How to enhance enzymatic reaction rates? The Sabatier principle and beyond

Enhancing enzymatic reaction rates is essential for industrial applications; however, increasing catalytic efficiency (kcat/Km) through protein modification remains challenging due to the interdependence of kcat and Km. This review summarizes recent experimental and theoretical advances to improve enzymatic reaction rates by optimizing, rather than minimizing, Km. This concept originated from the Sabatier principle in artificial catalysis, which states that optimal catalytic activity occurs at an intermediate binding strength. When enzymes exhibit a trade-off between large kcat and small Km, the Km values that maximize reaction rates change depending on the substrate concentration. Although how much the optimum Km shifts depends on enzymes, the existence of an optimal Km that maximizes activity is expected to be applicable to a broad range of enzymes. We also discuss potential strategies to enhance kcat without altering Km by breaking their trade-off.