Theoretical studies on the decarboxylation reaction in thiamin catalysis

The conformational behavior and the stability of thiazolium and thiamin diphosphate (ThDP) adducts formed by the C2 addition of the substrates pyruvate and glyoxylate to the corresponding thiamin systems are investigated within the force-field version PIMM 90 as well as the semiempirical AM 1 and PM 3 methods. Moreover, the reaction coordinate of the decarboxylation process of the adducts with respect to the C2α(SINGLEBOND)COO⁻ bond are calculated by PM 3 and AM 1. The calculations on the key intermediates of the Breslow mechanism are performed in order to study the steric aspects of both substrate adducts that show a different pathway in the catalytic cycle. The alternative structural findings for the decarboxylation products are compared with first 6–31C * studies on the corresponding thiazolium model systems. Especially, the PM 3 calculations show that the elimination of CO₂ is favored if the arrangement of the carboxylate group is nearly perpendicular to the plane of the thiazolium ring. These results support the least-motion maximum-overlap mechanism in the enzymatic decarboxylation reaction, proposed by Kluger. The most stable conformers of the ThDP adducts and its decarboxylation products are characterized by V-like structures and the formation of a significant intramolecular hydrogen bonding under participation of the 4′-aminopyrimidine ring. © 1996 John Wiley & Sons, Inc.