Irreversible Inhibition - Online Tutor, Practice Problems & Exam Prep

Irreversible inhibitors, also known as inactivators, bind tightly to enzymes, permanently halting their activity by forming stable covalent bonds. This one-to-one interaction means that one irreversible inhibitor can neutralize one active enzyme. A specific type of irreversible inhibitor, suicide inhibitors, mimic substrates and require normal catalytic reactions before becoming covalently bound. Both types are crucial in understanding enzyme kinetics and can serve as powerful poisons or therapeutic agents in medicine.

Irreversible Inhibition

So now that we've introduced enzyme inhibition, in this video, we're going to talk about our first category of enzyme inhibition, which is irreversible inhibition. Now of course, irreversible inhibition is caused by irreversible inhibitors. And irreversible inhibitors are just enzyme inhibitors that bind very, very, very tightly and pretty much irreversibly to the enzyme to not only decrease its activity but completely stop or halt the enzyme's activity. Pretty much decreasing the enzyme's initial reaction velocity or \( v_0 \) all the way down to 0. Now these irreversible inhibitors can form stable covalent bonds with the enzyme and because these are such stable covalent bonds, they are very, very difficult to break which is why these bonds are pretty much irreversible. And because irreversible inhibitors pretty much stop and inactivate the enzyme activity, they're also known as inactivators. And so inactivators and irreversible inhibitors are pretty much synonyms with each other. Now, it's important to note that one irreversible inhibitor will permanently neutralize or remove one active enzyme. So it's a one to one ratio. And if we want to inactivate all of the enzyme that's present, then we need to add the exact same amount of irreversible inhibitor. Now, these irreversible inhibitors or inactivators are often powerful poisons. However, they can also be used by doctors as drugs in medicine as well. Notice down below in our example image, we're showing you how an irreversible inhibitor can interact with a free enzyme and form the enzyme-inhibitor complex. However, irreversible inhibitors can also interact with the enzyme-substrate complex as well to form the enzyme-substrate-inhibitor complex. Here, we're just showing you one version, but it can actually bind to both the free enzyme as well as the enzyme-substrate complex. But really the main point of irreversible inhibitors is that whenever they actually bind and form a complex, whether that complex be the enzyme-inhibitor complex or the enzyme-substrate-inhibitor complex, it is an irreversible formation of the complex. So notice that we have a one-direction arrow here and we don't have equilibrium arrows, which would suggest that the complex could break down backward. But here we just have this one-way arrow.

Notice down below, we're showing you how the molecule DIPF is an example of an irreversible inhibitor. DIPF is the molecule diisopropylphosphofluoridate and its structure is shown right here. Notice on the right what we have is the enzyme that we're pretty familiar with from our previous lesson videos, and it is chymotrypsin, and, of course, this is the active version of chymotrypsin. It turns out that the active version of chymotrypsin has a serine amino acid residue in the active site that's critical for proper catalysis by chymotrypsin. Notice that the irreversible inhibitor, DIPF, will actually react with this important serine residue and it will form an irreversible complex here where notice that the irreversible inhibitor, DIPF, is covalently bound here through this pink bond to the serine amino acid residue that is critical for chymotrypsin to be active. And so notice here now what we have is an inactive chymotrypsin. And because this is a stable covalent bond, it makes DIPF an irreversible inhibitor and it will essentially, again, completely inactivate chymotrypsin, decreasing this particular enzyme's And so, in our next video, we'll be able to get some practice applying these concepts. So, I'll see you guys there.

Which of the following statements about irreversible inhibitors is correct?

• A. Irreversible inhibitors can only bind to an enzyme active site.
• B. Dilution of the inhibited enzyme restores activity.
• C. Irreversible inhibitors do not have to bind to the active site.
• D. Increasing [S] restores activity to inhibited enzyme.
• E. Initially, irreversible inhibitors will reversibly bind.

