Drug Action and Enzyme-Substrate Kinetics

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Questions and Answers

Which of the following best describes the function of a catalyst in a chemical reaction?

  • Shifts the equilibrium of the reaction towards the products.
  • Decreases the activation energy of the reaction. (correct)
  • Increases the potential energy of the products.
  • Increases the activation energy of the reaction.

What is the significance of the Michaelis-Menten constant ($K_M$) in enzyme kinetics?

  • It describes the rate of product formation at very low substrate concentrations.
  • It indicates the degree to which pH affects enzyme activity.
  • It represents the maximum rate of reaction when the enzyme is saturated with substrate.
  • It is numerically equal to the substrate concentration at which the reaction rate is half of $V_{max}$. (correct)

How does an allosteric activator affect the binding of a substrate to an enzyme?

  • It prevents the substrate from undergoing a conformational change.
  • It directly competes with the substrate for binding to the active site.
  • It binds to a site distinct from the active site and induces a conformational change that increases the enzyme's affinity for the substrate. (correct)
  • It forms a covalent bond with the enzyme, permanently activating it.

Which characteristic distinguishes a specific drug action from a non-specific drug action?

<p>A specific drug action targets the specific agent responsible for the disease, while a non-specific drug action alleviates symptoms. (B)</p> Signup and view all the answers

What is the primary difference between reversible and irreversible enzyme inhibitors?

<p>Reversible inhibitors can detach from the enzyme, restoring its activity, whereas irreversible inhibitors permanently disable the enzyme. (A)</p> Signup and view all the answers

How does a competitive inhibitor affect an enzyme's kinetics?

<p>By increasing the $K_M$ without affecting the $V_{max}$. (C)</p> Signup and view all the answers

What is the mechanism of action of non-competitive enzyme inhibitors?

<p>Binding to an allosteric site, which changes the enzyme's conformation and reduces its catalytic activity. (A)</p> Signup and view all the answers

What is the defining characteristic of a mechanism-based enzyme inhibitor (suicide substrate)?

<p>It is converted by the enzyme into a reactive intermediate that irreversibly modifies the enzyme. (C)</p> Signup and view all the answers

Which type of enzyme inhibition is exemplified by drugs that act as transition state analogs?

<p>Mechanism-based reversible inhibition. (D)</p> Signup and view all the answers

What is the typical target of sulfa drugs, and how do they exert their effect?

<p>They interfere with bacterial folic acid synthesis by acting as competitive inhibitors. (C)</p> Signup and view all the answers

How does 6-mercaptopurine (6-MP) function as a purine antagonist in cancer therapy?

<p>It inhibits purine synthesis, leading to the formation of non-functional DNA and RNA. (A)</p> Signup and view all the answers

What is the role of clavulanic acid in combination antibiotic therapies?

<p>It acts as a beta-lactamase inhibitor, protecting antibiotics like penicillin from degradation. (B)</p> Signup and view all the answers

In the context of enzyme kinetics, what is the effect of transition state analogs?

<p>They stabilize the transition state, thereby acting as potent, reversible inhibitors. (D)</p> Signup and view all the answers

Which statement best describes the function of reaction coordinate analogs as enzyme inhibitors?

<p>They react with the active site to form a covalent complex that can't proceed to form product. (B)</p> Signup and view all the answers

Affinity labels are a type of irreversible enzyme inhibitor. What is their primary characteristic concerning enzyme interaction?

<p>They are designed to resemble the natural substrates and alkylate nucleophilic groups at the active site. (B)</p> Signup and view all the answers

How is the Lineweaver-Burk plot used to determine the impact of enzyme inhibitors on enzyme kinetics?

<p>It is used to linearize the Michaelis-Menten equation, allowing the $K_M$ and $V_{max}$ to be easily determined and compared in the presence and absence of inhibitors. (A)</p> Signup and view all the answers

In designing a new drug, why is understanding the drug's mechanism of action (MOA) important?

<p>It helps predict potential side effects and drug interactions, and optimize efficacy. (B)</p> Signup and view all the answers

How do the structural characteristics of a drug influence its ability to interact with its molecular target?

<p>The shape and chemical properties determine binding affinity and specificity. (B)</p> Signup and view all the answers

Which of the following is an example of drugs acting on the target by mechanism-based enzyme inhibition?

