Based on these very unusual stereochemical pathways, we propose that protonation and decarboxylation proceed in an enforced concerted manner, necessitating a 180° arrangement of the incoming Cys-SH proton and the leaving carboxyl group at opposite sides of the stereogenic carbon. This concerted mechanism reduces the requirement to stabilize the evolving charge after loss of the carboxylic group. The observed binding modes in a newly created hydrophobic pocket in AMDase variant ICPLLG allowed the conversion of 2-ethyl-2vinyl malonate with outstanding selectivity (>99.5% ee), reinforcing biocatalysis as a tool for exquisite enantiocontrol.