Acetylcholinesterase inhibitors prevent acetylcholinesterase from doing its job. Some do this for only a little bit, called reversible inhibitors and can be used as medicine in some situations. Others inhibit acetylcholinesterase permanently and can be very dangerous to humans, called irreversible inhibitors. Today, we're going to look at several examples of each.
Acetylcholinesterase inhibitors prevent acetylcholinesterase from breaking down acetylcholine
 |
Donepezil
Imagine waking up and not knowing who your most loved family members are. As you get out of bed, you're unsure of how to get to the bathroom. This doesn't feel like your house. Life is confusing, and often depressing. This bleak scenario is the life of patients with advanced Alzheimer's disease.
Alzheimer's disease is a type of neurodegenerative illness, where brain matter breaks down. One problem is the loss of neurons that use acetylcholine. To increase acetylcholine communication, doctors can prescribe donepezil, a reversible acetylcholinesterase inhibitor.
For acetylcholinesterase to do its job, it must be able to attach to acetylcholine at an opening called the active site. Donepezil binds near the active site of acetylcholinesterase called the peripheral anionic site. Think of this area as the gateway for acetylcholine to get into acetylcholinesterase. If the gateway is blocked, acetylcholine can't get in and can't be destroyed.
So, when patients take donepezil the amount of acetylcholine in their body increases, allowing for more acetylcholine signaling to offset the death of acetylcholinergic neurons in Alzheimer's. Donepezil has been shown to improve cognition in Alzhiemer's patients, however it does not cure the disease.
Sarin Gas
Not all acetylcholinesterase inhibitors are used for good though. Sarin gas was developed in 1938 by Germany and has been used extensively in chemical warfare. Sarin gas is extremely toxic and once released into the air, finds its way to water sources, food, and even sticks to clothing and surfaces, poisoning victims long after the initial exposure. Sarin is so frightening that Germany decided not to use it during World War II. Today, the United Nations has strict rules against chemical warfare like this, however it still persists, recently being used in attacks in Syria in 2017.
A sarin gas victim being rushed to medical treatment in Syria
 |
Sarin gas is an irreversible inhibitor of acetylcholinesterase. This means that once sarin binds to the enzyme, it cannot be removed. Another site on acetylcholinesterase is called the esteratic site. This site is directly involved in breaking apart acetylcholine. Sarin gas attaches to this site with an irreversible bond called a covalent bond. It can't be removed, and so any acetylcholinesterase affected won't ever work again. This is why it is called 'irreversible'.
Organic Phosphates (Organophosphates)
Although less toxic than sarin gas, organic phosphates, also known as organophosphates in the chemistry world, are also a type of irreversible inhibitor that can be poisonous to humans. Despite their toxicity, they are commonly used as an insecticide for crops.
With its ability to irreversibly inhibit acetylcholinesterase, organic phosphates are quite effective at killing insects. However, large amounts of exposure can be toxic to humans as well. People who manufacture and apply this pesticide are at risk of poisoning and death. It can be especially dangerous in countries with less oversight and fewer safety restrictions on handling these chemicals.
Limited protection when handling organic phosphates can lead to accidental poisonings
 |
Frighteningly similar to sarin gas, this insecticide attacks the esteratic site. It adds a molecule called a phosphate to the site, preventing it from working. Over a period of several days eventually the enzyme will remove the phosphate, but it will be too late for the victim. Acetylcholinesterase is working every second of the day to clear acetylcholine as needed. Shortly after a large exposure, patients can die of respiratory failure.
