TY - JOUR
T1 - Enzymatic transition states
T2 - Thermodynamics, dynamics and analogue design
AU - Schramm, Vern L.
N1 - Funding Information:
This work was supported by research Grants GM41916, CA72444, AI34342, and program project GM068036 from the National Institutes of Health.
PY - 2005/1/1
Y1 - 2005/1/1
N2 - Kinetic isotope effects and computational chemistry have defined the transition state structures for several members of the N-ribosyltransferase family. Transition state analogues designed to mimic their cognate transition state structures are among the most powerful enzyme inhibitors. In complexes of N-ribosyltransferases with their transition state analogues, the dynamic nature of the transition state is converted to an ordered, thermodynamic structure closely related to the transition state. This phenomenon is documented by peptide bond H/D exchange, crystallography and computational chemistry. Complexes with substrate, transition state and product analogues reveal reaction coordinate motion and catalytic interactions. Isotope-edited spectroscopic analysis and binding specificity of these complexes provides information about specific enzyme-transition state contacts. In combination with protein dynamic QM/MM models, it is proposed that the transition state is reached by stochastic dynamic excursions of the protein groups near the substrates in the closed conformation. Examples from fully dissociated (D N*A N), hybrid (D NA N) and symmetric nucleophilic displacement (A ND N) transition states are found in the N-ribosyltransferases. The success of transition state analogue inhibitor design based on kinetic isotope effects validates this approach to understanding enzymatic transition states.
AB - Kinetic isotope effects and computational chemistry have defined the transition state structures for several members of the N-ribosyltransferase family. Transition state analogues designed to mimic their cognate transition state structures are among the most powerful enzyme inhibitors. In complexes of N-ribosyltransferases with their transition state analogues, the dynamic nature of the transition state is converted to an ordered, thermodynamic structure closely related to the transition state. This phenomenon is documented by peptide bond H/D exchange, crystallography and computational chemistry. Complexes with substrate, transition state and product analogues reveal reaction coordinate motion and catalytic interactions. Isotope-edited spectroscopic analysis and binding specificity of these complexes provides information about specific enzyme-transition state contacts. In combination with protein dynamic QM/MM models, it is proposed that the transition state is reached by stochastic dynamic excursions of the protein groups near the substrates in the closed conformation. Examples from fully dissociated (D N*A N), hybrid (D NA N) and symmetric nucleophilic displacement (A ND N) transition states are found in the N-ribosyltransferases. The success of transition state analogue inhibitor design based on kinetic isotope effects validates this approach to understanding enzymatic transition states.
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U2 - 10.1016/j.abb.2004.08.035
DO - 10.1016/j.abb.2004.08.035
M3 - Short survey
C2 - 15581562
AN - SCOPUS:9744244983
SN - 0003-9861
VL - 433
SP - 13
EP - 26
JO - Archives of Biochemistry and Biophysics
JF - Archives of Biochemistry and Biophysics
IS - 1
ER -