Acetylcholinesterase
From Proteopedia
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Because of the relative ease in obtaining purified protein in abundance, AceytlCholinesterase was first crystallized by Joel Sussman of the Weizmann Institute, Rehovot Israel, after being extracted from the electric organ of the Pacific Sting Ray, '''Torpedo Californica''', order to determine its detailed | Because of the relative ease in obtaining purified protein in abundance, AceytlCholinesterase was first crystallized by Joel Sussman of the Weizmann Institute, Rehovot Israel, after being extracted from the electric organ of the Pacific Sting Ray, '''Torpedo Californica''', order to determine its detailed | ||
| - | 3-dimensional structure by X-ray crystallography. Subsequently its X-ray structure has been determined from over 20 species, ranging from the '''Drosophila''' | + | 3-dimensional structure by X-ray crystallography ([[2ace]]). Subsequently its X-ray structure has been determined from over 20 species, ranging from the fruit fly '''Drosophila''' to human. |
Acetylcholinesterase is a fairly large protein, consisting of at least 535 amino acid residues in a single peptide chain, that folds into a single protein domain | Acetylcholinesterase is a fairly large protein, consisting of at least 535 amino acid residues in a single peptide chain, that folds into a single protein domain | ||
| - | without any apparent symmetry. At its core is a | + | without any apparent symmetry. At its core is a large Beta sheet, surrounded |
| - | by a | + | by a canopy of about 26 alpha helices. |
| + | |||
| + | 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 long tunnel or gorge, 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 Trp 271 and Tyr 121 dominate the peripheral site, and Trp 84 and Phe 330 the active site, together with His 440. (These numbers are the sequential numbering | ||
| + | of the residues, starting from the N-terminus, according to the '''Torpedo Californica''' form of the enzyme.) | ||
==Selected structures== | ==Selected structures== | ||
Revision as of 11:53, 14 November 2007
[Article by Clifford Felder, Structural Biology, Weizmann Institute]
THIS PAGE IS **UNDER CONSTRUCTION**, PLEASE BE PATIENT UNTIL IT IS COMPLETED!
The increasing longevity of people's lifespans, and the resulting increased prevelance of dementias such as Alzheimers Syndrome, led scientists to study the animal enzyme AcetylCholinEsterase (AChE) as a possible culprit. This enzyme rapidly degrades 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 apparently not the cause of Alzheimers, it does seem to play a minor role, in that weak inibitory drugs such as Tacrine, E2020 (Aricept) and the natural Chinese natural produce Huperzine appear to delay symptoms. Furthermore, this enzyme is a key target of some very important nerve gasses and related insecticides. Furthermore, it is a pretty fascinating enzyme to study.
Because of the relative ease in obtaining purified protein in abundance, AceytlCholinesterase was first crystallized by Joel Sussman of the Weizmann Institute, Rehovot Israel, after being extracted from the electric organ of the Pacific Sting Ray, Torpedo Californica, order to determine its detailed 3-dimensional structure by X-ray crystallography (2ace). Subsequently its X-ray structure has been determined from over 20 species, ranging from the fruit fly Drosophila to human. Acetylcholinesterase is a fairly large protein, consisting of at least 535 amino acid residues in a single peptide chain, that folds into a single protein domain without any apparent symmetry. At its core is a large Beta sheet, surrounded by a canopy of about 26 alpha helices.
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 long tunnel or gorge, 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 Trp 271 and Tyr 121 dominate the peripheral site, and Trp 84 and Phe 330 the active site, together with His 440. (These numbers are the sequential numbering of the residues, starting from the N-terminus, according to the Torpedo Californica form of the enzyme.)
Selected structures
- 2ace This is a prime example of...
PDBs containing acetylcholinesterase
Proteopedia Page Contributors and Editors (what is this?)
Michal Harel, Joel L. Sussman, Alexander Berchansky, David Canner, Eran Hodis, Clifford Felder, Jaime Prilusky, Harry Greenblatt, Yechun Xu
