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Section 5: Enzymes, Equilibrium, Energy and the Metabolic Inhibitors

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Section 5: Enzymes, Equilibrium, Energy and the Metabolic Inhibitors Small World Initiative Instructor Guide Section 5: Enzymes, Equilibrium, Energy and the Metabolic Inhibitors Section 5: Enzymes, Equilibrium, Energy and the Metabolic Inhibitors TOPICS Enzyme kinetics Binding equilibrium Free energy Metabolic reactions/energy production Molecular binding specificity Mechanism of action of metabolic inhibitors SUMMARY We continue our investigation of antibiotic specificity by introducing the metabolic inhibitors. The two different classes of metabolic inhibitors use two different mechanisms to achieve specificity. Like the β-lactams, the sulfonamides achieve specificity by binding to and inhibiting a target molecule not present in eukaryotes. In contrast, trimethoprim is representative of those antibiotics that target a specific region of a molecule present in both prokaryotes and eukaryotes. The subtle structural difference between the prokaryotic and eukaryotic version of the target is such that binding affinity of the antibiotic to the eukaryotic version is reduced relative to the prokaryotic version. We use the metabolic inhibitors as a context for discussing enzyme kinetics and energy. Instructors may also wish to include the key conserved metabolic pathways (glycolysis, tricarboxylic acid cycle, oxidative phosphorylation) as well as highlighting the metabolic diversity of the prokaryotes, although that content is not represented in the slides. LEARNING GOALS • Be able to explain the mechanism of action of metabolic inhibitors at the molecular level • Know the factors that determine rates of chemical reactions. • Know the factors that determine equilibrium of chemical reactions. • Explain how enzymes achieve substrate specificity • Describe the molecular basis for antibiotic-target “binding” (covalent, non- covalent bond formation) • Explain binding equilibrium as it pertains to antibiotic-target binding (and how it affects efficacy of an antibiotic) • Describe how metabolic inhibitors achieve prokaryotic specificity. Additional metabolism-specific learning goals that could be incorporated • Summarize the overarching goal of glycolysis, the tricarboxylic acid cycle and the electron transport chain. • Explain the electron transport chain and how cells extract energy from it. • Know the role that oxygen plays in energy acquisition/catabolism • Explain the mechanisms by which bacteria can survive in the absence of oxygen Small World Initiative Instructor Guide Section 5: Enzymes, Equilibrium, Energy and the Metabolic Inhibitors • Know examples of terminal electron acceptors for aerobic respiration, fermentation and anaerobic respiration. • Know the cellular targets of non-selective killing agents such as cyanide, heat, bleach, etc.). • Explain chemiosmosis and its role in energy acquisition. PRE-CLASS PREPARATION Prior to class, students should read about thermodynamics of chemical reactions, enzymes, and the significance of Gibbs free energy in chemical reactions. If biochemical reactions of catabolism will be discussed, students should also gain a working knowledge glycolysis, cellular respiration, and the electron transport system prior to class. PRE-CLASS ASSESSMENT 1. Refer to first “Active Learning” activity for this section. These questions would serve as appropriate pre-class assessment that could then be reviewed in an electronic response-style during class. 2. If an enzyme contains a relatively non-polar active site, how is insertion of charged amino acids at that site likely to affect its activity? 3. An antibiotic that affects activity of an intracellular enzyme must be able to cross the cell membrane. Based on this, indicate structural features that you might expect to be shared by antibiotics. — Generally they are small molecules with varying polarity. Some antibiotics gain access through pores and others cross the membrane itself. Most antibiotics are generally non-polar, relative to water. GUIDE TO THE POWERPOINT SLIDES Outline • Introduction to metabolic inhibitors • Chemical reactions — Equilibrium — Gibbs free energy — ATP • Enzymes • Function • Specificity (sulfonamide as example) • Enzyme inhibitors (trimethoprim as example) Introduction to metabolic inhibitors The sulfonamides and trimethoprim are examples of metabolic inhibitors, drugs that inhibit metabolic pathways that are vital for the life of the microbe. Folic acid is important for human health; derivatives are necessary for synthesis of DNA and amino acids and deficiency during pregnancy can lead to neural tube defects. Humans must ingest folic acid in their diet while bacteria must synthesize their own folic acid derivatives. The slides highlight the similarities and differences in the pathway between