H₂S Is a Potential Universal Reducing Agent for Prx6-Type Peroxiredoxins

Area of Science:

• Biochemistry
• Molecular Biology
• Redox Biology

Background:

• Prx6-type peroxiredoxins lack a universal reducing agent, unlike Prx1-type subfamilies.
• A conserved histidyl residue in Prx6 active sites may hinder reduction by common agents.

Purpose of the Study:

• To investigate the reduction of Prx6-type peroxiredoxins by the hydrosulfide ion (HS⁻).
• To elucidate the role of the active-site histidine in Prx6 enzyme reactivity.

Main Methods:

• Enzymatic assays using oxidized wild-type and mutant PfPrx6 (Plasmodium falciparum) and human PrxVI.
• Kinetic analysis of reactions with hydrosulfide ion (HS⁻) at pH 7.4.
• Testing reduction of intermediate species by thioredoxin, glutaredoxin, and glutathione.

Main Results:

• HS⁻ rapidly reduced oxidized wild-type PfPrx6 and hPrxVI (k₂ > 10⁸ M⁻¹s⁻¹), but not histidyl mutants.
• The resulting protein-hydropersulfide intermediate reacted further with HS⁻ (k₂ ≈ 10⁴ M⁻¹s⁻¹).
• Thioredoxin, glutaredoxin, and glutathione did not reduce the hydropersulfide intermediate.

Conclusions:

• HS⁻ is identified as a highly reactive, potential universal electron donor for Prx6-type enzymes.
• This discovery is crucial for understanding H₂S detoxification, redox signaling, and persulfide metabolism.