Enzyme Induction and Repression

Enzyme Induction and Repression

Enzyme Induction and Repression

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Enzyme Synthesis Control - Regulating the Enzyme Factory

  • Cells precisely control enzyme concentrations by modulating their synthesis (gene expression) or degradation rates, crucial for metabolic adaptation.
  • Follows Central Dogma: $DNA \rightarrow mRNA \rightarrow Protein (Enzyme)$.
  • Key Regulation Levels:
    • Enzyme Quantity Control: Regulates total enzyme amount. Involves altering gene expression (induction/repression). Slower, long-term response.
    • Enzyme Activity Control: Modifies function of pre-existing enzymes (e.g., allosteric, covalent). Faster, immediate response. Cholesterol Biosynthesis Pathway and Enzyme Regulation

⭐ Regulation of enzyme quantity (induction/repression) is a slower, long-term adaptive response compared to allosteric regulation of enzyme activity.

Enzyme Induction - Crank Up the Volume!

  • Definition: ↑ synthesis of enzyme protein due to an inducer.
  • Mechanism:
    • Inducer (substrate, drug, hormone) binds regulatory protein (activator/de-repressor).
    • Alters protein conformation, ↑ gene transcription (mRNA synthesis).
    • Results in ↑ enzyme synthesis.
  • Examples:
    • Lac Operon (E. coli): Lactose (inducer) → ↑ β-galactosidase.
    • CYP450 Enzymes: Drug-induced; affects drug metabolism.
      • 📌 Phenytoin, Rifampicin, Alcohol (chronic), Carbamazepine, St. John's Wort, Griseofulvin, Phenobarbital Smoke (tobacco) induce CYP enzymes. (CRAPS GPS + Smoke)

Lac Operon: Repression and Induction

⭐ Rifampicin, a potent inducer of CYP3A4, can lead to therapeutic failure of drugs like oral contraceptives and warfarin.

Enzyme Repression - Mute the Messengers!

  • Definition: ↓ enzyme synthesis rate due to a signal, typically the pathway's end-product (feedback repression). Primarily affects anabolic enzymes.
  • Mechanism:
    • Corepressor: Signal molecule (e.g., end-product) binding the aporepressor.
    • Aporepressor: Inactive repressor protein; activated by corepressor.
    • Corepressor + Aporepressor → Active Repressor Complex.
    • Active repressor binds to the operator gene on DNA.
    • Blocks RNA polymerase → ↓ mRNA transcription → ↓ enzyme synthesis.
  • Key Examples:
    • Tryptophan (Trp) Operon: Tryptophan is the corepressor.

      ⭐ In the Tryptophan operon, tryptophan itself acts as a corepressor, leading to feedback inhibition of its own synthesis pathway.

    • Heme Synthesis: Heme (end-product) represses ALA synthase (δ-aminolevulinate synthase), its pathway's rate-limiting enzyme.

Enzyme Repression Mechanism

Clinical Correlates - Doctor's Dilemma: Enzyme Flux

  • Induction: ↑ enzyme (e.g., CYP450) synthesis by drugs → accelerated metabolism.
    • Impact: ↓ drug efficacy, ↑ toxic metabolites, interactions.
    • Therapeutic use: Phenobarbital: Crigler-Najjar II, neonatal jaundice (induces UGT).
  • Repression: ↓ enzyme synthesis → ↓ metabolism.
    • Impact: ↑ drug toxicity, ↓ active drug formation.
  • Faulty Regulation: Faulty induction/repression (genetics, disease) → metabolic disorders.

Key Drug Inducers & Clinical Impact

InducerEnzymes AffectedImpact
RifampicinCYP3A4, 2C9, 2C19↓ Warfarin, OCP efficacy
PhenobarbitalCYP2B6, 3A4, UGT↓ Drug levels; bilirubin conjugation (therapeutic)
CarbamazepineCYP3A4Auto-induction; ↓ drug levels
Chronic AlcoholCYP2E1↑ Paracetamol toxicity (↑NAPQI)

High‑Yield Points - ⚡ Biggest Takeaways

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Practice Questions: Enzyme Induction and Repression

Test your understanding with these related questions

A factor that is likely to increase the duration of action of a drug that is partially metabolized by CYP3A4 in the liver is:

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Flashcards: Enzyme Induction and Repression

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Serine proteases, aminotransferases and pyruvate carboxylase are examples of _____ reactions

TAP TO REVEAL ANSWER

Serine proteases, aminotransferases and pyruvate carboxylase are examples of _____ reactions

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