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Regulation of Metabolism

Regulation of Metabolism. Rationale for Regulation. Biological Efficiency. Flexibility : adaptaton to dietary changes Need for biosynthetic products Control of pre-existing enzymes Modulation : biosynthesis only as fast as needs for macromolecular syntesis. Competing Reactions: Regulation.

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Regulation of Metabolism

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  1. Regulation of Metabolism

  2. Rationale for Regulation

  3. Biological Efficiency • Flexibility: adaptaton to dietary changes • Need for biosynthetic products • Control of pre-existing enzymes • Modulation: biosynthesis only as fast as needs for macromolecular syntesis

  4. Competing Reactions: Regulation

  5. Kinetic Controls

  6. Control Mechanisms • Control of Enzyme Amount • Induction and Repression • Catabolite Repression • Attenuaton • Control of Enzyme Activity • Modulation of k or Vmax (rare) • Control of Km’s • Control of Substrate Availability

  7. Review of Genetic Regulation General Principles

  8. Types of Enzymes • Constitutive Enzymes: e.g. glycolytic enzymes and gluconeogenic enzymes • Inducible Enzymes: e.g. b-galactosidase • Repressible Enzymes: e.g. ten enzymes of histidine biosynthesis

  9. Sites of Regulation Prokaryotes: usually at transcription initiation. Eukaryotes: can be anywhere!

  10. Types of Regulation • Specific: one pathway’s substrate or product • General: needs for C or N sources or growth rates (e.g. energy charge)

  11. Signals Mediating Regulation Availability of Substrates or Products (Ligands) Regulatory Proteins

  12. Gene Organization and Control

  13. Gene Expression in Bacteria(Operon Model)

  14. Upstream Regulatory Sequences • Promoter (general term) • UAS (Upstream Activation Sequence) • Enhancers • URS (Upstream Repression Sequence) • Operator

  15. Binding of RNA Polymerase to Promoter • Affected by regulators • Affected by “strength” of promoter: provides appropriate variation in enzyme levels

  16. Gene Expression in Eukaryotes Dispersed Genes

  17. Mechanisms of Gene Regulation

  18. Negative Regulators[Bind to operators or upstream repression sequences (URS)]

  19. Positive Regulators[Bind to promoters, enhancers or upstream activation sequences (UAS)]

  20. Attenuation in Bacteria(Coupled Transcription and Translation)

  21. Mechanism of Attenuation NOTE: Negative Regulatory System

  22. Discovery of Attenuation Charles Yanofsky

  23. Control of Enzyme Activity

  24. Irreversible Covalent Modification • Zymogen Activation • Proteolysis • Lysosomes • Proteosomes (ubiquitin)

  25. Reversible Covalent Modification

  26. Non-covalent Modification Effectors or Ligands

  27. Negative Effectors

  28. Positive Effectors

  29. Allosteric Proteins

  30. Energy Charge(Daniel Atkinson) Steady-State E.C. = 0.93 ATP, ADP and AMP = Regulatory Ligands

  31. Regulation of Degradative Pathways

  32. Degradative Pathways

  33. Enzyme Amount Induction (Inducer = Substrate) Catabolite Repression

  34. Negative Regulators

  35. Positive Regulators

  36. Enzyme Activity Regulation Unnecessary No Substrate = No Flux

  37. Lactose Utilization NOTE: function is to provide carbon and energy when substrate is available and when products are needed.

  38. Regulation of Enzyme Amount

  39. Regulation • Specific Regulation: mediated by availability of substrate called effector (or inducer) – e.g. lactose (allolactose) through its interaction with a regulatory protein. • General Regulation: e.g. catabolite repression – analogous to repression in that endproduct effector (catabolite co-repressor) prevents gene expression, often by interacting with a regulatory protein, but may use second messenger system – e.g. cAMP.

  40. Physiological Manifestations of Catabolite Repression

  41. Structure of Lac Operon

  42. Regulation of the Lac Operon

  43. Requirements for Gene Expression • Availability of Substrate: Lactose (or allolactose) and • Need for Product: low [glucose) —> cAMP

  44. Mechanism of Catabolite Repression

  45. Inducible Operon(Positive Regulator)

  46. Hut Operon of Klebsiella aerogenes

  47. Pathway

  48. Regulation hisR+ Enzyme Levels hisRC Enzyme Levels

  49. Mechanism of Regulation Carbon Catabolite Repression Nitrogen Metabolite Repression

  50. Regulation of Biosynthetic Pathways

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