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Published on: July 19, 2019
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Electrostatic transition state stabilization rather than reactant destabilization provides the chemical basis for
Daniel Burschowsky1, André van Eerde1, Mats Ökvist1
1Department of Chemistry, University of Oslo, NO-0315 Oslo, Norway; and.
Summary
Enzyme catalysis relies on stabilizing transition states, not just substrate binding. This study shows electrostatic interactions are key for chorismate mutase (CM) to achieve high reaction rates.
Area of Science:
- Biochemistry
- Enzymology
- Structural Biology
Background:
- Transition state theory posits enzymes accelerate reactions by stabilizing transition states.
- Chorismate mutase (CM) is a metabolic enzyme catalyzing chorismate to prephenate rearrangement.
- Previous calculations suggested ground state destabilization, challenging traditional theory for CM.
Purpose of the Study:
- To investigate the catalytic mechanism of Bacillus subtilis chorismate mutase (CM).
- To determine whether transition state stabilization or ground state destabilization is the primary factor in CM catalysis.
- To elucidate the role of active site electrostatic interactions in enzyme catalysis.
Main Methods:
- X-ray crystallography was used to obtain high-resolution structures.
- Structural snapshots of the apo enzyme, substrate, transition state analog, and product complexes were captured.
- A variant of CM with a modified active site (arginine to citrulline) was analyzed.
Main Results:
- A sluggish CM variant with a neutral active site residue showed poor catalytic activity despite effective substrate preorganization.
- Structural analysis revealed that active site shape complementarity alone is insufficient for efficient catalysis.
- Electrostatic stabilization of the transition state was identified as crucial for high reaction rates in CM.
Conclusions:
- Contrary to some predictions, transition state stabilization, particularly via electrostatic interactions, is essential for chorismate mutase catalysis.
- Effective enzyme catalysis requires more than just substrate binding and preorganization; it necessitates specific transition state stabilization.
- This study reaffirms the importance of electrostatic interactions in the catalytic mechanisms of enzymes.
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