Mechanism of action of Acetylcholinesterase

 The mechanism of action of acetylcholinesterase (AChE) hydrolysis involves the breakdown of the neurotransmitter acetylcholine (ACh) at cholinergic synapses. This process is essential for terminating synaptic transmission and allowing the synapse to reset for subsequent signals. The hydrolysis occurs in several key steps:

1. Binding of Acetylcholine to the Active Site of AChE:

• Acetylcholine binds to the active site of acetylcholinesterase, which has two important sub-sites:
  • Anionic site: This site binds the quaternary ammonium group of acetylcholine, holding the molecule in place.
  • Esteratic site: This site contains a catalytic triad composed of serine, histidine, and glutamate/aspartate residues, which are crucial for catalysis.

2. Formation of Acetylated Enzyme (Acyl-enzyme intermediate):

• The serine residue at the esteratic site attacks the ester bond of acetylcholine, aided by the histidine and glutamate residues, resulting in a nucleophilic attack on the carbonyl carbon of the acetylcholine's ester bond.
• This leads to the cleavage of the ester bond and the formation of an acetyl-enzyme intermediate while releasing choline as a by-product.

3. Hydrolysis of Acetyl-enzyme Intermediate:

• Water molecules enter the active site and hydrolyze the acetyl-enzyme intermediate.
• The water molecule, activated by the catalytic triad, attacks the acetyl group, breaking it down into acetic acid and regenerating the active site of the enzyme.

4. Release of Products:

• The breakdown results in the release of acetic acid and choline, which are then cleared from the synaptic cleft.
• This allows the enzyme to reset and be ready for another round of acetylcholine hydrolysis.

In summary, acetylcholinesterase hydrolyzes acetylcholine by forming an intermediate acetylated enzyme, which is subsequently hydrolyzed, leading to the termination of acetylcholine signaling at the synapse.