Acetylcholinesterase

Sean Keil11-13-14

Acetylcholinesterase (AChE)• EC # 3.1.1.7 (Carboxylic Ester Hydrolysis)

• Found in Eukaryotes, animals • Motor neurons• Sensory neurons

Importance

• Terminates transmission of acetylcholine

• Acetylcholine is responsible for muscle contraction

• High catalytic efficiency (1.2E5 s-1)

• Overload leads to electrical short circuit

Structure

• Monomer• Often reported as a dimer

• Tetramer• Mammalian brain

• 24 α-helixes & 25 β-sheets

PDB: 3LII

3LII: Homo Sapiens

2WFZ: Torpedo Californica

Reaction

Active Site

• Catalytic Triad:Serine 200 – Histidine 440 – Glutamic Acid 327

• Sits in a gorge surrounded by 14 aromatic residues• Phenylalanine • Tryptophan • Tyrosine • Histidine

S203

H447

E334

PDB: 3LII

Sequence Alignment• Highly conserved between organisms

• Agreeable active site

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

Biological Warfare• Insecticides

• Acute poisoning as a nerve agent• Sarin

• Inhibits acetylcholinesterase• Causes permanent neurological damage• Fatal

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

References1) Wilson, I.B.; Harrison, M.A. Turnover Number of Acetylcholinesterase, J Biol Chem 1961, 236, 2292-2295.

2) Radić, Z. et al. Biochemistry 1992, 31, 9760-9767.

3) 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.

4) 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.

5) http://pdb.org/pdb/explore/remediatedSequence.do?structureId=3LII&bionumber=1 (accessed October 2014)

6) Birks, J. Cholinesterase Inhibitors for Alzheimer’s Disease. Cochrane Database System Review. 2006.