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The Transition State for Peptide Bond Formation Reveals the Ribosome As a Water Trap

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Specialty Science
Date 2010 Jan 19
PMID 20080677
Citations 27
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Abstract

Recent progress in elucidating the peptide bond formation process on the ribosome has led to notion of a proton shuttle mechanism where the 2'-hydroxyl group of the P-site tRNA plays a key role in mediating proton transfer between the nucleophile and leaving group, whereas ribosomal groups do not actively participate in the reaction. Despite these advances, the detailed nature of the transition state for peptidyl transfer and the role of several trapped water molecules in the peptidyl transferase center remain major open questions. Here, we employ high-level quantum chemical ab initio calculations to locate and characterize global transition states for the reaction, described by a molecular model encompassing all the key elements of the reaction center. The calculated activation enthalpy as well as structures are in excellent agreement with experimental data and point to feasibility of an eight-membered "double proton shuttle" mechanism in which an auxiliary water molecule, observed both in computer simulations and crystal structures, actively participates. A second conserved water molecule is found to be of key importance for stabilizing developing negative charge on the substrate oxyanion and its presence is catalytically favorable both in terms of activation enthalpy and entropy. Transition states calculated both for six- and eight-membered mechanisms are invariably late and do not involve significant charge development on the attacking amino group. Predicted kinetic isotope effects consistent with this picture are similar to those observed for uncatalyzed ester aminolysis reactions in solution.

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References
1.
Kingery D, Pfund E, Voorhees R, Okuda K, Wohlgemuth I, Kitchen D . An uncharged amine in the transition state of the ribosomal peptidyl transfer reaction. Chem Biol. 2008; 15(5):493-500. PMC: 2851197. DOI: 10.1016/j.chembiol.2008.04.005. View

2.
Sievers A, Beringer M, Rodnina M, Wolfenden R . The ribosome as an entropy trap. Proc Natl Acad Sci U S A. 2004; 101(21):7897-901. PMC: 419528. DOI: 10.1073/pnas.0402488101. View

3.
Rangelov M, Vayssilov G, Yomtova V, Petkov D . The syn-oriented 2-OH provides a favorable proton transfer geometry in 1,2-diol monoester aminolysis: implications for the ribosome mechanism. J Am Chem Soc. 2006; 128(15):4964-5. DOI: 10.1021/ja060648x. View

4.
Thompson J, Kim D, OConnor M, Lieberman K, Bayfield M, Gregory S . Analysis of mutations at residues A2451 and G2447 of 23S rRNA in the peptidyltransferase active site of the 50S ribosomal subunit. Proc Natl Acad Sci U S A. 2001; 98(16):9002-7. PMC: 55363. DOI: 10.1073/pnas.151257098. View

5.
Schmeing T, Huang K, Kitchen D, Strobel S, Steitz T . Structural insights into the roles of water and the 2' hydroxyl of the P site tRNA in the peptidyl transferase reaction. Mol Cell. 2005; 20(3):437-48. DOI: 10.1016/j.molcel.2005.09.006. View