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Radical reaction control in the AdoMet radical enzyme CDG Synthase (QueE): consolidate, destabilize, accelerate

Jäger, Christof M.; Croft, Anna K.

Authors

Christof M. Jäger

Anna K. Croft



Abstract

Controlling radical intermediates and thus catalysing and directing complex radical reactions is a central feature of S-adensosylmethionine (SAM)-dependent radical enzymes. We report ab initio and DFT calculations highlighting the specific influence of ion complexation, including Mg2+, identified as a key catalytic component on radical stability and reaction control in 7-carboxy-7-deazaguanine synthase (QueE). Radical stabilisation energies (RSEs) of key intermediates and radical clock-like model systems of the enzyme-catalysed rearrangement of 6-carboxytetrahydropterin (CPH4), reveals a directing role of Mg2+ in destabilising both the substrate-derived radical and corresponding side reactions, with the effect that the experimentally-observed rearrangement becomes dominant over possible alternatives. Importantly, this is achieved with minimal disruption of the thermodynamics of the substrate itself, affording a novel mechanism for an enzyme to both maintain binding potential and accelerate the rearrangement step. Other mono and divalent ions were probed with only dicationic species achieving the necessary radical conformation to facilitate the reaction.

Journal Article Type Article
Publication Date Jan 18, 2017
Journal Chemistry - a European Journal
Print ISSN 0947-6539
Electronic ISSN 1521-3765
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 23
Issue 4
APA6 Citation J├Ąger, C. M., & Croft, A. K. (2017). Radical reaction control in the AdoMet radical enzyme CDG Synthase (QueE): consolidate, destabilize, accelerate. Chemistry - A European Journal, 23(4), doi:10.1002/chem.201604719
DOI https://doi.org/10.1002/chem.201604719
Keywords Catalysis, Radical SAM enzymes, Radical stabilization energies, Computational chemistry, Radical clocks
Publisher URL http://dx.doi.org/10.1002/chem.201604719
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0
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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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