Protein degradation

• Protein Turnover


  Continuous biosynthesis and degradation to maintain cellular function and homeostasis
• Sites of Protein Turnover

  • Ribosomes (Cytoplasm)
  • Cytoplasmic Proteases
  • Lysosomes
  • Proteasome
• Points of Control in Protein Metabolism

  • Transcriptional Control
  • RNA Processing Control
  • mRNA Degradation
  • Translational Control
  • RNA Transport & Location
  • Post-translational Modifications (PTMs)
  • Protein Degradation
• Protein Degradation


  Removal of proteins through various degradation pathways
• Functions of Protein Degradation

  • Provides Amino Acids
  • Regulation
  • Energy Production
• Main Degradation Pathways


  • Extracellular Proteases
  • Intracellular Proteases
• Extracellular Proteases


  Involved in the digestion of dietary proteins and activation of extracellular signaling molecules
• Extracellular Proteases


  • Trypsin
  • Thrombin
• Intracellular Proteases


  • Lysosomal Degradation
  • Ubiquitin-Proteasome System (UPS)
• Digestive (Gastrointestinal) Tract


  • Stomach
  • Small Intestine
• Pepsin


  Initiates protein degradation, activated by HCl
• Pancreatic Enzymes


  • Trypsin
  • Chymotrypsin
• Intestinal Enzymes


  Aminopeptidases further digest proteins to free amino acids
• Absorption


  Free amino acids are absorbed through the intestinal mucosa into the bloodstream for distribution to tissues
• Activation Mechanisms


  • Pepsinogen to Pepsin
  • Trypsinogen to Trypsin
  • Chymotrypsinogen to Chymotrypsin
• Catalytic Classes


  • Serine Proteases
  • Threonine Proteases
  • Cysteine Proteases
  • Aspartate Proteases
  • Glutamic Proteases
  • Metalloproteases
• pH Specificity


  • Acid Proteases
  • Neutral Proteases
  • Basic Proteases
• Lysosomal System


  Membrane-bound vesicles containing more than 50 different hydrolytic enzymes, including proteases (cathepsins), lipases, nucleases, and phosphatases
• Function of Lysosomes


  Degrade various biomolecules and protect the cell from damage by compartmentalizing these enzymes
• pH Dependence of Lysosomal Enzymes

  Function optimally at acidic pH (~5), whereas the cytosol is neutral (pH 7.2), providing protection from leakage
• Formation and Role of Lysosomes


  • Exocytosis
  • Autophagy
  • Endocytosis
  • Autolysis
• Structure of the Proteasome Complex

  • 20S Core Particle
  • 19S Regulatory Caps
  • 26S Proteasome
• Function of the Proteasome

  Degrades ubiquitin-tagged proteins in an ATP-dependent manner
• Catalytic Activities of the Proteasome

  • Chymotrypsin-like activity
  • Trypsin-like activity
  • Post-acidic like activity
• Ubiquitination Process


  1. E1 (Ub-Activating Enzyme)

  2. E2 (Ub-Conjugating Enzyme)

  3. E3 (Ub-Protein Ligase)

  4. Polyubiquitination
• Outcome of Polyubiquitination


  Polyubiquitinated proteins are recognized by the proteasome, unfolded, deubiquitinated, and degraded into peptides
• Urea Cycle and Ammonia Excretion

  1. Carbamoyl Phosphate Synthetase I

  2. Ornithine Transcarbamylase

  3. Argininosuccinate Synthetase

  4. Argininosuccinate Lyase

  5. Arginase
• Purpose of the Urea Cycle

  Convert toxic ammonia to urea for safe excretion
• Fumarate produced in the urea cycle

  Enters the TCA cycle, linking nitrogen and carbon metabolism
• Detailed Steps of the Urea Cycle

  1. Carbamoyl Phosphate Synthetase I Reaction

  2. Carbamoyl Group Transfer

  3. Citrulline Transport and Reaction with Aspartate

  4. Argininosuccinate Cleavage

  5. Urea Formation
• Links Between Urea Cycle and TCA Cycle

  • Aspartate-Argininosuccinate Shunt
  • Enzyme Localization
• Summary


  • Main Degradation Pathways
  • Function of Proteases
  • Molecular Mechanisms
  • Cell Cycle Control
  • Urea Cycle