<p>Drugs that are converted by the enzyme into a reactive intermediate that irreversibly modifies the enzyme. (A)</p> Signup and view all the answers

What is the role of receptors as drug targets?

<p>They bind drugs, initiating a cascade of intracellular events leading to a physiological response. (D)</p> Signup and view all the answers

What is the significance of the two-state receptor model in pharmacology?

<p>It explains how receptors exist in both active and inactive states, and how drugs can shift the equilibrium between these states. (D)</p> Signup and view all the answers

How do inverse agonists differ from antagonists in their interaction with receptors?

<p>Inverse agonists shift the receptor equilibrium toward the inactive state, whereas antagonists have no effect on the equilibrium. (B)</p> Signup and view all the answers

When considering the course of drug administration to drug action, what happens immediately after a drug is dissolved in gastrointestinal fluids?

<p>The drug is either degraded or absorbed in the intestine. (A)</p> Signup and view all the answers

Which of the following best describes how drugs may act remotely to produce a similar effect?

<p>Drugs may act internally or externally to the target organ to produce the desired effect. (B)</p> Signup and view all the answers

What is the role of the drug target in the context of drug action?

<p>It is the specific molecule in the body that the drug interacts with to produce its effects. (D)</p> Signup and view all the answers

Why is it important to identify the molecular basis for the selective action of drugs?

<p>To understand how drugs exploit differences in metabolic pathways, enzyme structures, etc. to target specific cells or organisms. (C)</p> Signup and view all the answers

What is the fundamental principle behind non-selective drug action?

<p>Drugs act on ubiquitous targets, affecting a wide range of cells and processes. (C)</p> Signup and view all the answers

Between receptors and enzymes, which is the more common drug target?

<p>Receptors (B)</p> Signup and view all the answers

Which example is most consistent with classical reversible enzyme inhibition?

<p>A drug forming a transient bond in the active site and preventing substrate access (C)</p> Signup and view all the answers

Which of the following is a direct target of chemotherapeutic drugs?

<p>Nucleic acid biosynthesis (B)</p> Signup and view all the answers

Which of these options correctly relates reversible enzyme inhibition?

<p>Involves drugs detaching from the enzyme active site, restoring its activity (B)</p> Signup and view all the answers

Which of the following is an example of direct enzyme inhibition by a transition state analog?

<p>Inhibiting with similar structure to the transition state (C)</p> Signup and view all the answers

What is a common consequence of suicide substrate binding?

<p>The active site of the enzyme converts the drug into a highly reactive form that subsequently forms a covalent bond with the active site (C)</p> Signup and view all the answers

How does enzyme structure relate to selective drug action?

<p>The spatial arrangement will impact binding and influence activity (B)</p> Signup and view all the answers

Which are considered the most common drug targets?

<p>Receptors and enzymes (D)</p> Signup and view all the answers

How does the concept of stereochemistry relate to drug action?

<p>Drugs can have multiple forms, each with very divergent properties (B)</p> Signup and view all the answers

How does a drug that acts non-specifically exert its effects?

<p>By alleviating symptoms of a disease without directly addressing the underlying cause. (A)</p> Signup and view all the answers

What distinguishes transition state analogs from reaction coordinate analogs in enzyme inhibition?

<p>Transition state analogs mimic the intermediate state of the enzyme reaction, while reaction coordinate analogs resemble the enzyme's substrate but form stable covalent complexes. (C)</p> Signup and view all the answers

How do suicide substrates (mechanism-based inhibitors) differ from classical reversible inhibitors?

<p>Suicide substrates require the enzyme's catalytic activity to be converted into an active inhibitor, while classical reversible inhibitors do not. (B)</p> Signup and view all the answers

Which of the following distinguishes competitive enzyme inhibitors from non-competitive enzyme inhibitors?

<p>Competitive inhibitors can be overcome by high substrate concentrations, while non-competitive inhibitors cannot. (B)</p> Signup and view all the answers

How does clavulanic acid enhance the effectiveness of certain penicillin antibiotics?

<p>By acting as a suicide substrate that inhibits bacterial beta-lactamase, preventing the degradation of the antibiotic. (D)</p> Signup and view all the answers

Flashcards

Activation Energy

Enzymes speed up reactions by lowering this.

