Our bodies’ normal functioning relies on chemical reactions (for instance, the conversion of food into energy or the replenishment of cells in tissue, like in muscles or organs). These biochemical reactions are controlled by enzymes.
An enzyme is a protein that acts as biological catalyst (or “biocatalyst” for short). Catalysis is the process of accelerating a chemical reaction. To do their work, these enzymes act on molecules which are called “substrates” – these substrates are then converted into different molecules (then called “products”).
To give you a concrete example, the energy in food will be broken down into energy that is “compatible” with our bodies, that chemical reaction is thus “hastened” by enzymes that will act on the food molecules (“substrates”) to create energy that can be used by the body (“product”).
You might think, “if the chemical reaction is already happening, why even need enzymes?” It is because they are needed to speed up that reaction to a level that can sustain life. That is why almost all metabolic processes (all the chemical reactions in organisms) need this “enzyme catalysis” in order to happen fast enough.
You can see why this process is ubiquitous in our bodies and why disrupting it may have dire consequences (think about if your body cannot replenish your cells fast enough, you cannot heal, your muscles may break down, etc.).
Understanding this process is key in understanding how “enzyme inhibitors” work. They are a molecule that binds to an enzyme and inhibits its “catalytic activity”. Enzyme inhibitors thus “slow down” the metabolic processes by reducing the compatibility between substrate and enzyme (they will prevent the enzymes from doing their job by “taking their place” and preventing them from binding together).
If you think back to the process mentioned earlier, you will understand that enzyme inhibitors can thus reduce (or sometimes completely remove) the amount of “product” (the molecules produced, like the energy that we can use from food or the proteins that can be used to replenish our tissues) that ends up being produced by a reaction.
Enzyme inhibitors are thus “slowing down” the process, by removing the “speeding up” agent (the enzyme). And on the contrary, enzyme activators can help stimulate them. If you think about it, poisons and drugs are examples of enzyme inhibitors, since they slow down or outright block some of the processes we are talking about.
Different types of enzyme inhibitors
The various enzyme inhibitors are classified according to their action and interactions with metabolism. First there are specific and non-specific inhibitors.
Nonspecific inhibitors have the same effect on all enzymes. These effects include all kinds of physical or chemical changes affecting the enzyme (and more specifically its protein part). Those changes are irreversible.
For instance, temperature changes can inhibit enzyme reactions: up until a certain point, rising temperatures increase enzyme reaction rate; but after it, reaction rate decreases as temperature rises – at higher temperatures, the protein in the enzyme starts denaturing (its geometry and structure is altered and it does not work the same anymore) and the reaction is therefore inhibited.
If you need a more concrete example, think of how heat affects us: a warm environment can make us more active (you have better reactions and faster movements than in a colder environment), but too much heat will overwhelm us and make us slower (think about how you feel in a scorching summer heat, or in a hammam; you will definitely not feel like being very active).
In the same vein, changes in pH can alter reaction speed: if the environment is too acidic or too basic, the enzyme’s structure is altered (again, think about how you would feel about too much acidity in food for instance). Other inhibitors such as alcohol or heavy metals (like the dangerous mercury or lead) can cause the same kind of reaction.
When an enzyme has been denatured, its activity will most likely not be restored, this is what we call an “irreversible inhibition”. The irreversible inhibitors’ effect cannot be changed by having more substrate, either because their bond with an enzyme is too strong (they will not let the enzyme bond with its target) or because the enzyme’s basic structure has been modified too much for it to keep working.
Specific inhibitors however only effect one type of enzyme. Most poisons are specific enzyme inhibitors, but so are a lot of drugs – that could affect only enzymes in viruses, cancerous cells or bacteria.
Some specific inhibitors are irreversible, others are not.
Among specific reversible inhibitors, there are competitive and non-competitive inhibitors. Any element that is close enough to the chemical structure and overall form of the substrate will thus “compete” to bind “first”.
This kind of inhibitor then just “sticks” on the enzyme in another molecule’s place, preventing it from binding and preventing the reaction from happening (like how a lockpick emulates the shape of a key’s “teeth” to open a lock, except here the “lockpick” just stays in the “lock” to block the actual key from entering).
Competitive inhibition is mostly reversible if there is enough substrate to displace the inhibitor (so enough “locks” will make the “lockpicks” irrelevant). So how much the reaction is inhibited depends on how much inhibitor and how much substrate are in the area. Hence the “competitive” part, as substrate and inhibitor “fight” to bind to the enzyme, and whoever is more numerous or most compatible “wins”.
To give a tangible example: ethanol (alcohol) is metabolised by being transformed into acetaldehyde, which is then transformed into acetic acid by enzymes. Among its side-effects, acetaldehyde can cause nausea and vomiting. Under normal circumstances, this second reaction is fast enough for the acetaldehyde to not accumulate in the body. But the drug disulfiram (commercialised as Antabuse) is a competitive inhibitor to acetaldehyde.
This drug is thus sometimes used to help people against alcoholism, since consuming alcohol makes you sick that much faster by not letting acetaldehyde be metabolised fast enough. So, in this example the lock is acetaldehyde and the lockpick is disulfiram, while the key is the enzymes that would have transformed acetaldehyde into the more harmless acetic acid.
On the other hand, non-competitive inhibitors interact with the enzyme, but in general not at the active site. They change the enzyme so that the substrate cannot interact with it anymore. While they are mostly reversible, adding more substrate will not revert its effect, as the enzyme has changed shape and can technically not interact with it anymore.
Why are enzyme inhibitors important?
First and foremost, they can be used as drugs to treat diseases. Diseases work with metabolic processes just like the entire body. For instance, a virus can be blocked from replicating itself by using the right enzyme inhibitor, since it will prevent it from creating new protein coats (remember how the Covid-19 virus for instance is a protein shell around genetic material; well, preventing it from re/generating this “coat” can possibly help deactivate it).
Other processes can also be altered thanks to drugs: Viagra for instance (sildenafil) inhibits the metabolic process of the molecule that regulates erections – since the enzyme activity is slowed down, the “signal” lasts longer, and therefore, so does the erection. Another important use for enzyme inhibitors is to treat cancer: chemotherapy often uses methotrexate, a drug that is toxic to rapidly growing cells (but also to non-dividing cells); the point is therefore to “kill” the cancerous cells faster than the drugs deteriorate the patient’s health.
They can also therefore be used for metabolic control: for instance, the pancreas naturally produces an enzyme inhibitor to prevent the organ from digesting itself. The inhibitor binds with trypsin (a molecule that breaks down proteins for digestion) to prevent it from being overly active and start dissolving the organ itself (this condition is called pancreatitis).
As mentioned earlier with viruses, enzyme inhibitors can also help prevent bacteria from reproducing. This is the same process: for instance, penicillin will inhibit the enzymes that produce the cell wall that surrounds bacteria (it however works better if the enzyme is not already one produced by the human body).
As mentioned earlier as well, poisons work as enzyme inhibitors. At lower, controlled doses, some poisons can be used in medicine for their inhibition mechanisms.
In the same vein, pesticides and herbicides are also enzyme inhibitors. The infamous glyphosate for instance inhibits enzymes that create amino-acids in plants, crucial to their survival.
Many drugs are enzyme inhibitors, and their effects as well as their possible uses are varied. Pharmacology is constantly researching new inhibitors and improving existing ones. Pre-clinical testing is pivotal in figuring out an enzyme inhibitor’s potential toxicity and effects.