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Radical Reaction Control in the AdoMet Radical Enzyme CDG Synthase (QueE): Consolidate, Destabilize, Accelerate.

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.

SUBMITTER: Jager CM

PROVIDER: S-EPMC5347944 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:7-Carboxy-7-deazaguanine synthase, QueE, catalyzes the radical mediated ring contraction of 6-carboxy-5,6,7,8-tetrahydropterin, forming the characteristic pyrrolopyrimidine core of all 7-deazaguanine natural products. QueE is a member of the S-adenosyl-L-methionine (AdoMet) radical enzyme superfamily, which harnesses the reactivity of radical intermediates to perform challenging chemical reactions. Members of the AdoMet radical enzyme superfamily utilize a canonical binding motif, a CX3 CXϕC motif, to bind a [4Fe-4S] cluster, and a partial (β/α)6 TIM barrel fold for the arrangement of AdoMet and substrates for catalysis. Although variations to both the cluster-binding motif and the core fold have been observed, visualization of drastic variations in the structure of QueE from Burkholderia multivorans called into question whether a re-haul of the defining characteristics of this superfamily was in order. Surprisingly, the structure of QueE from Bacillus subtilis revealed an architecture more reminiscent of the classical AdoMet radical enzyme. With these two QueE structures revealing varying degrees of alterations to the classical AdoMet fold, a new question arises: what is the purpose of these alterations? Here, we present the structure of a third QueE enzyme from Escherichia coli, which establishes the middle range of the spectrum of variation observed in these homologs. With these three homologs, we compare and contrast the structural architecture and make hypotheses about the role of these structural variations in binding and recognizing the biological reductant, flavodoxin. Broader impact statement: We know more about how enzymes are tailored for catalytic activity than about how enzymes are tailored to react with a physiological reductant. Here, we consider structural differences between three 7-carboxy-7-deazaguanine synthases and how these differences may be related to the interaction between these enzymes and their biological reductant, flavodoxin.

Dataset Information

Radical Reaction Control in the AdoMet Radical Enzyme CDG Synthase (QueE): Consolidate, Destabilize, Accelerate.

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