High-level quantum chemistry calculations have been used to examine the hydrogen-abstraction reactions of diol dehydratase (DDH) in the context of both the catalytic mechanism and the enzyme dysfunction phenomenon termed suicide inactivation. The barriers for the catalytic hydrogen-abstraction reactions of ethane-1,2-diol and propane-1,2-diol are examined in isolation, as well as in the presence of various Bransted acids and bases. Modest changes in the magnitudes of the initial and final abstraction barriers are seen, depending on the strength of the acid or base, and on whether these effects are considered individually or together. The most significant changes (ca. 20 kJ mol -1) are found for the initial abstraction barrier when the spectator OH group is partially deprotonated. Kinetic isotope effects including Eckart tunneling corrections (KIEs) have also been calculated for these model systems. We find that contributions from tunneling are of a magnitude similar to that of the contributions from semiclassical theory alone, meaning that quantum effects serve to significantly accelerate the rate of hydrogen transfer. The calculated KIEs for the partially deprotonated system are in qualitative agreement with experimentally determined values. In complementary investigations, the ability of DDH to become deactivated by certain substrate analogues is examined. In all cases, the formation of a stable radical intermediate causes the hydrogen re-abstraction step to become an extremely endothermic process. The consequent inability of 5′-deoxyadenosyl radical to be regenerated breaks the catalytic cycle, resulting in the suicide inactivation of DDH.