bacteria and humans. Small World Initiative Instructor Guide Section 5: Enzymes, Equilibrium, Energy and the Metabolic Inhibitors Bacteria synthesize their own folic acid derivatives Folic Acid is important for human health Dihydropteroate p-aminobenzoic acid diphosphate + (PABA) • Derivatives are necessary for (DHPP) synthesis of DNA and amino acids Dihydropteroate • Especially important for rapidly synthase Intake from diet dividing cells (DHPS) • Deficiency in pregnancy can lead to neural tube defects Dihydropteroic acid conversion Folic acid in liver conversion (vitamin B ) Dihydrofolic acid (DHF) 9 Folic acid in liver Dihydrofolic acid (DHF) Dihydrofolate (vitamin B9) Thymidine reductase Dihydrofolate (DHFR) synthesis reductase Thymidine tetrahydrofolic acid (THF) (DHFR) synthesis Amino acid tetrahydrofolic acid (THF) Amino synthesis acid synthesis The dihydropteroate synthase (DHPS) enzyme is present in bacteria, not humans and is a target of the sulfonamides. The dihydrofolate reductase (DHFR) enzyme is present in both humans and bacteria, yet trimethoprim targets only the bacterial version. The human version is structurally different enough from the bacterial version that trimethoprim binds with affinity several thousand-fold less than to the bacterial DHFR. Metabolic inhibitor antibiotics interfere with function of critical enzymes in the pathway Dihydropteroate p-aminobenzoic acid diphosphate + (PABA) (DHPP) Dihydropteroate synthase X sulfonamides (DHPS) Dihydropteroic acid conversion in liver Folic acid (vitamin B9) Dihydrofolic acid (DHF) Dihydrofolate reductase trimethoprim (DHFR) X Thymidine synthesis tetrahydrofolic acid (THF) Amino acid synthesis Chemical reactions At this point, the following key concepts can be introduced: - Equilibrium - Gibbs free energy - ATP Since these topics are standard concepts covered in all general biology texts, we leave it to each instructor to determine the content and level of detail required. Key points: — Collision theory: probability of molecules encountering each other is influenced by reactant concentration, temperature, etc. — Equilibrium is affected by the concentration of products and reactants as well as the change in free energy — Rate is affected by the concentration of products and reactants as well as by Key Principle in Biology and Chemistry temperature Equilibrium — Introduction of ATP as the universal energy Most things are in equilibrium between two states currency An atom can bond with and dissociate from a carboxylic acid More likely to be bound at lower pH Small World Initiative Instructor Guide Section 5: Enzymes, Equilibrium, Energy and the Metabolic Inhibitors At this point, students should be able to meet the learning goals: ü Know the factors that determine rates of chemical reactions. ü Know the factors that determine equilibrium of chemical reactions. Enzymes Enzymes increase the rate of reaction but Figure 5.2 do not alter equilibrium or the change in free energy. Most biological reactions have spontaneous rates that are too low to sustain life, and so we depend on enzymes to drive most reactions in the cell. Enzyme function relies on a specific interaction between the enzyme and substrate. We eluded to specificity of molecular binding interactions starting in Section 3 with our discussion of the β-lactams as cell wall inhibitors. Now that non- covalent bonding interactions have been introduced (Section 4), we can elaborate on the concept of molecular binding interactions using enzyme-substrate binding as our context. Non-covalent binding interactions between enzyme and substrate dictate specificity. Again, this is an opportunity to point out how structure relates to function. Active learning Activity type: Electronic response The following electronic response questions are intended to help students self-assess and synthesize the information presented. True or False: Question: 1) The free energy released will be greater if the reaction is catalyzed by an enzyme. 2) The rate of the reaction increases in the presence of an enzyme. 3) The activation energy required for a reaction to proceed decreased in the presence of enzyme. 1) The free energy released will be greater if the reaction is catalyzed by an enzymeFalse. Enzymes lower activation energy but do not alter the change in free energy. 2) The rate of the reaction increases in the presence of an enzyme.True. Enzymes increase the rate of a reaction, essentially by increasing the association of reactants. Enzymes tether reactants so that they are in the proper orientation and there is a higher effective concentation. Small World Initiative Instructor Guide Section 5: Enzymes, Equilibrium, Energy and the Metabolic Inhibitors 3) The activation energy required for a reaction to proceed decreased in the presence of enzyme. True. Enzymes decrease the activation energy, thus increasing
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