Home » Module 4: Military Pharmacology: It Takes Nerves! » Content Background: Hydrolysis of Acetylcholine

Content Background: Hydrolysis of Acetylcholine

Normally, the actions of acetylcholine1 are terminated by a specific mechanism to keep the target cells from becoming overactivated. Acetylcholine is destroyed by an enzyme2, acetylcholinesterase3, that is located in every acetylcholine synapse4. This enzyme catalyzes the hydrolysis of acetylcholine. Hydrolysis is a chemical reaction that involves water. Basically, a molecule is cleaved into two parts by reacting with water; part of the molecule binds to the H of water and the other part of the molecule binds to the OH of water, thus splitting the molecule and using up a molecule of water in the process. Compounds that are “esters”5 (they have an O atom sandwiched between a C chain and a C==O group) are easily hydrolyzed. When esters are hydrolyzed by water, the bond between the O atom and the C chain breaks. This forms an alcohol (a molecule containing an OH bound to the C chain) and an acid (a molecule containing a COOH group). Since acetylcholine has an ester group, it is especially vulnerable to hydrolysis6 by water (Figure 7). In this case, the ester bond which connects an acetyl group to the C chain, is hydrolyzed to give acetic acid (vinegar) and choline. These 2 compounds recombine inside the nerve terminal to synthesize new acetylcholine.

Figure 7 A typical hydrolysis reaction of ester compounds (acetylcholine) by water generates an alcohol (choline) and an acid (acetic acid). The red indicates where the ester bond (in green) is broken.


However, the hydrolysis of acetylcholine doesn’t occur without the help of the enzyme, acetylcholinesterase. Acetylcholinesterase is the catalyst that makes this happen very quickly (Figure 8). First, acetylcholine binds to the enzyme at 2 different sites; the acetylcholine acetyl group (part of the ester) binds to a specific OH group (from the amino acid, serine) in one place on the enzyme and the other end of acetylcholine binds to atoms on the enzyme in another place. The bonds formed are ionic7 or electrostatic in nature; opposite charges on the acetylcholine and the enzyme attract each other. In the presence of water, the acetylcholine breaks its ester bond between the C chain and the O of the acetyl group. Water donates an OH group to the C chain end, forming choline, which then separates from the enzyme. Water donates one of its H atoms to the acetyl group, forming acetic acid, which also separates from the enzyme. This reaction is extremely fast – it’s one of the fastest enzyme reactions in the body. Then the enzyme is restored to its normal state, free to destroy another molecule of acetylcholine.

Figure 8 Hydrolysis of acetylcholine catalyzed by acetylcholinesterase generates choline and acetic acid. As acetylcholine approaches the enzyme, electrostatic forces pull them together to bind and in the presence of water the ester bond (in green) is broken and they separate from the enzyme (lower section).

1 a neurotransmitter stored in vesicles of nerve terminals; it is found in neurons within the central nervous system, the somatic nervous system, the parasympathetic nervous system and the sympathetic nervous system.
2 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.
3 the enzyme that facilitates the hydrolysis (by water) of acetylcholine into choline and acetic acid. It is found near neurons that release acetylcholine.
4 the connection between two neurons; neurotransmitters are released from the terminal into the synaptic space and bind to receptors on the neighboring neuron.
5 a part of a molecule that has an O atom bound to a chain of C and also to a C==O.
6 a chemical reaction that involves the cleavage of a molecule in the presence of water. Water donates a H atom to one side of the broken bond and an OH molecule to the other side of the broken bond, forming 2 products. In the case of an ester, hydrolysis produces an alcohol and an acid.
7 an atom, radical, or molecule that has gained or lost one or more electrons. Therefore it acquires a net negative or positive charge.