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

Bioorganic Chemistry
John P Richard, Tina L Amyes

Abstract

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.

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Citations

May 26, 2006·Proceedings of the National Academy of Sciences of the United States of America·Bindu PillaiMichael N G James
Feb 15, 2007·Journal of the American Chemical Society·Krisztina Toth, John P Richard
Feb 26, 2008·Accounts of Chemical Research·Janet R MorrowJohn P Richard
Sep 9, 2010·Journal of the American Chemical Society·Maybelle K GoJohn P Richard
Mar 4, 2011·Journal of the American Chemical Society·Yen-lin Lin, Jiali Gao
Jan 19, 2013·Biochemistry·Tina L Amyes, John P Richard
Aug 27, 2013·Science China. Chemistry·Jiali Gao
Jun 28, 2011·Biochimica Et Biophysica Acta·Hans-Heinrich LimbachMichael D Toney
Nov 21, 2007·Journal of Molecular Graphics & Modelling·L BrunettiA Bottoni
Sep 25, 2007·Biochemical and Biophysical Research Communications·Bindu PillaiMichael N G James
May 13, 2014·Current Opinion in Chemical Biology·Maria P FrushichevaArieh Warshel
Sep 25, 2014·BioMed Research International·Bhupender SharmaShamsher S Kanwar
Apr 9, 2014·Nature Communications·Benoît DesguinPascal Hols
May 30, 2013·Chemical Communications : Chem Comm·Ashutosh S Singh, Shih-Sheng Sun
Feb 7, 2012·Organic & Biomolecular Chemistry·David DietrichJohn C Vederas

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