Relevant anion-pi interactions in biological systems: the case of Urate Oxidase

Abstract

[eng] Enzyme inhibited: The important role of anion-π interactions that are present in the active site of the urate oxidase enzyme is reported (see picture). The inhibition of this enzyme by cyanide ions is caused by the existence of an anion-π interaction between the inhibitor and the enzymatic substrate. This investigation extends the relevance of anion-π interactions to important fields such as enzyme chemistry. Supramolecular chemistry involves the intelligent utilization of noncovalent interactions between molecules. All biological systems are based on these impressively efficient interactions.1 Interactions between predesigned binding centers can lead to complex functions in highly organized molecular systems, which is one fundamental aspect of supramolecular chemistry.2 The importance of anion-π interactions has been widely recognized3 and has led to many theoretical and experimental investigations.4 Several pioneering theoretical studies revealed that these interactions are energetically favorable.5 Anion-π interactions are gaining significant interest; for instance, Matile and co‐workers have reported remarkable synthetic ion channels based on anion-π interactions.6 However, clear evidence of anion-π interactions that likely play a key role in enzymes is lacking in the literature. The ultimate step to prove the importance of this noncovalent interaction is to demonstrate its crucial role in a biological system. Herein we report several selected examples retrieved from the Protein Data Bank (PDB).7 In these examples, relevant anion-π interactions are present in the active site of the urate oxidase enzyme, and lead either to interactions with the substrate (uric acid) that inhibits the enzymatic activity or to interactions with the inhibitor (8‐azaxanthine). In addition, taking advantage of quantum mechanical calculations, we demonstrate that the interactions observed in the solid state are relevant and energetically favorable.