DFT and MP2 studies on the C2 C2α bond cleavage in thiamin catalysis

• Published in: Journal of molecular catalysis. B, Enzymatic Enzymatic, 2009-11, Vol.61 (1), p.36-38
• Main Authors: Friedemann, Rudolf, Tittmann, Kai, Golbik, Ralph, Hübner, Gerhard
• Format: Article
• Language: English
• Subjects: Ab initio calculations; Bioconversions. Hemisynthesis; Biological and medical sciences; Biotechnology; Fundamental and applied biological sciences. Psychology; Intermediates; Methods. Procedures. Technologies; Reaction coordinate; Transition state
• ISSN: 1381-1177; 1873-3158
• DOI: 10.1016/j.molcatb.2009.03.012

Thiamin diphosphate (ThDP), the biologically active derivative of vitamin B 1, is an important cofactor of several enzymes that catalyze the oxidative and non-oxidative conversion of α-keto acids. The final step of non-oxidative decarboxylation of pyruvate by pyruvate decarboxylase – the liberation of acetaldehyde – requires deprotonation of the α-hydroxyl group and cleavage of the C2–C2α bond of the transitory 2-(1-hydroxyethyl)-ThDP intermediate. It has been proposed that the cofactor 4′-amino/imino function is essentially involved in the deprotonation of the α-hydroxyl group. Proton transfer and C2–C2α cleavage may occur in a stepwise manner, or, alternatively in a concerted mechanism. Here, density functional theory (DFT) calculations as well as second order Møller–Plesset perturbation theory (MP2) studies were performed on a simple model for the enzyme using the program package Gaussian 03. Calculations favor a stepwise mechanism with initial formation of the C2α alkoxide, followed by C2–C2α bond cleavage.