A mechanism is proposed to explain the activity of orotidine 5’-monophosphate decarboxylase (ODCase). This enzyme is the one of the most proficient known, with a catalytic proficiency (k(cat)/K-m)/k(non) = 10(23) M-1. Quantum mechanical calculations predict a mechanism involving a stabilized carbene intermediate, which represents a previously unrecognized mode of enzymatic activity for ODCase. The proposed mechanism involves proton transfer from a weak acid (pK(a) = 7, where K-a is the acid constant) concerted with decarboxylation, in a nonpolar enzyme environment. Such a mechanism makes possible different approaches to the design of ODCase inhibitors. Furthermore, the prediction that general acid catalysis may only be effective in low dielectric media is of general significance for understanding the activity of many enzymes.