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Acc Chem Res. 2012 Apr 17;45(4):495-503. doi: 10.1021/ar100162b. Epub 2011 Nov 28.

Analysis of enzymatic transacylase Brønsted studies with application to the ribosome.

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Department of Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Avenue, New Haven, Connecticut 06520, USA.


Preferential binding of an enzyme to the transition state relative to the ground state is a key strategy for enzyme catalysis. When there is a difference between the ground and transition state charge distributions, enzymes maximize electrostatic interactions to achieve this enhanced transition state binding. Although the transition state is difficult to observe directly by structural methods, the chemical details of this transient species can be characterized by studies of substituent effects (Brønsted, Hammett, Swain-Scott, etc.) and isotope effects. Brønsted analysis can provide an estimate of transition state charges for the nucleophile and leaving group of a reaction. This Account will discuss the theoretical basis of Brønsted analysis and describe its practical application to the study of transacylase enzyme systems including the peptidyl transferase reaction of the ribosome. The Brønsted coefficient is derived from the linear free energy relationship (LFER) that correlates the acidity (pK(a)) of a reactive atom to the log of its rate constant. The Brønsted coefficient establishes the change in atomic charge as the reaction proceeds from the ground state to the transition state. Bonding events alter the electrostatics of atoms and the extent of bonding can be extrapolated from transition state charges. Therefore, well-defined nucleophile and leaving group transition state charges limit the number of mechanisms that are consistent with a particular transition state. Brønsted results are most informative when interpreted in the context of other mechanistic data, especially for enzymatic studies where an active site may promote a transition state that differs significantly from a prediction based on uncatalyzed solution reactions. Here we review Brønsted analyses performed on transacylases to illustrate how these data enhanced the enzymatic mechanistic studies. Through a systematic comparison of five enzymes, we reveal a wide spectrum of Brønsted values that are possible for what otherwise appear to be similar chemical reactions. The variations in the Brønsted coefficients predict different transition states for the various enzymes. This Account explores an overriding theme in the enzymatic mechanisms that catalysis enhances commensurate bond formation and proton abstraction events. The extent of the two bonding events in relationship to each other can be inferred from the Brønsted coefficient. When viewed in the context of recent ribosomal studies, this interpretation provides mechanistic insights into peptide bond formation.

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