1. Acetylcholinesterase Sean Keil Dr. Friesen CHE 442 10-28-14

2. Background Acetylcholinesterase (AChE) EC # 3.1.1.7 (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, 2292-2295. Radić, Z. et al. Biochemistry 1992, 31, 9760-9767.

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

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

5. 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. 187. 10-22.

6. 6 S203 H447 E334 PDB: 3LII

7. Sequence Alignment Asian shrub… Short sequence Numbering issues Highly conserved between organisms 7 182200 203

8. 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, 13186-13194.

9. 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. 2006.

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

11. 11