Acetylcholinesterase (AChE) catalyzes the reaction of acetylcholine plus water to form acetate and choline. Acetylcholine is a substance used as a neurotransmitter. As well as at cholinergic synapses. AChE is also found within the bloodstream so that the acetylcholine does not affect any other sites within the body, thus maintaining its synaptic specificity. Due to the topology of AChE, there exists an active site gorge of about 20A long that penetrates basically halfway through the enzyme and widens near the base. At the very bottom of the gorge lies the active catalytic site of the esterase.The active site is lined with 14 aromatic residues that play an important part in guiding the substrate to the active site. Susseman et al.suggests that the movement of acetylcholine down the gorge toward the active site at its base is assisted by an "aromatic guidance" mechanism, in which the side groups of acetylcholine would interact with the aromatic rings that make upthe gorge. In one way it can be seen as a single massive dipole.
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Basic Structure of AChE
Shown are the alpha-helices and the beta-sheets. The twelve band beta-sheets are surrounded by fourteen alpha-helices. The anionic gorge is mainly composed of alpha-helical sheets.
Peripheral Choline Binding Site
Shown on the AChE model are the amino acids Tyr70 and Trp279. These two binding sites are located near the gorge opening, the peripheral anionic site. Trp279 is believed to also be in involved in ligand binding. Harel et al. propose that the peripheral anionic site may also be the substrate binding site involved in substrate inhibition.
Constrained Narrow Section of AChE
The model of AChE shows the amino acids Tyr121 and Phe330. The upper and lower part of the gorge are separated by a narrow section that is formed mainly by Tyr121 and Phe330.
Choline Recognition Site
The model of AChE shows the amino acids Trp84 and Phe330. The choline recognition involves Trp84 and Phe330 through cation-pi interactions. It is believed that Trp84, in conjunction with Phe330 , contribute to the stabilization of the quaternary amine. Trp84 is adjacent to the catalytic triad site. Both Trp84 and Phe330 are assigned to the "anionic" subsite of the active site. The pi-electrons of Trp84 interact with the quaternary nitrogen of the choline.
Acetyl Ester Specificity
The model of AChE shows the residues: Gly119, Trp233, Phe288 , Phe290, and Phe331. These residues form a pocket within the gorge. There also exists an oxy-anion binding site formed by the main chain amine Gly119 that interacts with the carbonyl oxygen. The location and presence of Gly199 assists in the proper orientation of ACh for catalysis.
Overall Structure of AChE Gorge
The model shown is a combination of the previously discussed aromatic residues onto one molecule of AChE to show their location relative to each other.
Zoomed View of AChE Gorge
This view shows the pocket and gorge at closer range.