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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.
Highlights
Reactive radical intermediates are able to achieve complex chemical conversions that are either inaccessible or extremely difficult to achieve through alternative approaches
The theoretical study by Zhu and Liu,[15] uses MD snapshot-based QM/MM calculations to rule out one possible reaction mechanism. They suggest that the predominant effect of the ion is electrostatic, with its role to hold the substrate in its reactive conformation and that the different coordination to Na+ might be the main reason for different activities, leaving the question open as to what is the distinct effect of the metal complexation on the radical intermediate and the reaction as a whole
We have looked at the rearrangement by means of high level ab initio and DFT calculations, focusing on a deeper understanding of the nature of the radicals and how both the metal coordination and the enzyme influence the radical intermediates and guide the catalysis away from unwanted side reactions
Summary
Reactive radical intermediates are able to achieve complex chemical conversions that are either inaccessible or extremely difficult to achieve through alternative approaches. Examples include CÀC bond[1] and thioether bond forming reactions,[2] insertion reactions,[3] and carbon-skeleton rearrangements.[4] One major limitation in carrying out radical reactions is that the benefits incurred by high reactivity are attenuated through lower selectivity of reaction, potentially leading to unwanted by-products. Nature has overcome this challenge through developing careful mechanisms for the control of radical reactions within enzymes. As generated from coenzyme B12, have provided in-
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