Acetylcholinesterase

From Proteopedia

Revision as of 05:49, 17 December 2007

Key Enzyme in the Nervous System

Acetylcholinesterase (AChE) is key enzyme in the nervous system of animals. By rapid hydrolysis of the neurotransmitter, acetylcholine (ACh), AChE terminates neurotransmission at cholinergic synapses. It is a very fast enzyme, especially for a serine hydrolase, functioning at a rate approaching that of a diffusion-controlled reaction. AChE inhibitors are utilized in the treatment of various neurological and are among the key drugs approved by the FDA for management of Alzheimer's disease (AD). The powerful toxicity of organophosphorus (OP) poisons is attributed primarily to their potent AChE inhibitors. Many carbamates and OPs serve as potent insecticides, by selectively inhibiting insect AChE.

Solution of the three-dimensional (3D) structure of Torpedo californica acetylcholinesterase (TcAChE) in 1991 (Sussman et al. (1991)) opened up new horizons in research on an enzyme that had already been the subject of intensive investigation. The unanticipated structure of this extremely rapid enzyme, in which the active site was found to be buried at the bottom of a , lined by aromatic residues, led to a revision of the views then held concerning substrate traffic, recognition, and hydrolysis (Botti et al. Sussman & Silman (1999)). This led to a series of theoretical and experimental studies, which took advantage of recent advances in theoretical techniques for treatment of proteins, such as molecular dynamics and electrostatics, and of sitedirected mutagenesis, utilizing suitable expression systems.

The increasing longevity of people's lifespans, and the resulting increased prevelance of dementias such as Alzheimers Disease, led scientists to study the animal enzyme Acetylcholinesterase (AChE) as a possible cause. This enzyme rapidly degrades or hydrolizes the neurotransmitter acetylcholine in synapses (junctions between nerve cells) of cholinergic nerve pathways into acetic acid and choline, to turn off the chemical signal for the nerve to fire. Should something happen to deactivate or kill this vital enzyme, nervous paralysis of vital functions occurs, leading to rapid death. Although AChE is does not the cause Alzheimers, it does seem to play a key role due to the acetylcholine deficit often seen in AD patients. Thus drugs that are mild inhibitors of AChE, like Tacrine, E2020 (Aricept) and the natural Chinese produce Huperzine appear to retard symptoms of AD.

Acetylcholinesterase is a fairly large protein, consisting of a single polypeptide chain made of ~537 amino acid residues, that folds into a. , with a large Beta sheets (orange), surrounded by a canopy of about 26 alpha helices (violet).

The active site region of this enzyme has two sites, a catalytic site and a peripheral site, which helps prebind the substrate and direct it toward the active site. When the 3-D structure was first determined, the big surprise was that the active site was deep inside the protein, at the end or base of a , lined with aromatic residues, with the peripheral site at the top or lip of this gorge. Amazingly, there were no acidic or negatively charged residues anywhere in these 2 sites or along this gorge, as would be expected to help attract and bind the basic, positively charged acetylcholine substrate, although are are some acidic residues nearby. Instead, bulky aromatic residues (These numbers are the sequential numbering of the residues, starting from the N-terminus, according to the Torpedo Californica form of the enzyme.) See: AChE inhibitors and substrates

Selected 3D Structures of AChE

• 2ace This is the original solved structure for Torpedo Californica
• 1ea5 This is one of the highest quality representative X-ray structures in the PDB.
• 1eve The E2020 (Aricept) complex.
• 1ax9 Endrophonium complex.
• 1vot Complex with Huperzine, a Chinese folk medicine.
• 1fss Complex with snake venum toxin Fasciculin-II.
• 1vzj Model complex of the Cholinesterase tetramer.

More structures can be obtained by searching for 'AChE' at the left <-.