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Structure of Session 3

Molecule, Gene, and disease Sun. 2 – 3 – 2014 Session 3 Enzymes and enzyme regulation Dr. Muna A. R. Structure of Session 3. Lecture 5: Enzyme activity: kinetics and inhibition 8:00 – 8:50 Lecture 6: Regulation of enzyme activity 8:50 – 9:40 Work Session 2

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Structure of Session 3

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  1. Molecule, Gene, and diseaseSun. 2 – 3 – 2014 Session 3Enzymes and enzyme regulationDr. Muna A. R.

  2. Structure of Session 3 Lecture 5: Enzyme activity: kinetics and inhibition 8:00 – 8:50 Lecture 6: Regulation of enzyme activity 8:50 – 9:40 Work Session 2 10:00 – 12:00

  3. Learning outcomes 1) Explain the effects of enzymes on chemical reactions. 2) Describe how reaction rates vary as a function of enzyme and substrate concentration. 3) Define the terms activity, international unit of enzyme activity, Km and Vmax. 4) Analyse and interpret kinetic data for enzyme-catalysed reactions. 5) Describe the effects of enzyme inhibitors on enzyme kinetics and be able to distinguish between the two from simple graphs. 6) List the major regulatory mechanisms that control enzyme activity (plus examples).

  4. Learning outcomes 7) Discuss the allosteric properties of a key regulatory enzyme such as phosphofructokinase. 8) Discuss the concept of enzyme cascades and the use of protein kinases and phosphatases to regulate activity. 9) Define the term zymogen and give examples of enzymes that are derived from zymogens. 10) Explain how activation of the clotting cascade leads to the formation of a fibrin clot. 11) Discuss the mechanisms that are involved in the regulation of clot formation and breakdown.

  5. Suggested reading • Marks’ Basic Medical Biochemistry Chapters 8, 9, 45 • Medical Biochemistry Chapters 6, 7 • Lippincott’s Illustrated Reviews: Biochemistry Chapter 5

  6. Nomenclature Enzymes are named by the type of reaction that they catalyse. Usually this means adding the suffix –aseto the name of their substrate or reaction that they catalyse e.g. Lactase hydrolyses lactose into glucose and galactose DNA polymerase, polymerises deoxynucleotides to form DNA

  7. Properties of enzymes 1. Virtually all enzymes are proteins Some enzymes also require the presence of additional chemical components to catalyse reactions. *Cofactors are inorganic ions such as Fe2+, Mn2+etc. *Coenzymes are organic compounds that act as temporary carriers of groups in the reaction e.g. nicotinamide adenine dinucletide (NAD), Coenzyme A (CoA). *Coenzymes or cofactors that are tightly or covalently linked to the enzyme protein are known as prosthetic groups. 2. Enzymes are highly specific Interact with one or only a few substrates and catalyse one type of reaction.

  8. • The protein part of the enzyme (apo-enzyme) +Cofactor,prostheticgroup,or the coenzyme= Holoenzyme

  9. Properties of enzymes 3. Enzymes increase the rate of a reaction Enzymes increase the rate of the reaction by factors of 1 million or more. They DO NOT affect the equilibrium of a reaction. 4. Enzymes are left unchanged after the reaction has occurred. Enzymes provide a place for the reaction occur. Although there may be changes to the enzyme during the course of the reaction on completion the enzyme will be unchanged.

  10. How do enzymes work?

  11. The active site The active site of an enzyme is the place where the reaction occurs. Only molecules that have a complementary shape to the active site will be able to bind (Lock and Key Hypothesis). The substrate is held in the active site by multiple weak bonds with amino acids in this part of the enzyme.

  12. The Michaelis-Menten Model : E + S ES E + P Vo = Vmax [S] [S] + Km WhereV0= initial reaction velocity [S] = substrate concentration Vmax = maximal velocity Km = Michaelis constant *Low Km means high affinity of the enzyme to the substrate. *High Km means low affinity of the enzyme to the substrate.

  13. Enzymes – Lineweaver-Burk Equation V = Vmax [S] [S] + Km Inverting the Equation yields: 1 = Km + 1 V Vmax [S] Vmax Inverting the Equation yields: (Lineweaver-Burke Equation) By plotting 1/ V as a function of 1/[S], a linear plot is obtained: Slope = Km/Vmax y-intercept = 1/Vmax

  14. FACTORS AFFECTING REACTIO N VELOCIT Y • Substrate concentration

  15. FACTORS AFFECTING REACTIO N VELOCITY

  16. FACTORS AFFECTING REACTIO N VELOCIT Y

  17. Inhibition of enzyme activity Many drugs work by inhibiting the activity of enzymes. 1-Irreversible inhibitors: Bind covalently to the enzyme molecule to destroy enzyme function

  18. 2-Reversible inhibitors i) Competitive inhibitors: -Binds at the active site -Affects Km not Vmax -Can be overcome by increasing the substrate concentration

  19. Examples of competitive inhibitors: *Allopurinol competes with hypoxanthine for xanthine oxidase inhibiting the formation of uric acid, so it is used in treatment of hyperuricemia (gout). *Statins (e.g. atorvastatin) competes with HMGCoA for its reductase, so, it inhibits cholesterol synthesis.

  20. ii) Non-competitive inhibitors:

  21. Non-competitive inhibitors

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