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Understanding Irreversible Enzyme Inhibitors

Irreversible enzyme inhibitors are compounds that permanently deactivate enzymes by forming stable bonds, typically covalent, at the active site. Unlike reversible inhibitors, they do not dissociate, leading to a lasting loss of enzymatic activity. These inhibitors are crucial in regulating metabolic pathways, serving as pharmaceuticals, and are used in agriculture and sanitation. The text explores their potency, measurement, and examples like DFP and DFMO in medical treatments.

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1

Nature of bond in irreversible enzyme inhibitors

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Form stable, often covalent bonds, causing permanent loss of enzymatic activity.

2

Common reactive groups in irreversible inhibitors

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Include nitrogen mustards, aldehydes, haloalkanes, alkenes, Michael acceptors, phenyl sulfonates, fluorophosphonates.

3

Amino acid residues targeted by irreversible inhibitors

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React with nucleophilic residues like serine, cysteine, threonine, tyrosine in the enzyme's active site.

4

Irreversible inhibitors modify the ______ of an enzyme, while preserving its overall ______.

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active site protein structure

5

Irreversible inactivation can be caused by extreme ______, high ______, or certain ______, which may lead to protein denaturation.

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pH temperatures chemicals

6

Processes like protein aggregation or dissociation into ______ are often non-specific and can affect many ______, not just enzymes.

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subunits proteins

7

Difference between IC50 and kobs/[I] in inhibitor potency measurement.

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IC50 is used for reversible inhibitors, while kobs/[I] measures irreversible inhibitor potency, excluding enzyme saturation.

8

Significance of kobs reaching kinact.

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Indicates maximum rate of enzyme inactivation by the inhibitor, occurring when enzyme saturation with inhibitor is achieved.

9

Condition for kobs/[I] as a valid potency measure.

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Enzyme must not be saturated with inhibitor for kobs/[I] to accurately reflect inhibitor's potency.

10

Initially, the enzyme and inhibitor may form a ______ complex, which later becomes a covalently bonded, inactive complex (EI*).

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reversible non-covalent

11

The ______ of enzyme inactivation (kinact) is calculated by fitting the loss of activity over time to a specific ______ equation.

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rate rate

12

______, such as MALDI-TOF, can be used to detect the enzyme's mass increase due to inhibitor binding, shedding light on the ______ of their interaction.

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Mass spectrometry techniques stoichiometry

13

Characteristic of slow-binding inhibitors initial interaction

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Initially form reversible complex with enzyme before tight binding

14

Conformational change in enzyme due to slow-binding inhibitors

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Tight binding often involves enzyme's conformational change

15

Examples of slow-binding inhibitors

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Methotrexate, allopurinol, activated acyclovir

16

______, used to combat African sleeping sickness, becomes active by the enzyme it targets and subsequently renders it inactive.

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α-difluoromethylornithine (DFMO)

17

Quinacrine mustard demonstrates a ______ inhibition of trypanothione reductase, with one molecule binding in a reversible manner and another covalently.

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dual mode

18

Natural role of enzyme inhibitors

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Regulate metabolic pathways, maintain homeostasis, evolved as toxins.

19

Synthetic enzyme inhibitors usage

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Used as pharmaceuticals, pesticides, herbicides, disinfectants.

20

Enzyme inhibition in metabolic regulation

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Controls metabolic pathways, e.g., ATP inhibits phosphofructokinase 1 in glycolysis.

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Understanding Irreversible Enzyme Inhibitors

Irreversible enzyme inhibitors are compounds that form a stable, often covalent, bond with enzymes, leading to a permanent loss of enzymatic activity. These inhibitors differ from reversible inhibitors, which associate and dissociate from enzymes without forming a permanent bond. Irreversible inhibitors often contain reactive groups such as nitrogen mustards, aldehydes, haloalkanes, alkenes, Michael acceptors, phenyl sulfonates, or fluorophosphonates, which can react with nucleophilic residues in the enzyme's active site—typically serine, cysteine, threonine, or tyrosine—to form a stable, covalently modified enzyme that is no longer functional.
Close-up of a laboratory bench with sealed blue liquid vial, metal syringe, mortar with powder and transparent flask.

