Reactive oxygen species, formation and significance, antioxidants.
Introduction[edit | edit source]
Reactive oxygen species (ROS) are highly reactive molecules derived from molecular oxygen. They are continuously produced in cells as byproducts of aerobic metabolism, especially in the mitochondria. While low levels of ROS function in cell signaling, excessive accumulation leads to oxidative stress, damaging lipids, proteins, and DNA. To counteract this, organisms have evolved a complex system of antioxidants and enzymatic defenses to maintain redox homeostasis.
Sources of reactive oxygen species[edit | edit source]
1. Mitochondrial electron transport chain (ETC)[edit | edit source]
- Main source of ROS under physiological conditions
- Complexes I and III leak electrons to oxygen, forming superoxide (O₂⁻·)
2. Enzymatic reactions[edit | edit source]
- Xanthine oxidase
- Cytochrome P450 enzymes
- NADPH oxidase (NOX) – important in phagocytes during respiratory burst
3. Environmental factors[edit | edit source]
- UV radiation
- Ionizing radiation
- Pollutants, drugs, toxins
Types of reactive oxygen species[edit | edit source]
| ROS | Description |
|---|---|
| Superoxide (O₂⁻·) | Formed by one-electron reduction of O₂ |
| Hydrogen peroxide (H₂O₂) | Not a radical, but membrane-permeable |
| Hydroxyl radical (·OH) | Highly reactive, damages all biomolecules |
| Singlet oxygen (¹O₂) | Excited-state form of oxygen |
| Peroxyl radicals (ROO·) | Lipid peroxidation intermediates |
Source: Halliwell B, Gutteridge JMC. Free Radicals in Biology and Medicine. 5th ed. 2015.
Oxidative damage[edit | edit source]
Reactive oxygen species can damage all classes of biomolecules, especially under conditions of oxidative stress. Key types of oxidative damage include:
1. Lipid peroxidation[edit | edit source]
ROS attack polyunsaturated fatty acids in membrane lipids, initiating a chain reaction that compromises membrane integrity. The process consists of three stages:
- Initiation: RH (lipid) + ⋅OH → R⋅ + H2O
- Propagation: R⋅ + O2 → ROO⋅ and ROO⋅ + RH → ROOH + R⋅
- Termination: R⋅ + R⋅ → R−R / ROO⋅ + ROO⋅ → non−radical products
Byproducts like malondialdehyde (MDA) and 4-hydroxynonenal (HNE) are commonly measured markers of lipid peroxidation.
2. Protein oxidation[edit | edit source]
ROS can oxidize amino acid side chains (notably cysteine and methionine), induce protein fragmentation, or form carbonyl groups. This results in:
- Loss of enzymatic activity
- Protein misfolding
- Increased susceptibility to proteolysis
- Aggregation (as seen in neurodegenerative diseases)
3. DNA damage[edit | edit source]
ROS, especially hydroxyl radicals, can cause:
- Base modifications (e.g., 8-oxo-guanine, a mutagenic lesion)
- Single- and double-strand breaks
- Cross-linking between DNA and proteins
These changes can result in mutations, carcinogenesis, or cell death if not repaired.
Antioxidant defense systems[edit | edit source]
Divided into enzymatic and non-enzymatic systems:
Enzymatic antioxidants[edit | edit source]
1. Superoxide dismutase (SOD)[edit | edit source]
2O2−⋅ + 2H+ → H2O2 + O2
- Cytosolic: Cu/Zn-SOD (SOD1)
- Mitochondrial: Mn-SOD (SOD2)
- Extracellular: EC-SOD (SOD3)
2. Catalase[edit | edit source]
2H2O2 → 2H2O + O2
Located mainly in peroxisomes
3. Glutathione peroxidase (GPx)[edit | edit source]
H2O2+ 2GSH → 2H2O + GSSG
- Selenium-dependent
- Reduces lipid hydroperoxides and H₂O₂
- Requires glutathione reductase and NADPH to regenerate GSH
Source: Devlin TM. Textbook of Biochemistry with Clinical Correlations. 7th ed. 2010.
Non-enzymatic antioxidants[edit | edit source]
| Antioxidant | Source | Function |
|---|---|---|
| Vitamin E (α-tocopherol) | Vegetable oils, nuts | Lipid-soluble; protects membranes |
| Vitamin C (ascorbate) | Citrus fruits, vegetables | Water-soluble; regenerates vitamin E |
| Glutathione (GSH) | Endogenous tripeptide | Detoxifies peroxides via GPx |
| Uric acid | Endogenous (purine catabolism) | Scavenger of singlet oxygen |
| Flavonoids, carotenoids | Fruits, vegetables | Quench free radicals |
Redox signaling[edit | edit source]
Low/moderate ROS levels act as second messengers in pathways controlling:
- Cell proliferation
- Differentiation
- Inflammation
- Apoptosis
Regulation is mediated through:
- NF-κB
- Nrf2 (nuclear factor erythroid 2–related factor 2) → Activates transcription of antioxidant response genes
Oxidative stress[edit | edit source]
Occurs when ROS production exceeds antioxidant capacity. Linked to numerous diseases:
| Condition | Mechanism of oxidative injury |
|---|---|
| Atherosclerosis | LDL oxidation → foam cells, inflammation |
| Cancer | DNA damage → mutations, proliferation |
| Neurodegeneration | Protein aggregation (e.g., in Alzheimer’s, Parkinson’s) |
| Diabetes mellitus | ROS from hyperglycemia damages endothelium |
| Ischemia-reperfusion | Sudden ROS burst damages tissues after reoxygenation |
| Inflammatory diseases | Neutrophils/macrophages generate ROS |
Source: Valko M et al. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39(1):44–84.
Antioxidant therapies[edit | edit source]
Lifestyle & dietary[edit | edit source]
- Diet rich in fruits and vegetables
- Avoidance of smoking and pollutants
- Physical activity (improves endogenous antioxidant response)
Pharmacological[edit | edit source]
- N-acetylcysteine (NAC) → GSH precursor
- Vitamin C and E supplements (controversial efficacy)
- Coenzyme Q10, melatonin, flavonoids
→ Note: Excessive antioxidant supplementation may blunt beneficial effects of physiological ROS
Summary[edit | edit source]
Reactive oxygen species are normal byproducts of aerobic metabolism and play important roles in cell signaling. However, when in excess, they cause oxidative damage to cellular macromolecules. Cells are protected by a wide array of enzymatic and non-enzymatic antioxidants. Imbalance in this system can lead to oxidative stress, contributing to a wide spectrum of diseases. Understanding the dual role of ROS is crucial for targeting oxidative stress in clinical practice.
