Noncompetitive Enzyme Inhibition

Noncompetitive Enzyme Inhibition


Hi, this is Dr. Vijay. Today we’re going to study about noncompetitive
enzyme inhibition. In the noncompetitive enzyme inhibition, an
inhibitor molecule binds to an example other than substrate binding site or active site. So, this binding could be to the free enzyme
itself or even this binding of noncompetitive inhibitor to the enzyme substrate complex,
whereas in competitive inhibitor, inhibitor binds to active site, here noncompetitive
enzyme inhibition, inhibitor molecule binds to a site other than active site and this
binding either to the free enzyme or even after enzyme substrate complex formation. Unlike competitive inhibitor, these noncompetitive
inhibitors are not structural analogues of that substrate. So, their structure is not similar to substrates. So, let me explain this noncompetitive enzyme
inhibition mechanism. We have an enzyme here. Normally substrate binds to enzyme and forms
enzyme substrate complex, later it will give enzyme and product. This is the usual mechanism. You might have noticed in the enzyme other
than active site, this particular enzyme also has got another binding site sometimes we
call it as allosteric binding site or allosteric site, that we will discuss when we discuss
enzyme regulation. Here we have an inhibitor and this inhibitor
can bind to free enzyme and forms enzyme inhibitor complex. You might have noticed here this inhibitor
molecule is not binding to the active site of an enzyme, it binds to a separate site
and forms enzyme inhibitor complex and as I said earlier, this inhibitor can bind to
free enzyme or even it can bind to enzyme substrate complex and forming enzyme inhibitor
substrate complex, OK. There are 2 possibilities here, either enzyme
inhibitor complex or enzyme inhibitor substrate complex. Even enzyme inhibitor complex formed then
also substrate can bind but, in both cases, there is no product formation. In other words, there is decrease in the rate
of enzyme catalyzed reaction. Here you can see; the inhibitor has same affinity
for both the enzyme as well as enzyme substrate complex. Binding of inhibitor to the enzyme or to the
enzyme substrate complex inactivate this enzyme or decrease the function of enzyme there by
there will not be any product and you should remember here there is no competition between
inhibitor and the substrate for the active site. We will study this noncompetitive enzyme inhibition
mechanism with the help of enzyme kinetics. Normally enzyme catalyzed reaction without
inhibitors graph is like this. It is a hyperbolic curve, where we can see
the maximum velocity, that is zero order kinetics. If you add an inhibitor to this particular
reaction the graph could be like this. You can see here, there is decrease in the
maximum velocity when inhibitor is added, so which type of inhibitor it is noncompetitive
inhibitor. When noncompetitive added there is decrease
in the maximum velocity. So, half max for the normal catalyze, enzyme
catalyzed reaction is here, whereas half max with the noncompetitive inhibitor is here. Now what happens to Km value? You can see the Km value or Michaelis Menten
value with inhibitor or without inhibitor is same in case of noncompetitive enzyme inhibition. Even though there is decrease in maximum velocity
or Vmax but the Km or affinity for the enzyme is same in both with inhibitor and without
noncompetitive inhibitor. So, in this case there is no change in the
Km value but there is decrease in the Vmax. We can explain the mechanism of noncompetitive
enzyme inhibition even by double reciprocal plot or Lineweaver-Burk plot, where we are
plotting the reciprocal of velocity and reciprocal of substrate concentration. Normally without inhibitor, the normal enzyme
catalyzed reaction, the graph could be like this. The line which intersect Y axis is 1/Vmax
and where it touches X axis is -1/Km. Now if you add a noncompetitive inhibitor,
the graph would be like this. Please notice here there is no change in the
Km, you can see here in both the cases the -1/Km is at the same point whereas the line
intersects Y axis in 2 different points. So, in with inhibitor because, since this
is a reciprocal, there is decrease in the Vmax value or there is a decrease in maximum
velocity. We will see some of the uses or clinical significance
of this noncompetitive inhibitors. So, these noncompetitive inhibitors are mainly
studied in toxicology either these noncompetitive inhibitors itself are poisonous or toxic substances
or sometimes we can make use of this mechanism and we can make a drug to treat poisoning
or like an antidote. So, both they are poisons or sometimes they
can use as a drug to treat poisoning and there are many drugs even anticancer drugs and many
drugs which have mechanism as noncompetitive inhibitors. We will study some of the examples. Cyanide is a potent rapidly acting fatal substance,
if ingested it is a very poisonous chemical. It noncompetitively inhibits an enzyme called
cytochrome c oxidase, which is an important enzyme or complex IV of electron transport
chain or respiratory chain. So, the mechanism of action of cyanide poisoning
is it inhibits noncompetitively the enzyme cytochrome c oxidase. In case of heavy metal poisoning, like mercury,
cadmium and lead poisoning. So, these metals actually they inhibit noncompetitively,
they will bind to some of the sulfhydryl groups of the enzyme. So, they are noncompetitive inhibitors for
the essential or vital enzymes in our body, that is why they leads to poisoning like lead
poisoning, mercury poisoning. Recent studies have demonstrated, researchers
have demonstrated copper and mercury can be used in case of botulinum neurotoxin poisoning. They have demonstrated in rodents, where this
copper and mercury can inhibit noncompetitively light chain protease, so that we can treat
botulinum neurotoxin poisoning. The recent researchers have shown that we
can use these heavy metals to treat some of the poisonings also. Here I have a table where you can see there
are many examples. Here we have a drug Etoposide, which can be
used to treat cancer. The mechanism of action of this drug it noncompetitively
inhibits DNA topoisomerase II enzyme, which is an enzyme of DNA replication. Similarly, we can treat Alzheimer’s disease,
or we can control Alzheimer’s disease by a drug called Tacrine, which inhibits noncompetitively
acetylcholine esterase, Trazodone, which is an antidepressant to treat depression which
actually inhibits noncompetitively adenosine deaminase. To treat benign enlargement of prostrate or
benign prostate hyperplasia, we can use this drug TF-505, which actually inhibits steroid
5 α- reductase noncompetitively. Doxycycline is an antibiotic which actually
inhibits matrix metalloproteinase enzyme. So, all these drugs are noncompetitive inhibitors. In other words, they have a mechanism of action
based on noncompetitive inhibitors. Here there is no change in the Km value but
there is decrease in the maximum velocity or Vmax and noncompetitive inhibitors bind
to enzyme a site other than substrate binding site and noncompetitive inhibitors can bind
to free enzyme or enzyme substrate complex, so that it decreases the rate of enzyme catalyzed
reaction or enzyme activity. Thanks for watching.

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