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Lecture 4

about kinetic of enzyme

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10 views

Lecture 4

about kinetic of enzyme

Uploaded by

ahmedallord1449
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Biochemistry Of Enzyme. Prof.Dr.Khalid F.

AL-RAWI

4.1 : Introduction

Inhibitors are chemical compounds that decrease the rate of an enzyme-catalyzed


reaction. They are usually specific and they work at low concentrations. They block the
enzyme, but they do not usually destroy it.
Enzyme inhibition is one of the ways in which enzyme activity is regulated
experimentally and naturally. Most therapeutic drugs function by inhibiting a specific
enzyme. In the body, some of the processes controlled by enzyme inhibition are blood
coagulation, blood clot dissolution (fibrinolysis), connective tissue turnover, and
inflammatory reactions.
Inhibitors of the catalytic activities of enzymes provide both pharmacological agents and
research tools for the study of the mechanism of enzyme action. Many drugs and poisons
are inhibitors of enzymes in the nervous system.

4.2 :The Effect of Enzyme Inhibition


 Irreversible inhibitors: combine with the functional groups of the amino acids in
the active site irreversibly. Very tightly bound to the enzyme, either covalently or
noncovalently, but effectively don't come off.
 Reversible inhibitors: these can be washed out of the solution of enzyme by
dialysis. Rapid binding/release from enzyme in an equilibrium.
 Enzyme inhibitors defined by their effects on enzyme kinetic parameters, K m
and/or Vmax.

4.3 : Applications of Inhibitors


- Negative feedback; end point, or end product inhibitors.
-Poisons; snake bite, plant alkaloids, and nerve gases.
-Medicine antibiotics, suphonamides, and sedatives.

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Biochemistry Of Enzyme. Prof.Dr.Khalid F. AL-RAWI

4.4 : Types of Reversible Enzyme Inhibition


 Competitive enzyme inhibition.
 Non competitive enzyme inhibition.
 Uncompetitive enzyme inhibition.
 Suicide enzyme inhibition.
1- Competitive Inhibition. In this case, the inhibitor has a similar structure to substrate,
both the substrate (S) and the inhibitor (I) compete for the active site, the effect of
inhibitor decreased by increasing substrate concentration.
The reactions are

Note: that the complex EI does not react with S to form products. Applying the steady-
state approximation for ES. The KM term has been modified by, thereby
reducing v0.

Vmax remain same but Km is increased (Explain why?).


A classic example of competitive inhibition occurs with the succinate dehydrogenase
reaction:

2
Biochemistry Of Enzyme. Prof.Dr.Khalid F. AL-RAWI

This enzyme is competitively inhibited by malonate, oxalate or oxaloacetate, which are


all structural analogues of succinate.

Dihydrofolate Reductase
Folate-dependent reactions in the body are inhibited by folate analogues (or
antagonists, e.g., methotrexate). Before it can function as a coenzyme in one-carbon
transfer reactions, folate (F) must be reduced by dihydrofolate reductase to
tetrahydrofolate (FH4). Dihydrofolate reductase is competitively inhibited by
methotrexate. Since FH4 is needed for the synthesis of DNA precursors, a deficiency
causes most harm to those cells which synthesize DNA rapidly. Certain types of
cancers (e.g., the leukemias) exhibit an extremely high rate of cell division and are
particularly susceptible to folate antagonists.

2- Noncompetitive Inhibition. In this case, the inhibitor bears little or no structural


resemblance to substrate, A noncompetitive inhibitor binds to the enzyme at a site that is
distinct from the substrate binding site; therefore, it can bind to both the free enzyme and
the enzyme–substrate complex, forming both ES and EIS complexes is possible. The
binding of the inhibitor has no effect on the substrate binding, and vice versa. The
reactions are;

3
Biochemistry Of Enzyme. Prof.Dr.Khalid F. AL-RAWI

Because I does not interfere with the formation of ES, noncompetitive


cannot be reversed by increasing the substrate concentration.
The initial rate is given by;

The Vmax has been reduced by the factor but Km is unchanged.


Examples of non-competitive enzyme inhibitors.
1- Cyanide inhibits cytochrome oxidase.
2- Fluoride inhibits enolase and hence glycolysis.

4
Biochemistry Of Enzyme. Prof.Dr.Khalid F. AL-RAWI

3- Uncompetitive Inhibition. An uncompetitive inhibitor does not bind to the free


enzyme; instead, it binds reversibly to the enzyme–substrate complex to yield an inactive
ESI complex. The reactions are;

The initial rate is given by:

Both Vmax and KM have been reduced by the factor .


Example; inhibition of alkaline phosphatase by phenylalanine.

5
Biochemistry Of Enzyme. Prof.Dr.Khalid F. AL-RAWI

Lineweaver–Burk plots: (a) competitive inhibition, (b) noncompetitive inhibition, and (c)
uncompetitive inhibition.

4- Suicide inhibition: in this case the inhibitor is a structural analog of the substrate is
converted to more effective inhibitor with the help of the enzyme to be inhibited. The
new product irreversibly binds to the enzyme and inhibits further reaction.
For example:
1- Difluormethyl ornithine inhibited ornithine decarboxylase, as a result multiplication of
parasite is arrested.
2- Aspirn; Aspirin's ability to suppress the production of prostaglandins and thromboxane
is due to its irreversible inactivation of the cyclooxygenase.

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