Suicide Enzyme Inhibition

Suicide Enzyme Inhibition


Hi, this is Dr. Vijay. Today we are going
to study suicide enzyme inhibition. So, this suicide enzyme inhibition is
irreversible inhibition. Here the inhibitor molecules or you can say the
modified substrates, they are actually looks similar to substrates. They are
substrate analogs, their structure is almost similar to the substrate just
like competitive enzyme inhibition and they bind to active site as that of
competitive enzyme inhibition but here unlike competitive enzyme inhibition, in
suicide enzyme inhibition the substrate analog or inhibitor molecule binds to
active site of an enzyme and produce some products, usually the abnormal
products or sometimes if it is in a pathway, it produces normal products
for next 2 to 3 reactions of that particular pathway and then produce an
abnormal product and this abnormal product binds to the enzyme and makes it
inactive. This abnormal product binds to enzyme covalently, bind to enzyme tightly
and make it inactive or it may modify the active site of that particular
enzyme so that it cannot catalyze the specific enzymatic reaction. So this is
actually just a brief introduction of suicide enzyme inhibition. This suicide
enzyme inhibition is also called mechanism based inactivation because the
substrate analog itself is not going to inhibit, when the reaction takes place
the product formed will bind to enzyme active site and make this particular
enzyme inactive. Let me explain this concept. First, we will see normal enzymatic reaction. So when enzyme combines with its natural
substrate it will produce enzyme substrate complex and later on it will
give enzyme unchanged and the product. This is the usual mechanism of enzyme-catalyzed reaction. With suicide inhibition, here we have an enzyme and we have an inhibitor in the form of substrate analog or modified substrate.
Now here it binds to active site of an enzyme, we can call it as enzyme
inhibitor complex because later on it will produce a actual inhibitor. Now this
reaction proceeds and give the enzyme and so you can see here the enzyme is
unchanged same enzyme and an abnormal product,
because of this substrate analog binding to the active site, there is going to be
an abnormal product formation. Now this abnormal product going to bind to the
active site of an enzyme, that particular enzyme and make that enzyme inactive. Now you can see here, you can appreciate here the conformation of the enzyme is
altered, maybe its active site is modified and this abnormal product binds
to this enzyme covalently so that it commits suicide here. In other
words this enzyme is inactivated so that is why it is called mechanism-based
inactivation. So unlike all other inhibition, this inhibition there is a
product formed, maybe if it is a particular pathway there may be a subsequent one or
two normal reaction then later on an abnormal product is formed this abnormal
product binds to that enzyme and make it inactive or it induces conformational
change in the enzyme so that it no longer catalyze the specific reaction.
This is actually mechanism of suicide enzyme inhibition. We will see the
clinical significance of suicide enzyme inhibitors. There are many drugs useful
for treating many diseases or disorders. You can see the aspirin, it is an
analgesic, it is a painkiller not only it is an analgesic it also decreases fever
antipyretic and anti-inflammatory. This aspirin is a suicide inhibitor, it’s
going to bind to active site of cyclooxygenase and produce a product
that will bind to cyclooxygenase and make cyclooxygenase inactive.
Similarly in alcoholic deaddiction or chronic alcoholic patient, if you give
disulfiram, it is a drug which bind to acetaldehyde dehydrogenase and make this enzyme inactive so that there is accumulation of acetaldehyde in the
liver and it produce nausea vomiting and alcohol avoidance in that chronic
alcoholic patient. Similarly an antibiotic which usually kills the
bacteria that is penicillin which actually, inhibit a bacterial
transpeptidase, this particular enzyme is very much essential for bacterial cell
wall synthesis. Now this penicillin binds to this bacterial transpeptidase and
make this enzyme inactive so that bacteria cannot survive without cell
wall. It can be used as anti-bacterial or antibiotic. Similarly to treat depression
and Parkinson’s disease we can use deprenyl which is again a
suicide inhibitor for the enzyme monoamine oxidase. This
deprenyll can be used to treat depression and Parkinson’s disease.
5-fluorouracil which is an anti-cancer drug to treat
cancer which actually inhibits thymidylate synthase which is an important
or essential enzyme for biosynthesis like thymine or uracil. So if this enzyme
is inhibited there is no cell division so that we can arrest excessive cell
division in cancerous tissues. So these are the few examples for suicide
inhibitors. Suicide enzyme inhibition is irreversible enzyme inhibition where the
substrate analog bind to active site of an enzyme and carry out reaction and
produce abnormal product and this abnormal product going to bind to that
active site of an enzyme and this binding is covalently binding or tight
binding, so that enzyme becomes inactive. Thanks for watching.

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