Transketolase: Mechanistic aspects from QM and QM/MM investigations

Transketolase (TK) is a pivotal enzyme of living systems metabolism, catalyzing the transfer of two-carbon units between substrates, like pentose phosphates in pentose phosphate pathway. Due to its central activity and involvement in biologically relevant routes, the inhibition of transketolase is object of interest for new therapeutics to contrast diabetes and cardiovascular diseases among the others, as well as due to its catalytic power for elongation/shortening carbon skeleton of molecules is of interest for production of chemicals. With atomistic details of TK's activity, therefore, faster steps forward can be done in a number fields and, for these reasons, the in-depth knowledge of TK activity is required. In the current chapter, the molecular description of H. Sapiens TK (hTK) catalytic reaction, which was gained in the framework of computational investigation, is presented. In particular, DFT-based studies applying quantum-chemical (QM) cluster approach and quantum mechanics/molecular mechanics (QM/MM) in its ONIOM scheme, on the conversion of D-xylulose-5-phosphate (X5P) and D-erythrose-4-phosphate (E4P) in D-fructose-6-phosphate (F6P) and D-glyceraldehyde-3-phosphate (G3P) are shown, presenting to the reader the main technical details of performing such calculations to study the reaction mechanism of the enzyme. Finally, focus on the effect of the distortion to the catalysis will be further discussed.