Enzyme Therapy and Inhibitors as Drugs

Enzyme Therapy Basics - Healing Helper Enzymes

• Principle: Utilizing enzymes as therapeutic agents to correct metabolic disorders or act as specific drugs.
• Rationale:
  • Supplementing deficient/absent enzymes (Enzyme Replacement Therapy - ERT).
  • Degrading pathological/toxic substances.
  • Activating prodrugs at target sites.
• Key Applications:
  • ERT for Lysosomal Storage Diseases (LSDs): e.g., Gaucher disease (glucocerebrosidase), Fabry disease (α-galactosidase A).
  • Digestive enzyme supplements: Pancrelipase for pancreatic insufficiency.
  • Thrombolytics: Streptokinase, Urokinase.
  • Anti-cancer: L-asparaginase for Acute Lymphoblastic Leukemia (ALL).
• Challenges: Immunogenicity, short half-life, delivery to target tissues, high cost.

⭐ PEGylation (covalent attachment of Polyethylene Glycol) is a common strategy to increase enzyme half-life and reduce immunogenicity. 📌 PEG helps enzymes Persist Effectively & Gently!

Key Therapeutic Enzymes - Enzymes on Duty

• L-Asparaginase
  • Indication: Acute Lymphoblastic Leukemia (ALL).
  • Mechanism: Depletes L-asparagine $\rightarrow$ inhibits protein synthesis in leukemic cells.
  • AEs: Hypersensitivity, pancreatitis, hyperglycemia, coagulopathy.
• Thrombolytics (e.g., Alteplase, Streptokinase)
  • Indication: MI, ischemic stroke, PE.
  • Mechanism: Plasminogen $\rightarrow$ Plasmin $\rightarrow$ Fibrin degradation.
  • AEs: Bleeding, hypersensitivity (Streptokinase).
• Rasburicase
  • Indication: Tumor Lysis Syndrome (TLS) prevention/treatment.
  • Mechanism: Uric acid $\rightarrow$ Allantoin (soluble).
  • AEs: Hemolysis (G6PD deficiency), methemoglobinemia, anaphylaxis.
• Pancrelipase
  • Indication: Pancreatic insufficiency (CF, chronic pancreatitis).
  • Mechanism: Replaces lipase, amylase, protease.
  • AEs: Fibrosing colonopathy (high dose), GI upset.
• Pegloticase
  • Indication: Chronic refractory gout.
  • Mechanism: Pegylated uricase: Uric acid $\rightarrow$ Allantoin.
  • AEs: Gout flares, infusion reactions. ⚠️ G6PD deficiency.

⭐ Rasburicase is contraindicated in G6PD deficient patients due to risk of severe hemolysis and methemoglobinemia.

Enzyme Inhibition Principles - Blocking Bad Guys

Enzyme inhibitors: key drugs modulating enzyme activity.

• Reversible Inhibition:
  • Competitive: Inhibitor (I) resembles Substrate (S); binds active site.
    • Effect: $K_m$ ↑ (affinity ↓), $V_{max}$ ↔.
    • Overcome by ↑[S].
  • Non-competitive: I binds E or ES at allosteric site.
    • Effect: $K_m$ ↔, $V_{max}$ ↓.
    • Not overcome by ↑[S].
  • Uncompetitive: I binds ES complex only.
    • Effect: $K_m$ ↓, $V_{max}$ ↓.
• Irreversible Inhibition:
  • Covalent binding, permanent enzyme inactivation. $V_{max}$ ↓↓↓.
  • E.g., Aspirin, Organophosphates.

📌 Mnemonic: Comp ↑$K_m$ ($V_{max}$↔). Non-comp: $V_{max}$↓ ($K_m$↔). Uncomp: Both $K_m$↓, $V_{max}$↓.

⭐ Statins are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, lowering blood cholesterol levels. This is a very frequently tested concept for NEET PG.

Star Inhibitor Drugs - Master Blockers

📌 All Smart Aspirants Must Study Drugs! (Aspirin, Statins, ACE-I, Allopurinol, Methotrexate, Sildenafil, Disulfiram)

High‑Yield Points - ⚡ Biggest Takeaways

• Enzyme replacement therapy (ERT) treats genetic deficiencies (e.g., Gaucher's disease with imiglucerase).
• PEGylation ↑ enzyme half-life and ↓ immunogenicity, improving ERT efficacy.
• Statins are competitive inhibitors of HMG-CoA reductase, crucial for lowering cholesterol.
• ACE inhibitors (e.g., enalapril) block angiotensin-converting enzyme, managing hypertension.
• Aspirin causes irreversible inhibition of COX enzymes, reducing inflammation and platelet aggregation.
• Allopurinol inhibits xanthine oxidase (gout treatment); methotrexate inhibits dihydrofolate reductase (DHFR) (cancer/autoimmune).