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Solutions For An Introduction to Medicinal Chemistry Chapter 7 Problem 2Q

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Solution 1

Acetylcholinesterase is an enzyme, which mainly found at the neuromuscular junction, as well as in the chemical synapses. It catalyzes the acetylcholine breakdown, which functions as the neurotransmitters. It is also found responsible for terminating the action of acetylcholine so that it can terminate the nerve signal.

The hydrolysis of acetylcholine by acetylcholinesterase involves the amino acids triad, such as serine, glutamate, and histidine at the active site of the enzyme. Acetylcholinesterase is also a part of the serine hydrolase family, which involves two sites, including catalytic and anionic sites.

Acetylcholine binds to acetylcholinesterase where the quaternary nitrogen of acetylcholine binds to the anionic site. This helps the ester group to position itself in the catalytic site. This step is further followed by the nucleophilic attack by serine on ester unit, which results in acetylation of the serine residue followed by the hydrolysis.

The acetylated serine residue rapidly hydrolyses the regenerating enzyme. Neostigmine is described as the quaternary ammonium cholinesterase inhibitor. Clinically, it is used for treating the nondepolarizing muscle blockade. It is a covalent reversible inhibitor to enzyme acetylcholinesterase. It binds to the enzyme and gets hydrolyzed.

Here, the rate of hydrolysis is very slow as the carbamylated enzyme intermediate being more stable than the acetylated enzyme produced by the hydrolysis of acetylcholine. This is possibly caused due to the resonance between the carboxylate group and amine nitrogen as shown in the given figure:

Figure: Hydrolysis reaction of Neostigmine

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Solutions For Problems in Chapter 7