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Unraveling Entropic Rate Acceleration Induced by Solvent Dynamics in Membrane Enzymes
Published on: January 16, 2016
Hydrogen tunneling steps in cyclooxygenase-2 catalysis.
Husain H Danish1, Irina S Doncheva, Justine P Roth
1Department of Chemistry, Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, United States.
Journal of the American Chemical Society
|September 10, 2011
Summary
Cyclooxygenase-2 (COX-2) enzyme activity was studied using linoleic acid. Researchers observed significant deuterium kinetic isotope effects, indicating reversible hydrogen tunneling during the oxidation process.
Area of Science:
- Biochemistry
- Enzymology
- Chemical Kinetics
Background:
- Cyclooxygenases-1 and -2 (COX-1 and COX-2) are hemoproteins that utilize tyrosyl radicals for synthesizing lipid-derived autocoids.
- COX-2 is a key mediator of inflammation and is often upregulated in various cancers.
Purpose of the Study:
- To investigate the COX-2-catalyzed oxidation of linoleic acid, a substrate analogue.
- To elucidate the mechanism of hydrogen atom abstraction and the role of the catalytic tyrosyl radical.
Main Methods:
- Enzyme kinetics studies using linoleic acid as a substrate analogue.
- Measurement of deuterium kinetic isotope effects (KIEs) under varying oxygen concentrations.
- Analysis of temperature dependence of KIEs.
Main Results:
- Observed very large (≥20) temperature-independent deuterium KIEs for enzyme turnover, attributed to hydrogen atom abstraction from the bisallylic C-H(D) of linoleic acid.
- KIE magnitude was dependent on O(2) concentration, suggesting reversible H/D tunneling mediated by the catalytic tyrosyl radical.
- At physiological O(2) levels, temperature-dependent KIEs on O-H(D) homolysis were observed, consistent with nuclear tunneling.
Conclusions:
- The study provides novel insights into the mechanism of COX-2-catalyzed fatty acid oxidation.
- Evidence supports the involvement of reversible hydrogen tunneling mediated by the catalytic tyrosyl radical in COX-2 function.
- Findings contribute to understanding COX-2's role in inflammation and cancer biology.
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