Negative catalysis or non-Bell-Evans-Polanyi reactivity by metalloenzymes: Examples from mononuclear heme and non-heme iron oxygenases

Abstract There are many examples in bioinorganic chemistry, where metalloenzymes produce different reaction products than analogous biomimetic model complexes despite them having the same transition metal and first-coordination sphere environment. As a result, a lot of research has been devoted to the understanding of the effect of the first- and second coordination sphere of catalytic reaction centers. Thermodynamically, catalysis should follow the Bell-Evans-Polanyi principle, where the product with the largest driving force gives the lowest reaction barrier and consequently highest reaction rate and dominant reaction products. However, there are many examples in the literature, where the dominant products of an enzymatic reaction do not correspond to the reaction process with the largest exothermicity. In general, catalysis that follows the Bell-Evans-Polanyi principle is designated positive catalysis, whereas when products are obtained from non-Bell-Evans-Polanyi reactivity, it is defined as negative catalysis. In enzymes; however, the first- and second-coordination sphere determines whether positive or negative catalysis happens but many intricate details on how selectivities are reversed are still unknown. In this review paper, we cover recent advances on enzyme understanding where negative catalysis is dominant over positive catalysis. We show that the enzyme can achieve this feat, e.g., through the positioning of substrate and oxidant that then gives the desired product distributions. In particular, often the substrate is positioned such that the desired group of the substrate is placed as close as possible to the oxidant, while unwanted activation channels are blocked by electrostatic perturbations or shielded by protein residues. Furthermore, recent work has shown that reactivity patterns in enzymes can also be influenced by long-range electrostatic interactions like an electric dipole field that can weaken or strengthen chemical bonds through long-range polarization effects. As a result of these electric field effects and long-range electrostatic interactions, enzymes can react through negative catalysis, where a thermodynamically less likely process gives the dominant products. In this review paper, we define and describe positive and negative catalysis in enzymes and compare structure and reactivity with biomimetic and homogeneous catalysts for a number of mononuclear iron-type enzymes including the cytochromes P450 and non-heme iron dioxygenases.