Hydrogen tunneling in quinoproteins

Abstract

It is now widely accepted that substrate C–H bond breakage by quinoprotein enzymes occurs by quantum mechanical tunneling. This paradigm shift in the conceptual framework for these reactions away from semi-classical transition state theory (i.e., including zero-point energy but with no tunneling correction) has been driven over recent years by experimental studies of the temperature dependence of kinetic isotope effects for these reactions in the TTQ-dependent enzymes methylamine dehydrogenase and aromatic amine dehydrogenase, which produced observations also inconsistent with the simple Bell correction model of tunneling. However, these data—specifically, the strong temperature dependence of reaction rates and the variable temperature dependence of kinetic isotope effects—are consistent with other tunneling models (denoted full tunneling models) in which protein and/or substrate fluctuations generate a configuration compatible with tunneling. These models accommodate substrate/protein (environment) fluctuations required to attain a configuration with degenerate quantum states and, when necessary, motion required to increase the probability of tunneling in these states. Furthermore, tunneling mechanisms in quinoproteins are supported by computational studies employing variational transition state theory with multidimensional tunneling corrections; these studies are also discussed in this review. Potential pitfalls in analyzing the temperature dependence of kinetic isotope effects as probes of tunneling are also discussed with reference to PQQ-dependent methanol dehydrogenase.