Antioxidant Enzymes

Antioxidant Enzymes: Basics - Oxidative Stress Busters

• Oxidative stress: Imbalance between pro-oxidants (ROS/RNS) and antioxidant defenses.
• Reactive Oxygen Species (ROS): Highly reactive molecules, e.g., superoxide radical ($O_2^{\cdot-}$), hydroxyl radical ($\cdot OH$), hydrogen peroxide ($H_2O_2$).
• Cellular damage: ROS attack lipids (peroxidation), proteins (denaturation), and DNA (mutations).
• Antioxidant enzymes: Endogenous defense system; neutralize ROS to protect cellular integrity.
  • Key examples: Superoxide Dismutase (SOD), Catalase (CAT), Glutathione Peroxidase (GPx).

⭐ The primary defense against superoxide radicals ($O_2^{\cdot-}$) is Superoxide Dismutase (SOD), converting them to $H_2O_2$ and $O_2$.

Antioxidant Enzymes: SOD - Superoxide Slayer

• Full Name: Superoxide Dismutase.
• Core Function: Neutralizes highly reactive superoxide radicals ($O_2^{\cdot-}$), preventing oxidative damage.
• Reaction: $2O_2^{\cdot-} + 2H^+ \rightarrow H_2O_2 + O_2$.
• Key Isoenzymes & Locations:
  • SOD1 (Cu/Zn-SOD): Cytosol. 📌 Cu/Zn in Cytosol.
  • SOD2 (Mn-SOD): Mitochondrial matrix. 📌 Mn in Mitochondria.
  • SOD3 (EC-SOD): Extracellular space.
• Significance: Critical first-line enzymatic defense against $O_2^{\cdot-}$ toxicity.

⭐ Mutations in the gene for SOD1 (Cu/Zn-SOD) are associated with familial Amyotrophic Lateral Sclerosis (fALS).

Antioxidant Enzymes: Catalase - Peroxide Pacifier

• Function: Neutralizes hydrogen peroxide ($H_2O_2$) into water and oxygen.
  • Reaction: $2 H_2O_2 \rightarrow 2 H_2O + O_2$
• Location: Predominantly in peroxisomes; also cytoplasm, mitochondria.
• Structure: Tetrameric; each subunit contains a heme (iron protoporphyrin IX) prosthetic group.
• High turnover number: Extremely efficient in detoxification.
• Clinical Significance:
  • Acatalesemia (Takatsuki disease): Rare genetic deficiency; leads to ↑ risk of oral ulcerations, progressive gangrene.
  • Protects cells from oxidative damage by $H_2O_2$.

⭐ Catalase has one of the highest turnover numbers of all enzymes, decomposing millions of $H_2O_2$ molecules per second per active site at its optimum pH (around 7.0).

Antioxidant Enzymes: Glutathione System - Detox Dynamo Duo

Critical enzymatic defense neutralizing $H_2O_2$ and lipid peroxides (ROOH), protecting cells from oxidative damage.

• Glutathione (GSH):
  • Tripeptide ($\gamma$-Glu-Cys-Gly); major water-soluble antioxidant and cellular reductant.
  • Cysteine's sulfhydryl (-SH) group donates reducing equivalents.
• Glutathione Peroxidase (GPx):
  • Selenium-dependent enzyme (contains selenocysteine).
  • Catalyzes: $2GSH + H_2O_2 \rightarrow GSSG + 2H_2O$; also reduces organic peroxides (ROOH to ROH).
  • Forms oxidized Glutathione Disulfide (GSSG).
• Glutathione Reductase (GR):
  • FAD-dependent flavoenzyme (FAD from Vit B2 - Riboflavin).
  • Regenerates active GSH from GSSG: $GSSG + NADPH + H^+ \rightarrow 2GSH + NADP^+$.
  • Requires NADPH, mainly from Hexose Monophosphate (HMP) Shunt.

⭐ G6PD deficiency causes ↓NADPH, impairing GR's GSH regeneration. This increases RBC susceptibility to oxidative hemolysis, especially with oxidant drugs like primaquine. (📌 G6PD for GSH)

Antioxidant Enzymes: Clinical Links - When Defenses Falter

• SOD1 mutations: Linked to Amyotrophic Lateral Sclerosis (ALS).
• Catalase deficiency (Acatalasemia): Rare; may cause oral ulcers (Takahara's disease).
• GPx dysfunction: Selenium deficiency impairs activity; linked to Keshan disease (cardiomyopathy).
• GR dysfunction: Riboflavin (B2) deficiency reduces activity; impacts glutathione recycling.
• G6PD deficiency: ↓NADPH → ↓reduced glutathione → hemolytic anemia on oxidant exposure.

⭐ G6PD deficiency is the most common human enzyme defect, predisposing to drug-induced hemolytic anemia.

High‑Yield Points - ⚡ Biggest Takeaways

• Superoxide Dismutase (SOD): Mn-SOD (mitochondrial) & Cu/Zn-SOD (cytosolic) convert superoxide (O₂⁻) to H₂O₂.
• Catalase: Peroxisomal enzyme; degrades H₂O₂ to H₂O + O₂. High in liver, erythrocytes.
• Glutathione Peroxidase (GPx): Selenium-dependent; reduces H₂O₂ and lipid peroxides using GSH.
• Glutathione Reductase (GR): Regenerates GSH from GSSG using NADPH (from HMP shunt).
• Deficiencies in these enzymes ↑ oxidative stress, leading to cellular damage and disease.