1932

Abstract

Experimental analysis of enzymatic transition-state structures uses kinetic isotope effects (KIEs) to report on bonding and geometry differences between reactants and the transition state. Computational correlation of experimental values with chemical models permits three-dimensional geometric and electrostatic assignment of transition states formed at enzymatic catalytic sites. The combination of experimental and computational access to transition-state information permits () the design of transition-state analogs as powerful enzymatic inhibitors, () exploration of protein features linked to transition-state structure, () analysis of ensemble atomic motions involved in achieving the transition state, () transition-state lifetimes, and () separation of ground-state (Michaelis complexes) from transition-state effects. Transition-state analogs with picomolar dissociation constants have been achieved for several enzymatic targets. Transition states of closely related isozymes indicate that the protein's dynamic architecture is linked to transition-state structure. Fast dynamic motions in catalytic sites are linked to transition-state generation. Enzymatic transition states have lifetimes of femtoseconds, the lifetime of bond vibrations. Binding isotope effects (BIEs) reveal relative reactant and transition-state analog binding distortion for comparison with actual transition states.

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/content/journals/10.1146/annurev-biochem-061809-100742
2011-07-07
2024-06-25
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  • Article Type: Review Article
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