Acetylcholinesterase

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Presentation transcript:

Acetylcholinesterase Sean Keil 11-13-14

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

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

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

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.

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.

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. 187. 10-22.

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

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

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. 2006.

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

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

References 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. 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. 187. 10-22. http://pdb.org/pdb/explore/remediatedSequence.do?structureId=3LII&bionumber=1 (accessed October 2014) Birks, J. Cholinesterase Inhibitors for Alzheimer’s Disease. Cochrane Database System Review. 2006.