Binding Affinity (Km)

A measure of how tightly an enzyme binds a substrate.

Enzyme Kinetics Curve

Graph showing the relationship between substrate concentration and reaction rate.

Michaelis-Menten Kinetics

Mathematical model describing enzyme kinetics.

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Lineweaver-Burk Plot

Graph used to determine Km and Vmax.

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Competitive Inhibition

Inhibition where the inhibitor binds to the same site as the substrate.

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Non-Competitive Inhibition

Inhibition where the inhibitor binds to a different site than the substrate.

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Enzyme Activator

A molecule that promotes enzyme activity.

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Enzyme Inhibitor

A molecule that diminishes enzyme activity.

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Allosteric Regulation

When an inhibitor binds to a site other than the active site, altering enzyme shape.

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Specific vs. Non-Specific Drug Action

Direct action targets the cause; Non-specific alleviates symptoms.

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Drug Target

The desired target of the drug to cause an effect.

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Agonist

A molecule that binds to a receptor and activates it.

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Antagonist

A molecule that binds to a receptor and blocks its activation.

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Competitive Inhibition

Binds to the active site.

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Non-competitive Inhibition

Binds to a site on the enzyme other than the active site.

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Irreversible Inhibition

Drug binds permanently, inactivating the enzyme.

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Suicide Substrate

Drug mimics the substrate then inactivates the enzyme.

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Transition State Analog

Drug resembles transition state, tightly binding the enzyme.

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Para-aminobenzoic acid (PABA)

Sulfa drugs inhibit dihydrofolate reductase by mimicking this molecule.

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Clavulanic acid

Example of a suicide substrate.

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Beta-lactamase

Decrease of beta-lactam antibiotics activity.

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Specific vs. Non-Specific Actions

Specific - Directly targets the cause of the disease; Non-Specific - alleviates symptoms.

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Catalysts effect

Enzymatic reaction proceeds more rapidly.

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Competitive inhibition

Classical Reversible Enzyme Inhibition.

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Affinity Labels

Irreversible Enzyme Inhibition.

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Transition State Analogs

Non-classical Reversible Enzyme Inhibition.

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Reaction Coordinate Analogs

Non-classical Reversible Enzyme Inhibition.

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Study Notes

Fundamentals of Enzyme-Substrate Kinetics

  • Drugs targeting enzyme function have different modes of action.
  • Enzyme inhibition categories include classical reversible, mechanism-based reversible, and irreversible enzyme inhibition.

Action and Targets of Drugs

  • Major drug classes have structural and chemical features that influence their mode of action and molecular targets.
  • Specific drugs modes of action target: nucleic acid biosynthesis and catabolism, protein biosynthesis, bacterial cell wall biosynthesis, viruses, and fungi.

Selective Action of Drugs

  • The molecular basis for selective drug action is found in: metabolic pathways, enzyme structure, cellular architecture, and biochemical processes.

Drug Action

  • Specific direction of action directly targets the agent responsible for the disease.
  • Nonspecific action occurs when a symptom of the disease is improved, such as fever, without treating the condition.
  • Drugs may act directly at the site of action, or remotely to produce a similar effect.
  • General concepts of drug action should be identified.
  • Identify various drug targets.
  • Specific examples of drugs acting on targets by the mechanisms above should be discussed.
  • Understand suicide substrates and Kcat inhibitors.

Enzyme-Substrate and Receptor-Ligand Interactions

  • Enzyme-substrate and receptor-ligand interactions is fundamental.

Specific vs Non-Specific Action

  • Specific and non-specific drug actions should be distinguished.

Enzyme Inhibition

  • Distinguish the fundamentals of reversible, irreversible, and mechanism-based enzyme inhibition.

Drug Administration

  • Course of drug administration to drug action:
    • Total drug in oral dosage form is either disintegrated and dissolved, or the drug isn't dissolved.
      • Drug dissolved in GI fluids
      • Drug is either degraded in the gastric medium, or the stomach emptying time is affected.
        • Drug in solution is in the intestine
        • Drug is either not absorbed and lost by degradation in the intestinal medium, or the binding to food or other intestinal contents is affected.
          • Drug in solution is absorbed
            • Drug in liver
            • Drug either lost by secretion into bile, or is bound to tissue and lost by biotransofmration.
              • Drug reaches general circulation
              • Drug either lost by biotransformation, or is bound to plasma protein. - Drug distributed to body - Drug either distributed to tissues and organs other than the site of action, or bound to tissue - Causes the drug to be lost by biotransformation and excertion - Drug at site of action.

