1. Acetylcholinesterase
Sean Keil

2. Acetylcholinesterase (AChE)
EC # (Carboxylic Ester Hydrolysis)
Found in Eukaryotes, animals
Motor neurons
Sensory neurons
Wilson, I.B.; Harrison, M.A. Turnover Number of Acetylcholinesterase, J Biol Chem 1961, 236,
Radić, Z. et al. Biochemistry 1992, 31,

3. Importance Terminates transmission of acetylcholine
Acetylcholine is responsible for muscle contraction
High catalytic efficiency (1.2E5 s-1)
Overload leads to electrical short circuit

4. Structure Monomer Often reported as a dimer Tetramer Mammalian brain
PDB: 3LII
Structure
Monomer
Often reported as a dimer
Tetramer
Mammalian brain
24 α-helixes & 25 β-sheets

5. 2WFZ: Torpedo Californica
3LII: Homo Sapiens
Torpedo Californica, Pacific electric ray: homo-monomer
Homo Sapiens, Humans: homo-dimer

6. Reaction
Then, the acyl-enzyme undergoes nucleophilic attack by a water molecule, assisted by the histidine 440 group,
liberating acetic acid and regenerating the free enzyme.

7. Colovic M. B. , Krstic D. Z. , Lazarevic-Pasti T. D. , Bondzic A. M
Colovic M.B., Krstic D.Z., Lazarevic-Pasti T.D., Bondzic A.M., Vasic V.M. Acetylcholinesterase inhibitors: Pharmacology and toxicology. Curr. Neuropharmacol. 2013;11:315–335.

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

9. PDB: 3LII H447 S203 E334 S203 not 200 E334 not 327 H447 not 440
Gorge in blue (Y119x121; F338x330; W286x279; W86x84)
H447
S203
E334
PDB: 3LII

10. Sequence Alignment Highly conserved between organisms
Agreeable active site
Asian shrub inhibits acetylcholine signals
Serine 182, 200, and 203 indicated

14. 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
2050: 1 in 85
Birks, J. Cholinesterase Inhibitors for Alzheimer’s Disease. Cochrane Database System Review

15. Biological Warfare Insecticides Acute poisoning as a nerve agent Sarin
Inhibits acetylcholinesterase
Causes permanent neurological damage
Fatal

16. Serine 200 – Histidine 440 – Glutamic Acid 327
Takeaway Message
Large, highly conserved, membrane bound protein
Catalytic triad:
Serine 200 – Histidine 440 – Glutamic Acid 327
AChE is constantly working
Temporary inhibition may be beneficial
Long-term inhibition is fatal

17. References
Wilson, I.B.; Harrison, M.A. Turnover Number of Acetylcholinesterase, J Biol Chem 1961, 236,
Radić, Z. et al. Biochemistry 1992, 31,
Colovic M.B., Krstic D.Z., Lazarevic-Pasti T.D., Bondzic A.M., Vasic V.M. Acetylcholinesterase inhibitors: Pharmacology and toxicology. Curr. Neuropharmacol. 2013, 11, 315–335.
Dvir, H., Silman, I., Harel, M. Roseberry, T. L., and Sussman, J. L. (2010) Acetylcholinesterase: from 3D structure to function. Chem. Biol. Interact
(accessed October 2014)
Birks, J. Cholinesterase Inhibitors for Alzheimer’s Disease. Cochrane Database System Review