Theoretical Studies on Thiamin-Substrate Adducts

The conformational behavior and stability of thiamin adducts formed by the C2 addition of the substrates pyruvate and glyoxylate to the thiamin system as well as its decarboxylation products are investigated within the force field version PIMM90 and the semiempirical PM3 method. The calculations on the key intermediates of the Breslow mechanism are performed in order to study the steric aspects of both adducts which show a different pathway in the catalytic cycle. Moreover, the energetic and steric influence of the 4′-aminopyrimidine ring on the generation of the relevant conformations of the intermediates is taken into account. The most stable conformers of the adducts are characterized by V-like structures and the formation of a significant intramolecular hydrogen bonding under participation of the 4′-amino group. The findings support the "least-motion-maximum-overlap mechanism" and the relay function of the substituted pyrimidine ring. The calculations on the decarboxylation products of both adducts show that the energetically preferred structure essentially corresponds to an enamine resonance contributor in comparison with the α-carbanion resonance. There are no hints for a different stabilization of the intermediates of both substrate adducts by steric reasons within the simple nonenzymatic model.