40 Questions
What is a characteristic of uncompetitive inhibitors?
They bind to the enzyme-substrate complex.
What is the purpose of designing drugs that mimic the transition state of an enzyme-catalysed reaction?
To bind more strongly to the enzyme.
What is the result of renin inhibitors blocking the synthesis of angiotensin I and II?
Decreased blood pressure.
What is the role of angiotensin II in the body?
To compress blood vessels and retain fluid in the kidneys.
What is the mechanism by which renin inhibitors lower blood pressure?
By inhibiting the synthesis of angiotensin I and II.
What is the purpose of designing transition-state analogues?
To design drugs that bind more strongly to the enzyme.
What is the role of renin in the body?
To hydrolyse a specific peptide bond in angiotensinogen.
What is the result of increasing the substrate concentration in the presence of an uncompetitive inhibitor?
The inhibition is unaffected.
What is a possible reason why drugs with a different skeleton to the substrate can act as competitive inhibitors?
They bind to a combination of binding regions within the active site, some of which are used by the substrate and some of which are not
What type of inhibitors can resemble the product of an enzyme-catalyzed reaction more closely than the substrate?
Competitive inhibitors
What is the mechanism of action of competitive inhibitors that do not compete with the substrate?
They bind to the cofactor binding region
What is a characteristic of irreversible inhibitors?
They form a covalent bond with the enzyme
Why do irreversible inhibitors block the affected enzyme permanently?
They form a covalent bond with a key amino acid in the active site
What type of functional group is commonly found in effective irreversible inhibitors?
Electrophilic group
What happens to the substrate when an irreversible inhibitor binds to the active site?
The substrate is blocked from the active site
Why does increasing substrate concentration not reverse the inhibition of irreversible inhibitors?
Because the inhibitor forms a covalent bond with the enzyme
What is the function of the hydroxyethylene transition-state mimic in Aliskiren?
To mimic the tetrahedral geometry of the reaction intermediate
What is the characteristic of the transition-state inhibitor Aliskiren?
Stable due to the absence of a leaving group
What is the role of the tetrahedral intermediate in enzyme-catalyzed reactions?
It is a short-lived intermediate that forms during the reaction
Which of the following is an example of a transition-state inhibitor?
Aliskiren
What is the function of the two aspartyl residues in enzyme-catalyzed reactions?
They are involved in the formation of a tetrahedral intermediate
What is the mechanism of inhibition of ACE inhibitors?
They bind to the enzyme's active site and inhibit the reaction
What is the mechanism by which clavulanic acid functions?
Irreversible alkylation
What is the bond formed between the enzyme and the suicide substrate?
Covalent bond
What is the name of the enzyme inhibited by clavulanic acid?
Alanine transaminase
What is the outcome of the reaction between the enzyme and the suicide substrate?
Irreversible inhibition of the enzyme
What is the byproduct of the condensation reaction?
Imine
What is the function of the CH3 group in the suicide substrate?
To increase the electrophilicity of the substrate
What is the type of inhibition exhibited by clavulanic acid?
Irreversible non-competitive inhibition
What is the role of the fluorine atom in the suicide substrate?
To increase the electrophilicity of the substrate
What is the outcome of the reaction between the enzyme and the substrate in the absence of the suicide substrate?
Formation of a stable enzyme-substrate complex
What type of inhibitors are converted to irreversible inhibitors by the enzyme-catalysed reaction?
Suicide substrates
What is the purpose of using clavulanic acid in antibacterial medication?
To inhibit the enzyme alanine transaminase
What is the function of Trifluoroalanine in the context of enzyme inhibition?
It is a suicide substrate of alanine transaminase
What is the product of the reaction between pyridoxal phosphate and alanine?
Pyridoxamine monophosphate
What is the role of the enzyme transaminase in the reaction between pyridoxal phosphate and alanine?
It catalyses the reaction between pyridoxal phosphate and alanine
What is the structure of the molecule shown in the figure?
Trifluoroalanine
What is the functional group of the molecule shown in the figure?
Fluoroalkyl
What is the type of inhibition that occurs when a suicide substrate reacts with an enzyme?
Irreversible inhibition
What is the purpose of using transition-state inhibitors?
To inhibit enzyme activity
Study Notes
Competitive Inhibitors
- Can bind to a combination of binding regions within the active site, some used by the substrate and some not
- Can resemble the structure of the product more closely than the substrate
- Some competitive inhibitors bind to the active site but do not compete with the substrate, instead occupying the binding region normally occupied by the cofactor
Irreversible Inhibitors
- Bind irreversibly to the active site, forming a covalent bond
- Block the substrate from the active site
- Increasing substrate concentration does not reverse inhibition
- Likely to be similar in structure to the substrate
Transition-state Analogues
- Designed to mimic the transition state of an enzyme-catalyzed reaction
- Bind more strongly than drugs mimicking the substrate or product
- High energy, transient species that cannot be isolated or synthesized
- Drug design is based on reaction intermediates closer to transition states than substrates or products
- Examples: renin inhibitors, statins, ACE inhibitors, protease inhibitors
Renin Inhibitors
- Renin is a protease enzyme responsible for hydrolyzing a specific peptide bond in angiotensinogen to form angiotensin I
- Angiotensin I is converted to angiotensin II, which raises blood pressure
- Renin inhibitors should act as antihypertensives by preventing the first stage of this process
- Examples: aliskiren, which contains a hydroxyethylene transition-state mimic
Suicide Substrates
- Agents converted to irreversible inhibitors by the enzyme-catalyzed reaction
- React with the target enzyme once formed
- Example: trifluoroalanine as a suicide substrate of alanine transaminase
- Inhibition mechanism: irreversible alkylation of the enzyme
Learn about competitive inhibition in enzyme catalysis, where drugs with different skeletons can act as inhibitors by binding to various regions in the active site. Understand how enzyme inhibitors can interact with the active site and affect enzymatic reactions.
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