AChE and Inhibition

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History

In order to further understand acetylcholinesterase and its medical implications, it is important to look at the discovery of its substrate, acetylcholine. Although acetylcholine had been previously identified and studied, it wasn’t until 1914 when Sir Henry Hallet Dale discovered its function as a chemical mediator. Dale was able to determine that ACh was necessary to transmit certain electrical impulses within the human body. His findings were later confirmed by Otto Loewi and this was celebrated as the first identification of a neurotransmitter. Both Dale and Loewi were awarded the Nobel Prize in Physiology and Medicine in 1936 for their findings. ^[3] It wasn’t until years later that further studies were performed to discern more fully the function of acetylcholine in the body and specifically how it is recycled. It was during this time that acetylcholinesterase was realized and its role in the function of ACh more fully understood. In more recent years, more extensive work has been completed to look at the medical implications of acetylcholinesterase and more importantly how inhibitors of it could be used as symptomatic treatment in some diseases. ^[3]

Function

Acetylcholinesterase plays an essential role in neurotransmission throughout the human body, including the central nervous system and muscular systems. Specifically, its function is in relation to the neurotransmitter acetylcholine. ^[4] Acetylcholine, synthesized in nerve terminals from acetyl CoA and choline, works at cholinergic synapses within the nervous system. While some neurotransmitters are terminated at the postsynaptic terminal by reuptake, ACh is broken down by acetylcholinesterase through the process of hydrolysis. ^[5] This hydrolysis breaks acetylcholine down into an acetate and choline. AChE has a relatively high catalytic activity; each molecule of AChE can degrade 25000 molecules of ACh per second. Later, these are recycled to again form acetylcholine for use in these same neuromuscular junctions throughout the body or within the central nervous system itself. Importance of the enzyme AChE is shown during inhibition with a nerve gas such as sarin. With this irreversible inhibitor present, there is an excess of acetylcholine within the synapses and continued activation of the ACh receptors. This can have a number of dire effects such as respiratory and/or cardiac dysfunction and possible death. However, reversible acetylcholinesterase inhibitors can be used in numerous therapeutic medications to treat symptoms related to diseases such as Alzheimer’s disease and myasthenia gravis. ^[6]