Irreversible Inhibition

So now that we've introduced irreversible inhibitors, in this video, we're going to talk about suicide inhibitors, which are really just a specific type of irreversible inhibitor. And so, suicide inhibitors are irreversible inhibitors that will partially mimic a substrate in the active site of an enzyme. But just like all irreversible inhibitors, ultimately, they will end up irreversibly bound and stuck to the enzyme and deactivating it completely. And so, suicide inhibitors initially are going to act just like a normal substrate would and what that means is that these suicide inhibitors, they actually require these normal catalysis reactions to begin to bind to the enzyme. But ultimately, these normal catalytic reactions are going to proceed up to a point where the suicide inhibitor is going to remain covalently bound to the enzyme just like all irreversible inhibitors. And so, how exactly do suicide inhibitors differ from other irreversible inhibitors? Well, suicide inhibitors have to undergo some normal catalytic reactions because again, they mimic a substrate, whereas other irreversible inhibitors don't necessarily have to undergo these normal catalytic reactions to end up irreversibly bound and stuck to the enzyme. And so this concludes our brief lesson on suicide inhibitors and we'll be able to get some practice utilizing these concepts in our next video. So I'll see you guys there.

A suicide inhibitor of an enzyme is one that:

• A. Is reversible.
• B. Is activated by one type of enzyme for the purpose of inhibiting a second type of enzyme.
• C. Is competitive with the enzyme and inactivates the substrate.
• D. Is competitive with the substrate and inactivates the enzyme.

Here’s what students ask on this topic:

What is irreversible inhibition in biochemistry?

Irreversible inhibition in biochemistry refers to a process where an inhibitor binds very tightly to an enzyme, forming a stable covalent bond that permanently halts the enzyme's activity. This binding decreases the enzyme's initial reaction velocity (v₀) to zero. Irreversible inhibitors, also known as inactivators, can neutralize one active enzyme in a one-to-one ratio. These inhibitors can bind to either the free enzyme or the enzyme-substrate complex, forming an irreversible complex. They are often powerful poisons but can also be used as therapeutic agents in medicine.

How do suicide inhibitors differ from other irreversible inhibitors?

Suicide inhibitors are a specific type of irreversible inhibitor that initially mimic a substrate in the enzyme's active site. They require normal catalytic reactions to begin binding to the enzyme. During these reactions, the suicide inhibitor becomes covalently bound to the enzyme, permanently inactivating it. In contrast, other irreversible inhibitors do not necessarily need to undergo these normal catalytic reactions to bind irreversibly. This unique mechanism makes suicide inhibitors particularly interesting for studying enzyme kinetics and developing therapeutic agents.

What are some examples of irreversible inhibitors?

An example of an irreversible inhibitor is diisopropylphosphofluoridate (DIPF), which forms a stable covalent bond with the serine residue in the active site of the enzyme chymotrypsin. This bond inactivates the enzyme completely. Another example is aspirin, which irreversibly inhibits the enzyme cyclooxygenase, reducing the production of prostaglandins and thus alleviating pain and inflammation. These examples illustrate how irreversible inhibitors can be both powerful poisons and useful therapeutic agents.

Why are irreversible inhibitors important in medicine?

Irreversible inhibitors are important in medicine because they can be used to permanently inactivate specific enzymes that contribute to disease processes. For example, aspirin irreversibly inhibits cyclooxygenase to reduce inflammation and pain. Similarly, certain cancer treatments use irreversible inhibitors to target and inactivate enzymes essential for cancer cell survival. By understanding the mechanisms of these inhibitors, researchers can develop drugs that provide long-lasting therapeutic effects with potentially fewer doses.

How do irreversible inhibitors affect enzyme kinetics?

Irreversible inhibitors affect enzyme kinetics by permanently reducing the number of active enzyme molecules available for catalysis. This results in a decrease in the maximum reaction velocity (V_max) because the enzyme's active sites are permanently occupied by the inhibitor. Unlike reversible inhibitors, irreversible inhibitors do not affect the Michaelis constant (K_m) because they do not compete with the substrate for binding. The overall effect is a complete halt in enzyme activity, making these inhibitors useful for studying enzyme function and developing drugs.