Kinetics of Sequential Enzyme Reactions and Electrostatic Channeling

Abstract

In cells, many enzyme-catalyzed reactions are coupled as a series of biochemical steps. Thus, the reaction rate is dependent on the kinetics of intermediate reaction steps. In this work, we study the case of two coupled enzyme reactions, where the product of the first reaction serves as the substrate of the second reaction. Using a diffusion-limited reaction model, we demonstrate that the overall kinetics is strongly dependent on the separation distance between two enzymes, although interestingly, we find that in some cases, the maximal rate occurs at a finite, non-smallest separation between enzymes. This is because the second enzyme in proximity can block the access of substrate for the first enzyme reaction, which leads to the decrease of product of the first reaction (substrate for the second reaction). We further demonstrate how this reaction rate is additionally dependent on the nature of electrostatic interactions between reactants and the two enzymes. We demonstrate the interplay of these concepts for the dihydrofolate reductase-thymidylate synthase (DHFR-TS) systems, whereby methylene tetrahydrofolate is converted to tetrahydrofoloate.Our study suggests the role of species-specific electrostatic and geometric factors in optimizing reaction rates of substrate-channeling systems.