Enzymatic transition states: Thermodynamics, dynamics and analogue design

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)13-26
Number of pages14
JournalArchives of Biochemistry and Biophysics
Volume433
Issue number1
DOIs
StatePublished - Jan 1 2005

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Thermodynamics
Isotopes
Computational chemistry
Crystallography
Kinetics
Spectroscopic analysis
Enzyme Inhibitors
Substrates
Conformations
Proteins
Peptides
Enzymes

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Enzymatic transition states : Thermodynamics, dynamics and analogue design. / Schramm, Vern L.

In: Archives of Biochemistry and Biophysics, Vol. 433, No. 1, 01.01.2005, p. 13-26.

Research output: Contribution to journalArticle

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