Efficient product clearance through exit channels in substrate hydrolysis by acetylcholinesterase

• Published in: FEBS letters Vol. 349; no. 1; pp. 60 - 64
• Main Authors: Kovach, Ildiko M., Qian, Naifeng, Bencsura, Akos
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 25.07.1994
• Subjects: Acetates - metabolism; Acetylcholine - metabolism; Acetylcholinesterase - metabolism; Acetylcholinesterase active site; Acetylcholinesterase catalysis; Acetylcholinesterase mechanism; Acetylcholinesterase structure; Animals; Binding Sites; Biological Transport; Choline - metabolism; Computer Simulation; Hydrolysis; Models, Molecular; Protein Conformation; Torpedo; Acetylcholinesterase structure; Acetylcholinesterase active site; Acetylcholinesterase mechanism; Acetylcholinesterase catalysis
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/0014-5793(94)00580-X

The channels connecting the active site of acetylcholinesterase (AChE) to the protein exterior were mapped by computational techniques in order to find potential exit routes for charged reaction products. 3.9% of the total volume of the AChE monomer is hollow space and over 50% of the void is located in the center; it is partitioned into three chambers, a deep entry channel, below it a wide channel located in a slightly positive region of AChE and ideally suitable for the exit of negatively charged fragments and a small chamber above Trp 84 and Met 83. The latter serve as gates for the departure of the positively charged choline product of the hydrolysis of acetylcholine into the small cavity. An efficient product clearance is a prerequisite to a very low energy pathway for the irreversible hydrolysis of acetylcholine.