A hydrophobic binding site in acetylcholinesterase

Area of Science:

• Biochemistry
• Enzyme kinetics
• Molecular pharmacology

Background:

• Acetylcholinesterase (AChE) is a crucial enzyme in nerve function.
• Noncovalent inhibitors are vital for understanding enzyme-inhibitor interactions.
• 1,2,3,4-Tetrahydro-9-aminoacridine (THA) is a potent inhibitor of AChE.

Purpose of the Study:

• To determine and compare dissociation constants for reversible, noncovalent inhibitors of eel acetylcholinesterase.
• To elucidate the structural basis for the potent inhibition by THA and related compounds.
• To characterize the binding site interactions of acetylcholinesterase inhibitors.

Main Methods:

• Determination of dissociation constants (Kd) for a series of noncovalent inhibitors.
• Structural analysis of inhibitors related to THA.
• Spectroscopic analysis including UV absorbance maxima and pKa values.

Main Results:

• A series of reversible, noncovalent inhibitors of eel acetylcholinesterase were characterized.
• Dissociation constants were determined and compared, revealing structure-activity relationships.
• Evidence suggests a flexible, hydrophobic area adjacent to the anionic subsite of AChE.
• This hydrophobic area readily adopts a planar form, accommodating THA.

Conclusions:

• A conformationally flexible, hydrophobic area exists near the anionic subsite of eel acetylcholinesterase.
• This hydrophobic area, along with the anionic subsite, is responsible for the strong attraction of THA and related inhibitors.
• The findings provide insights into the molecular mechanisms of acetylcholinesterase inhibition.