxyflavonols do not react with O2 under any condition. Of the studied flavonol derivatives, η1 or η2, any which demonstrates ESIPT-like oxidopyrylium emissions also undergoes QDO-like ring-opening reactions with dioxygen.[ii] Implications of these results concerning the mechanism of QDOs and related dioxygenases will be discussed.
[i] Fetzner S. "Ring-cleaving dioxygenases with a cupin fold." Applied and Environmental Microbiology 2012, 78, 2505-14.
[ii] Rymbai, L.D.; Klausmeyer, K.K.; Farmer, P.J. ”The case for an oxidopyrylium intermediate in the mechanism of quercetin dioxygenases.” Journal of Inorganic Biochemistry 2023, 247, 112343.