Universal Design Principle to Enhance Enzymatic Activity using the Substrate Affinity

ABSTRACT

Design principles to improve enzymatic activity are essential to promote energy-material conversion using biological systems. For more than a century, the Michaelis-Menten equation has provided a fundamental framework of enzymatic activity. However, there is still no concrete guideline on how the parameters should be optimized to enhance enzymatic activity. Here, we demonstrate that tuning the Michaelis-Menten constant (K_m) to the substrate concentration (S) maximizes enzymatic activity. This guideline (K_m = S) was obtained by applying the Brønsted (Bell)-Evans-Polanyi (BEP) principle of heterogeneous catalysis to the Michaelis-Menten equation, and is robust even with mechanistic deviations such as reverse reactions and inhibition. Furthermore, K_m and S are consistent to within an order of magnitude over an experimental dataset of approximately 1000 wild-type enzymes, suggesting that even natural selection follows this principle. The concept of an optimum K_m offers the first quantitative guideline towards improving enzymatic activity which can be used for highthroughput enzyme screening.