Distinguishing Irreversible Inhibition from Enzyme Inactivation

It is important to distinguish between irreversible inhibition, which is a targeted and specific process, and general irreversible enzyme inactivation, which can occur through non-specific mechanisms. Irreversible inhibitors selectively modify the active site of an enzyme, preserving the overall protein structure, whereas irreversible inactivation can be caused by a variety of factors such as extreme pH, high temperatures, or certain chemicals, leading to protein denaturation, aggregation, or dissociation into subunits. These latter processes are often non-specific and can affect a wide range of proteins, not just a single type of enzyme.

Characterizing the Potency of Irreversible Inhibitors

The potency of irreversible inhibitors is characterized differently from that of reversible inhibitors. Instead of using the half-maximal inhibitory concentration (IC50), the rate of enzyme inactivation (kinact) and the concentration of the inhibitor ([I]) are used to calculate the observed pseudo-first order rate constant (kobs). The ratio kobs/[I] is a measure of the inhibitor's potency, provided that the enzyme is not saturated with the inhibitor. When saturation occurs, kobs reaches a maximum value equal to kinact, which represents the maximum rate at which the enzyme can be inactivated by the inhibitor.

Measuring Irreversible Inhibition

The measurement of irreversible inhibition involves monitoring the loss of enzyme activity over time after the addition of the inhibitor. Initially, a reversible non-covalent complex may form between the enzyme and inhibitor, which then undergoes a chemical reaction to create a covalently modified, inactive complex (EI*). The rate of inactivation (kinact) is determined by fitting the time-dependent loss of activity to an appropriate rate equation. Techniques such as mass spectrometry, including Matrix-Assisted Laser Desorption/Ionization-Time of Flight (MALDI-TOF), can be employed to detect the mass increase of the enzyme upon inhibitor binding, which provides insight into the stoichiometry of the inhibitor-enzyme interaction.

Slow Binding Inhibitors

Some inhibitors are termed slow-binding because they bind to their target enzymes with such high affinity that the binding is practically irreversible, even though no covalent bond is formed. These inhibitors initially form a reversible complex with the enzyme, which then undergoes a slow transition to a tightly bound state, often involving a conformational change in the enzyme. This type of inhibition can be mistaken for irreversible inhibition due to the slow dissociation rate. Examples of drugs that act as slow-binding inhibitors include methotrexate, allopurinol, and the activated form of acyclovir.

Examples of Irreversible Inhibitors in Action

Diisopropylfluorophosphate (DFP) is an example of an irreversible inhibitor that targets serine proteases, such as acetylcholinesterase, by covalently binding to the serine residue in the active site, leading to enzyme inactivation. Another form of irreversible inhibition is suicide inhibition, where the inhibitor is initially processed by the enzyme in a normal catalytic manner but then transforms into a reactive intermediate that covalently modifies and inactivates the enzyme. An example is α-difluoromethylornithine (DFMO), which is used to treat African trypanosomiasis and is activated by the enzyme ornithine decarboxylase. Additionally, some inhibitors, such as quinacrine mustard with trypanothione reductase, can exhibit dual modes of binding, with one molecule binding reversibly and another binding covalently.

Applications and Significance of Enzyme Inhibitors

Enzyme inhibitors play a crucial role in both natural biological processes and as synthetic agents. In nature, they regulate metabolic pathways and are essential for maintaining homeostasis, while some have evolved as toxins. Synthetic inhibitors are extensively used in medicine as pharmaceuticals, and in agriculture as pesticides and herbicides, as well as in sanitation as disinfectants. In metabolic regulation, enzyme inhibition serves as a mechanism to control the flow of metabolic pathways. For instance, ATP inhibits phosphofructokinase 1 in glycolysis, providing a feedback mechanism to regulate energy production in the cell. Conversely, certain metabolites can act as activators, highlighting the intricate balance of enzyme activity regulation through both inhibition and activation.