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Published on: June 7, 2018
Structural evidence that peroxiredoxin catalytic power is based on transition-state stabilization
Andrea Hall1, Derek Parsonage, Leslie B Poole
1Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA.
Journal of Molecular Biology
|July 21, 2010
Summary
Peroxiredoxins (Prxs) are crucial antioxidant enzymes. A new human PrxV structure reveals how diols can inhibit Prxs, offering insights into their high catalytic efficiency and redox signaling roles.
Area of Science:
- Biochemistry
- Structural Biology
- Enzymology
Background:
- Peroxiredoxins (Prxs) are vital peroxidases involved in antioxidant defense and redox signaling.
- Their high catalytic efficiency in reducing peroxide substrates has remained largely unexplained.
- Prxs utilize a conserved cysteine residue for peroxide reduction.
Purpose of the Study:
- To elucidate the structural basis for the high catalytic activity of peroxiredoxins.
- To identify novel inhibitors and understand the mechanism of Prx inhibition.
- To explore the role of the active-site microenvironment in Prx function.
Main Methods:
- X-ray crystallography of human PrxV at 1.45 Å resolution.
- Structural analysis of dithiothreitol bound to the PrxV active site.
- Comparative analysis of structures with peroxide-mimicking ligands.
Main Results:
- A novel structure of human PrxV revealed dithiothreitol's diol moiety mimicking peroxide substrates in the active site.
- Diols and similar di-oxygen compounds are identified as a new class of competitive Prx inhibitors.
- Structural features, including hydrogen bonding and steric factors, create an 'oxygen track' enhancing reactivity.
- The active-site microenvironment was shown to activate the catalytic cysteine and stabilize the transition state of peroxidation.
Conclusions:
- The study reveals structural insights into the high catalytic efficiency of peroxiredoxins.
- Diols represent a novel class of competitive inhibitors for Prxs.
- Understanding these mechanisms advances knowledge of redox signaling and antioxidant protection.
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