Acetylcholinesterase Sean Keil Dr. Friesen CHE

Background Acetylcholinesterase (AChE) EC # (Carboxylic Ester Hydrolysis) Found in Eukaryotes, animals Very active hydrolase (1.2 E 5 s -1 ) 2 Wilson, I.B.; Harrison, M.A. Turnover Number of Acetylcholinesterase, J Biol Chem 1961, 236, Radić, Z. et al. Biochemistry 1992, 31,

Importance Found in brain synapses Terminates transmission of acetylcholine Acetylcholine is responsible for muscle contraction 3

Crystal Structure 540 amino acids 24 α-helixes & 25 β-sheets Monomer Often reported as a dimer 4 PDB: 3LII

Catalytic Triad: Serine 200 – Histidine 440 – Glutamic Acid 327 Sits in a gorge surrounded by 14 aromatic residues Phenylalanine Tryptophan Tyrosine Histidine Active Site 5 Dvir, H., Silman, I., Harel, M. Roseberry, T. L., and Sussman, J. L. (2010) Acetylcholinesterase: from 3D structure to function. Chem. Biol. Interact

6 S203 H447 E334 PDB: 3LII

Sequence Alignment Asian shrub… Short sequence Numbering issues Highly conserved between organisms

Hydropathy Plot Membrane bound 8 Rotundo, R. L. (1984) Purification and properties of the membrane-bound form of acetylcholinesterase from chicken brain. J. Bio. Chem. 259,

Alzheimer’s Disease No known cure 4/5 AD drugs call on inhibition of acetylcholinesterase Various theories Strengthening of healthy synapses Inhibits breaking down of ACh, increasing concentration in the brain Not conclusive to delay/stop progression of disease 9 Birks, J. Cholinesterase Inhibitors for Alzheimer’s Disease. Cochrane Database System Review

Conclusions Large, membrane bound protein Catalytic triad Ser200-His440-Glu327 Lack of AChE leads to death Temporary inhibition may be beneficial 10

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