Therapeutic Target Database (2022)

  • Accumulation of drugs and their corresponding targets, in the latest and previous versions of the TTD database, has been tracked.

Therapeutic Target Classes

  • Therapeutic targets include: receptors (45%), enzymes (28%), hormones and factors (11%), nucleic acids (2%), nuclear receptors (2%), ion channels (5%), and unknown (7%).

Enzymes Compared to Receptors

  • Binding molecule: substrate for enzymes, ligand for receptors.
  • Complex: E-S for enzymes, R-L for receptors.
  • Outcome: product formation for enzymes, complex formation (or response) for receptors.
  • Number of binding sites: one or more for both.
  • Type of binding: specific or nonspecific for both.
  • Measurement of binding affinity: Km for enzymes, Kd for receptors.
  • Types of binding molecules: inhibitors, activators for enzymes, agonists, antagonists for receptors.
  • Regulation: allosteric activation for enzymes, gene regulation for receptors.

Enzymes and Catalysis

  • Catalysts lower the activation energy (Ea), which allows the reaction to proceed faster.

Enzymatic Modification

  • E + S yields ES, which then yields E + P
  • V = Vmax[S]/[S] + KM
    • Where KM is the Michaelis-Menten constant.

Lineweaver-Burk Plot

  • 1/V
  • Slope = KM/Vmax
  • Intercept = -1 / KM
  • Intercept = 1/Vmax

Classical Reversible Enzyme Inhibition

  • Competitive inhibition involves binding to the active site.
  • Non-competitive inhibition involves binding to an allosteric site and to an ES complex.

Mechanism-Based Reversible Enzyme Inhibition

  • Transition State Analogs mimic the reactive intermediate.
  • Reaction Coordinate Analogs react with the active site to form a covalent complex [EI] that is reversible but can't form a product.

Irreversible Enzyme Inhibition

  • Affinity labels alkylate the enzyme.
  • Mechanism-Based Irreversible Enzyme Inhibition:
    • Irreversible Reaction Coordinate Inhibitors include penicillin and 5-FU.
    • Suicide Substrate (Kcat) Inhibitors include beta-lactamase inhibitor and Clavulanic acid.

Competitive Inhibition of Enzymes

  • Binds to the enzyme's active site.
  • Competes with the substrate for binding.
  • Can be overcome by increasing the concentration of the substrate.
  • Vmax can be attained with the competitive inhibitor present.

Non-Competitive Inhibition of Enzymes

  • Binds to a location on the enzyme that is not the active site.
  • The inhibitor and substrate do not compete to bind.
  • Increasing substrate concentration cannot overcome inhibition.
  • Vmax is not attained in the presence of a non-competitive inhibitor.

Competitive Inhibition and the Folate Pathway

  • PABA is replaced by Sulfanilamide, inhibiting the synthesis of tetrahydrofolic acid, which is needed for DNA and methionine synthesis.

6-Mercaptopurine

  • 6-MP inhibits the conversion of inosine monophosphate to adenine and guanine
  • 6-MP, a purine antagonist, gets converted to nucleotide analog thioinosine monophosphate (TIMP), which inhibits the first step of de novo purine-ring biosynthesis.
  • TIMP converts to TGMP, which, after phosphorylation, incorporates into DNA and RNA, making them nonfunctional.

Suicide Substrates

  • Suicide Substrate (Kcat) Inhibitors include beta-lactamase and clavulanic acid. Penicillin is also an irreversible reaction coordinate inhibitor
  • Clavulanic acid is a beta-lactamase inhibitor, but not a cell wall biosynthesis inhibitor by itself.
  • Review points:
    • Most common drug targets
    • Direct vs remote action of drugs
    • Concept of Km and Kd
    • Orthosteric and allosteric sites and effect on drug action
    • Plots of enzyme kinetics for competitive and non-competitive enzyme inhibition
    • Names and mechanism of action (MOA) of specific examples of drugs that act as enzyme inhibitors
    • Concept of "suicide" substrates and Kcat inhibitors

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