Fenton Chemistry

The Reactions#

Classic Fenton Reaction (Iron)#

`` Fe2+ + H2O2 → Fe3+ + OH. + OH- ``

iron(II) (Fe2+) (ferrous iron) donates one electron to H2O2, generating a hydroxyl radical (OH.)—the most potent oxidizing species in biological systems (redox potential +2.31 vanadium (V)). The hydroxyl radical reacts with virtually any organic molecule within ~1 nm of its generation site.^{[1]Toxicity, Mechanism and Health Effects of Some Heavy MetalsMonisha Jaishankar, Tenzin Tseten, Naresh Anbalagan et al. · 2014Open reference 1 ↓}

Haber-Weiss Cycle (Catalytic Recycling)#

`` Fe3+ + O2.- → Fe2+ + O2 (superoxide reduces Fe3+ back to Fe2+) Fe2+ + H2O2 → Fe3+ + OH. + OH- (Fenton reaction) ─────────────────────────────── Net: O2.- + H2O2 → OH. + OH- + O2 ``

Superoxide (O2.-) recycles iron(III) (Fe3+) back to iron(II), making the process catalytic—a single iron atom can generate unlimited hydroxyl radicals as long as superoxide and peroxide are available.

This is why Superoxide Dismutase (which removes superoxide) is the first line of defense against Fenton-mediated damage.^{[2]Nong 2026 — Despite Inducing Antioxidant Regulation, Superoxide Dismutase Deficiency Makes E. coli More Sensitive to Hydrogen PeroxideYuejuan Nong, Jiaxin Qiao, Yixuan Zhao et al. · 2026Open reference 2 ↓}

Copper Fenton-Like Reaction#

`` Cu+ + H2O2 → Cu2+ + OH. + OH- ``

Copper participates in analogous Fenton-like chemistry. copper cycling between copper+ and copper(II) (Cu2+) generates hydroxyl radicals, contributing to the antimicrobial activity of copper surfaces and to copper toxicity in Cuproptosis.^{[3]Wang 2025 — Engineering Copper and Copper-Based Materials for a Post-Antibiotic EraYingxian Wang, Tongqiang Wen, Fuchao Mao et al. · 2025Open reference 3 ↓[4]Andrei 2020 — Cu Homeostasis in Bacteria: The Ins and OutsAndreea Andrei, Yavuz Ozturk, Bahia Khalfaoui-Hassani et al. · 2020Open reference 4 ↓}

Downstream Damage#

Lipid Peroxidation → Ferroptosis#

Hydroxyl radicals attack polyunsaturated fatty acids (PUFAs) in membranes, initiating lipid peroxidation chain reactions. When GPX4 (the primary lipid hydroperoxide scavenger) fails, uncontrolled lipid peroxidation triggers Ferroptosis—iron-dependent programmed cell death.^{[5]Microbial Metallomics and Parkinson's Disease: A Unified Metal-Driven Framework Linking Ferroptosis, Dysbiosis, and alpha-Synuclein PathologyKaren Pendergrass · 2025Open reference 5 ↓}

DNA Damage#

OH. generates 8-hydroxydeoxyguanosine (8-OHdG) and strand breaks, contributing to mutagenesis and carcinogenesis.

Protein Oxidation#

OH. oxidizes amino acid side chains, causes protein cross-linking, and damages metal-containing enzyme active sites.

Microbial Strategies#

PrrF sRNAs (Pseudomonas)#

PrrF small RNAs in Pseudomonas aeruginosa repress iron-using enzymes under iron limitation, preventing free iron accumulation that would drive Fenton chemistry. The PrrF/BrnD regulatory circuit balances iron utilization against Fenton risk.^{[7]Ouattara 2025 — Iron and Peroxide Regulation of the PrrF sRNAs and a Conserved Dps-Like Protein in Pseudomonas aeruginosa and Pseudomonas fluorescensKhady O Ouattara, Amanda G Oglesby · 2025Open reference 7 ↓}

Mn-for-Fe Substitution (Borrelia)#

Borrelia (B. burgdorferi) represents the most radical anti-Fenton strategy: complete elimination of iron from its biology. All iron-dependent enzymes replaced with manganese-dependent alternatives. manganese (Mn) does not participate in Fenton chemistry, making Borrelia immune to iron-mediated oxidative damage.^{[6]Londono 2025 — EPR Spectroscopy Reveals Antioxidant Manganese Defenses in the Lyme Disease Pathogen Borrelia burgdorferiAndres F Londono, Ajay Sharma, Venkatesan Kathiresan et al. · 2025Open reference 6 ↓}

SOD Deficiency Amplifies Fenton#

When SOD is absent or inhibited, superoxide accumulates, continuously recycling iron(III) (Fe3+) → iron(II) via the Haber-Weiss cycle. In E. coli SOD-deficient mutants, this cascading Fenton chemistry damages Iron-Sulfur Clusters, releasing even more free iron in a destructive feedback loop.^{[2]Nong 2026 — Despite Inducing Antioxidant Regulation, Superoxide Dismutase Deficiency Makes E. coli More Sensitive to Hydrogen PeroxideYuejuan Nong, Jiaxin Qiao, Yixuan Zhao et al. · 2026Open reference 2 ↓}

Kynurenine-Iron-Fenton Loop#

Quinolinic acid (a Kynurenine pathway metabolite) chelates iron and forms QUIN-iron (Fe) complexes that catalyze Fenton chemistry in neural tissue. This creates a self-amplifying neuroinflammatory loop: Metal-Driven Inflammation → IDO1 → kynurenine → quinolinic acid → QUIN-iron → Fenton → more inflammation.^{[8]Novikova 2025 -- Microbiome-Derived Metabolites in Parkinson's Disease (Thesis)Polina Novikova · 2025Open reference 8 ↓}

Cross-References#

• oxidative stress—Fenton chemistry as the primary ROS generation mechanism
• Ferroptosis—Iron-dependent cell death downstream of lipid peroxidation
• Iron—Primary Fenton catalyst
• Copper—Fenton-like chemistry
• Iron-Sulfur Clusters—iron (Fe)-S damage releases labile iron for Fenton
• Superoxide Dismutase—First-line defense against Haber-Weiss recycling
• Glutathione (GSH)—H2O2 scavenging prevents Fenton substrate accumulation
• Kynurenine—QUIN-iron Fenton loop in neuroinflammation
• Calprotectin (S100A8/A9)—Metal sequestration reducing Fenton at infection sites
• Cadmium—Non-redox metal that indirectly amplifies Fenton via iron displacement