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Prof. R. Boopathy Director School of Biotechnology and Genetic Engineering Bharathiar University, Coimbatore 641 046 boopathybiotech@yahoo.

com

Acetylcholinesterase
Potential directions of research for pesticide poisoning
1. What is known and relevant to the workshop?
(A Birds Eye View)

Slide 3 to 10 2. Why not AD drugs as antidote on OP poisoning? Slide 11 to 19 3. Our team research: Identification of peptides that could interact with AChE and its relevance Slide 20 to

Why not AD drugs as antidote on OP poisoning?

Alzheimer Disease Drugs against AChE


Name of the drug Donepezil1 Huperzine2 Tacrine3 Nature of the drug N-benzyl piperidine based compound Alkaloid Amino acridine compound Carbamate Type of Inhibition Reversible, Noncompetitive Reversible, Competitive Reversible, Noncompetitive Reversible, Competitive IC50* 22 nM > 47 nM 190 nM 800 nM

Galanthamine4 Alkaloid Rivastigmine5

Pseudo-irreversible, Non- 48 M competitive

*As reported for human AChE in the BRENDA enzyme database 1Kryger et al., (1999) Structure Vol 7, No 3, 297-306 2Dvir et al., (2002) Biochemistry Vol 41, 10810-10818 3Harel et al., (1993) PNAS Vol 90, 9031-9035 4Greenblatt et al., (1999) FEBS Letters Vol 463, 321-326 5Bar-on et al., (2002) Biochemistry Vol 41, 3555-3564

Mode of action of Donepezil


Occupies the catalytic and peripheral anionic site No direct interaction with the catalytic site

DIMETHOXYINDANONE MOIETY

PIPERIDINE MOIETY

BENZYL MOIETY

Binds to the PAS site residue Trp279

Cation- stacking with Phe330

Oriented towards CA site - stacking with Trp84

* Mode of drug binding with Torpedo AChE

Mode of action of Huperzine

Disruption of bond between Gly117-Gly118 and formation of new bonds by Gly117 with Gly119 and Ala201

H-bond with His440

Repels G117 carbonyl carbon (Carbonyl-carbonyl repulsion)

* Mode of drug binding with Torpedo AChE

Mode of action of Tacrine


- stacking of acridine against Trp84

H-bonding with His440

* Mode of drug binding with Torpedo AChE

Mode of action of Galantamine

Binds to choline binding site (Trp84) and acyl binding pocket (Phe288 & Phe290)
H-bond with Glu199 Binds with Ser200

Cation- stacking with Trp84

H-bond with Asp72

* Mode of drug binding with Torpedo AChE

Mode of action of Rivastigmine

Carbamyl moiety linked covalently to Ser200 Disruption of catalytic triad: H440 moves away from E327 Part of inhibitor occupies peripheral anionic site (Trp84, Phe330)

CARBAMYL GROUP
H-bonding with Gly119 & Ala201 Covalent linkage with Ser200
* Mode of drug binding with Torpedo AChE

S-3[1-(DIETHYL AMINO)ETHYL]PHENOL GROUP - stacking with Trp84, Phe330 H-bonding with Gly118

Can AD drugs be used as antidote? The story of DFP


Diisopropyl fluorophosphate (DFP) is a stable organophosphorus insecticide. DFP is a very potent neurotoxin (LD50 in rats is 1.3 mg/kg). It combines with the amino acid serine at the active site of the enzyme acetylcholinesterase inactivating it, finally paralysis and death occurs. Under conditions where AChE completely lost its enzyme activity due to DFP treatment, AChE pretreated with Tacrine retained 60% of its activity.
Ref: Wu et al., Mol Pharmacol. 1989 Jan;35(1):85-92.

Can AD drugs be used as antidote? The story of Soman


Soman is an extremely toxic chemical substance. It is a nerve agent inhibiting the cholinesterase enzyme.

When pretreated with Galantamine, the soman exposed guinea pigs showed no learning impairment and no memory retention deficit. Galantamine prevents both the acute toxicity and the delayed cognitive deficits triggered by soman poison and can be used against other organophosphorous compounds.
Ref: Mamczarz et al., Neurotoxicology. 2011 Dec;32(6):785-98. Epub 2011 Jul 19.

Identification of peptides that have interaction with AChE