Creating efficient artificial catalysts that can compete with biocatalysis has been an enduring challenge which has yet to be met. Reported herein is the synthesis and characterization of a series of zinc complexes designed to catalyze the hydrolysis of phosphate diesters. By introducing a hydrated aldehyde into the ligand we achieve turnover for DNA-like substrates which, combined with ligand methylation, increases reactivity by two orders of magnitude. In contrast to current orthodoxy and mechanistic explanations, we propose a mechanism where the nucleophile is not coordinated to the metal ion, but involves a tautomer with a more effective Lewis acid and more reactive nucleophile. This data suggests a new strategy for creating more efficient metal ion based catalysts, and highlights a possible mode of action for metalloenzymes.
Metal ion complexes are the most effective artificial catalysts capable of cleaving phosphate diesters under mild aqueous conditions. A central strategy for making these complexes highly reactive has been to use ligand based alcohols that are coordinated to the ion, providing an ionised nucleophile under neutral conditions but at the expense of deactivating it. We have created a highly reactive Zn complex that is 350-fold more reactive than an alcohol analogue by preventing the nucleophile binding to the metal ion. This strategy successfully delivers the benefits of efficient nucleophile delivery without strongly deactivating the metal ion Lewis acidity nor the oxyanion nucleophilicity. Varying the leaving group reveals that the transition state of the reaction is much further advanced than the reaction with hydroxide.
Creating efficient artificial catalysts that can compete with biocatalysis has been an enduring challenge which has yet to be met. Reported herein is the synthesis and characterization of a series of zinc complexes designed to catalyze the hydrolysis of phosphate diesters. By introducing a hydrated aldehyde into the ligand we achieve turnover for DNA-like substrates which, combined with ligand methylation, increases reactivity by two orders of magnitude. In contrast to current orthodoxy and mechanistic explanations, we propose a mechanism where the nucleophile is not coordinated to the metal ion, but involves a tautomer with a more effective Lewis acid and more reactive nucleophile. This data suggests a new strategy for creating more efficient metal ion based catalysts, and highlights a possible mode of action for metalloenzymes.Substantial efforts have been made to create metal ion complexes that are effective catalysts for phosphate ester hydrolysis.[1] These compounds provide insight into how biological catalysts might function, and hold the promise of creating novel therapeutics or laboratory agents for manipulating nucleic acids.[2] The challenges of sufficient activity to function usefully under biological conditions and achieving turnover remain. Herein we report how incorporating a hydrated aldehyde as a nucleophile can enhance reactivity and lead to turnover. Our mechanistic explanation provides a new strategy for designing metal ion complexes with nuclease activity.In developing artificial metal ion complexes to cleave RNA, the 2'OH group provides an intramolecular nucleophile which can be exploited.[3] For DNA, this is not possible, and the most effective strategies to date have used metal-ioncoordinated nucleophiles to enhance the attack at phosphorus. Chin and co-workers established that the effectiveness of this nucleophile can depend strongly on ligand structure.[4] If this nucleophile is part of the ligand structure, then its efficiency can be enhanced through careful design, and substantial rate enhancements achieved compared to that a metal-bound hydroxide. However, the flaw in this strategy is that the product is a phosphorylated ligand which is very stable, and so the complexes are not catalytic.A potential solution to this problem is suggested by the hydrolysis of model compounds also containing keto or aldehyde groups.[5] Bender and Silver showed that benzoate ester hydrolysis can be accelerated 10 5 -fold by the presence of an ortho aldehyde group. This hydrate form of the aldehyde provides an effective nucleophile, thus producing a product which can readily decompose to reform the carbonyl. [6] Similar effects have been reported for phosphate ester cleavage. [7] To create a catalytic system, Menger and Whitesell incorporated aldehydes into micellar head groups, and these aggregates showed both enhanced activity and turnover. [8] Interestingly, recent work with sulfatases and phosphonohydrolases has shown that a formyl glycine residue in the active site is believed to act as a nu...
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