Home » Module 4: Military Pharmacology: It Takes Nerves! » Content Background: Inhibition of Acetylcholinesterase by Nerve Gas

Content Background: Inhibition of Acetylcholinesterase by Nerve Gas

Nerve gas1 also binds to the acetylcholinesterase2 enzyme3, but only at 1 site. Nerve gases have a phosphorus group that is extremely attracted to the same OH group on the enzyme that is bound by acetylcholine (Figure 10). The bond is so strong that, for most types of nerve gases, it can’t be broken. This is called a covalent bond4 (see Module 5). Since the phosphorus atom of the nerve gas can’t come off of the enzyme, the enzyme is no longer able to interact with acetylcholine. Thus, the enzyme is inhibited and acetylcholine builds up in the vicinity of its receptors5. The body must synthesize new enzyme molecules to overcome the loss of acetylcholinesterase. Unfortunately, this doesn’t happen fast enough and the person succumbs to the toxic actions of the nerve gas. [There are some antidotes (called oxides6) that could work if given fast enough, before the nerve gas becomes irreversibly bound to the acetylcholinesterase. The oximes would have to be given within a few minutes of exposure to be effective.] As discussed above, the accumulation of acetylcholine due to acetylcholinesterase inhibition by nerve gas causes overactivation of acetylcholine receptors all over the body. The knowledge of where acetylcholine receptors are and how they participate in bodily functions provides a basic understanding of the many actions of nerve gas on the body. There are other examples of acetylcholinesterase inhibition that play a role in our lives. For example, insecticides are very good inhibitors of acetylcholinesterase. At the proper concentration, they kill insects not humans. However, humans who are chronically exposed to them (e.g. in the fields, etc.) do suffer neurological and mental disorders similar to those in people with chronic low-level exposure to nerve gas. In the case of the insecticides, they don’t bind to the acetylcholinesterase as tightly as does nerve gas, so the enzyme can become regenerated with time.

Definitions:
1 a group of very lipophilic compounds (e.g. sarin, tabun, soman) that can exist as a vapor at room temperature. They contain phosphorus groups and bind avidly to acetylcholinesterase to inhibit its activity. The inhibition of acetylcholinesterase causes the accumulation of acetylcholine in all areas of the nervous system, causing excessive muscle contraction followed by paralysis, secretions, seizures and death by respiratory failure.
2 the enzyme that facilitates the hydrolysis (by water) of acetylcholine into choline and acetic acid. It is found near neurons that release acetylcholine.
3 a protein that catalyzes the rate at which a reaction occurs. It binds to one of the reactants (a substrate) to cause a change in the reactant’s structure, facilitating the reaction.
4 type of bond that forms by the sharing of electrons between two molecules. It is one of the strongest chemical bonds and it rarely occurs in drug-receptor interactions.
5 a protein to which hormones, neurotransmitters and drugs bind. They are usually located on cell membranes and elicit a function once bound.
6 compounds that bind to the phosphorus group on the nerve gas to pull it off of the acetylcholinesterase. This reactivates the enzyme to its normal activity and inactivates the nerve gas. This antidote must be given fast enough before the nerve gas irreversibly binds to the acetylcholinesterase.

Figures:

Figure 10 The phosphorous atom of the nerve gas binds covalently (irreversibly) to acetylcholinesterase to inactivate it.