Rethinking biocatalysis and enzymology

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Enzymes are the catalysts used by Nature. They are a renewable resource, non-toxic, and the target of most drugs. Thanks to their complex 3D structure, enzymes show interesting characteristics rarely found in chemical catalysts. The use of enzymes to generate industrial products is advantageous both from a sustainability perspective and to access new reactivity. Our understanding of enzyme catalysis is often superficial, and how enzymes are used in synthesis has barely evolved over the past decades. Improving our knowledge of enzyme catalysis has direct implications in drug discovery, agriculture, and the production of commodity chemicals. This research aims at rethinking the way that we investigate enzyme mechanisms and how we employ them in biocatalysis, by establishing novel, unexpected approaches to study enzymes and design biocatalytic processes. The goals for the next 5 years are to: 1) explore new conditions for the use of biocatalysts and 2) combine various techniques to study enzymes. Although enzymes are typically used in dilute aqueous conditions, in nature they are rarely immersed in bulk water. For example, enzymes secreted in the environment by microorganisms operate on surfaces exposed to air moisture. Recently, we demonstrated that some enzymes are more efficient in moist-solid reaction mixtures than under standard dilute aqueous conditions, and that mechanical forces (a.k.a. mechanoenzymology) can positively affect enzymatic processes. We believe that such conditions better mimic the enzyme's natural environment, while minimizing waste and avoiding solubility issues. We propose to further explore the scope of this strategy, for example with enzymes from other classes, whole microorganisms, other substrates, and diverse types of reactions. To achieve their function, enzymes often rely on complex structural and dynamical effects. For example, in allostery, small molecules (called effectors) bind the enzyme away from the active site and increase or decrease their activity, the mechanism of which remains poorly understood. We have reported several new strategies to study allostery. We combine different biophysical and synthetic techniques. For example, we permanently attach the effectors to the enzymes to facilitate mechanistic studies, but also permanently activate the enzyme and create superior catalysts. We propose to combine several techniques to pursue our study of enzyme allostery and examine the reactivity and behavior of enzymes in moist-solid reaction mixtures and in mechanoenzymology. This research has high training value as it forces trainees to think outside the box. Since we work with non-traditional enzymatic reaction mixtures and create new methods to employ and study enzymes, we must innovate. This program also offers opportunities for a multidisciplinary training that spans biocatalysis, enzymology, microbiology, structural biology, biophysical chemistry, biochemistry, organic synthesis and material sciences.