On the importance of being zwitterionic: enzymatic catalysis of decarboxylation and deprotonation of cationic carbon

Carbanion ylides are strongly stabilized by electrostatic interactions between opposing charges at neighboring atoms and this stabilizing electrostatic interaction increases with decreasing dielectric constant of the medium through which the charges interact. Consequently, there is a large increase in the thermodynamic driving force, with decreasing dielectric constant of the reaction medium, for deprotonation of cationic carbon acids and decarboxylation to form related ylides. This favors catalysis of the formation of unstable ylides at enzyme active sites of low dielectric constant. A brief survey of enzymes that catalyze deprotonation of cationic carbon acids and related decarboxylation reactions shows catalysis generally occurs for substrates that are bound in a deep pocket on the protein, with an apparent dielectric constant that is much lower than for the solvent water. In several cases, proton transfer is to a catalytic residue that is relatively weakly solvated in water. We suggest that there is a strong advantage for evolution of protein catalysts that utilize weakly solvated basic side chains which are relatively easily buried in nonpolar active sites that are favorable for zwitterion formation.