Enzymatic transition states and transition state analog design

Research output: Contribution to journalArticle

216 Citations (Scopus)

Abstract

All chemical transformations pass through an unstable structure called the transition state, which is poised between the chemical structures of the substrates and products. The transition states for chemical reactions are proposed to have lifetimes near 10-13 see, the time for a single bond vibration. No physical or spectroscopic method is available to directly observe the structure of the transition state for enzymatic reactions. Yet transition state structure is central to understanding catalysis, because enzymes function by lowering activation energy. An accepted view of enzymatic catalysis is tight binding to the unstable transition state structure. Transition state mimics bind tightly to enzymes by capturing a fraction of the binding energy for the transition state species. The identification of numerous transition state inhibitors supports the transition state stabilization hypothesis for enzymatic catalysis. Advances in methods for measuring and interpreting kinetic isotope effects and advances in computational chemistry have provided an experimental route to understand transition state structure. Systematic analysis of intrinsic kinetic isotope effects provides geometric and electronic structure for enzyme-bound transition states. This information has been used to compare transition states for chemical and enzymatic reactions; determine whether enzymatic activators alter transition state structure; design transition state inhibitors; and provide the basis for predicting the affinity of enzymatic inhibitors. Enzymatic transition states provide an understanding of catalysis and permit the design of transition state inhibitors. This article reviews transition state theory for enzymatic reactions. Selected examples of enzymatic transition states are compared to the respective transition state inhibitors.

Original languageEnglish (US)
Pages (from-to)693-720
Number of pages28
JournalAnnual Review of Biochemistry
Volume67
DOIs
StatePublished - 1998

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Catalysis
Isotopes
Enzymes
Computational chemistry
Kinetics
Electron transitions
Vibration
Binding energy
Catalyst supports
Electronic structure
Chemical reactions
Stabilization
Activation energy
Substrates

Keywords

  • Catalysis
  • Enzymes
  • Inhibitor
  • Inhibitor design
  • Isotope effects

ASJC Scopus subject areas

  • Biochemistry

Cite this

Enzymatic transition states and transition state analog design. / Schramm, Vern L.

In: Annual Review of Biochemistry, Vol. 67, 1998, p. 693-720.

Research output: Contribution to journalArticle

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