Nucleotides and inorganic phosphates as potential antioxidants

Area of Science:

• Biochemistry
• Chemical Biology
• Free Radical Chemistry

Background:

• The Fenton reaction generates highly reactive hydroxyl radicals (*OH), implicated in various pathological conditions.
• Inhibiting the Fenton reaction via antioxidants (radical scavengers or metal chelators) is a long-standing research goal.
• The modulatory role of purine nucleotides in the Fenton reaction has been previously disputed.

Purpose of the Study:

• To resolve the dispute surrounding purine nucleotide modulation of the Fenton reaction.
• To investigate the concentration-dependent effects of nucleotides on *OH production.
• To identify potent, biocompatible antioxidants based on nucleotide structures.

Main Methods:

• Electron spin resonance (ESR) measurements to quantify *OH production.
• Iron(II) catalyzed Fenton reactions.
• Testing of natural nucleotides, modified nucleotides, dinucleotides, and inorganic phosphates.

Main Results:

• Purine nucleotides demonstrated a concentration-dependent biphasic modulation: *OH production increased at low concentrations and decreased exponentially at higher concentrations.
• The phosphate moiety, not the nucleoside, was identified as crucial for pro/antioxidant properties, suggesting chelation.
• Modified nucleotides, particularly ATP-gamma-S, inorganic thiophosphate, and Ap5A, showed significant antioxidant activity, with ATP-gamma-S being highly potent.

Conclusions:

• The biphasic modulation is likely due to the formation of diverse nucleotide-Fe(II) complexes.
• High concentrations of nucleotides, especially ATP, can inhibit the Fenton reaction by forming stable chelates that fully coordinate Fe(II).
• Modified nucleotides, particularly ATP-gamma-S, represent promising candidates for biocompatible Fenton reaction inhibitors.