The relationship between the two hydrogen isotope effects, k(H)/k(T) and k(D)/k(T), can provide a probe for the role of tunneling and coupled motion in enzyme-catalyzed reactions.(1,2) Using vibrational analysis and. the Bigeleisen-Mayer equation, we have developed a simple computational model to explain the unusual exponential relationships that have been experimentally observed in the yeast alcohol dehydrogenase (YADH)(3)-catalyzed oxidation of benzyl alcohol.(2) The experimental results are fitted by a model that has both substantial hydrogen tunneling and coupling between the reaction coordinate and a large number of vibrational modes; We show that the secondary k(D)/k(T) isotope effect is expected to be the most sensitive parameter to changes in reaction coordinate properties. A high degree of coupled motion leads to an unexpected suppression of the semiclassical secondary isotope effects, resulting in secondary isotope effects which are primarily manifestations of tunneling: This has implications for the use of secondary hydrogen isotope effects as probes of transition state position. During the course of these computational studies, primary carbon isotope effects were shown to undergo a consistent increase in magnitude upon substitution of the transferring protium with deuterium. We suggest that this effect can be explained using simple semiclassical principles and will apply to a broad range of reactions. Inference of reaction mechanism from the observation of a change in a heavy atom isotope effects upon substrate deuteration should be interpreted with caution when the position of heavy atom and hydrogen isotope substitution are the same.