Sandbox 1b41: Difference between revisions

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[[Image: Sites de l'AChE.jpg|400 px|]]

The peripheral site is a transitional binding site of the substrate. It provides a region rich in aromatic amino acids that guide the ligands (ACh or other agonists) by setting an array of low-affinity binding sites. This hydrophobic region ~~trapps~~ ACh and transfers it to the deep catalytic site.

The peripheral site is a transitional binding site of the substrate. It provides a region rich in aromatic amino acids that guide the ligands (ACh or other agonists) by setting an array of low-affinity binding sites. This hydrophobic region traps ACh and transfers it to the deep catalytic site.

The catalytic site of AChE consists of two subsites: the "esteratic" site and "the anionic" site.

In the "esteratic site" a catalytic triad consisting of <scene name='Sandbox_1b41/Esteratic_site/2'>E334, H447, S203</scene> forms a planar array that ~~ressembles~~ the catalytic triad of serine proteases.

In the "esteratic site" a catalytic triad consisting of <scene name='Sandbox_1b41/Esteratic_site/2'>E334, H447, S203</scene> forms a planar array that resembles the catalytic triad of serine proteases.

S203 is activated (it becomes nucleophilic) by E334 and H447. This activation allows the following reaction: the acylation between hydroxyl group of S203 and ACh oxygen (or other agonists). A covalent bond between the enzyme and the substrate creates an oxyanion. This oxyanion then reacts with two glycins setting up hydrogen bond.

S203 is activated (it becomes nucleophilic) by E334 and H447. This activation allows the following reaction: the acylation between hydroxyl group of S203 and ACh oxygen (or other agonists). A covalent bond between the enzyme and the substrate creates an oxyanion. This oxyanion then reacts with two glycins setting up a hydrogen bond.

In the "anionic" site, the <scene name='Sandbox_1b41/Anionic_site/1'>W86</scene> binds trimethylammonium group of ACh.

Further to these steps the ~~substrat~~ is well positioned to be hydrolysed into acetic acid and cholin.

Further to these steps the substrate is well positioned to be hydrolysed into acetic acid and cholin.

[[Image: Hydrolyse ACh par AChE.jpg|500 px|]]

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===Fasciculin II===

Fasciculin is a snake toxin. It's a little protein of 7kDa which inhibits AChE in ~~bindind~~ the peripheric site, preventing the substrate from ~~passage~~ through the narrower portion of the gorge towards the catalytic site. This inhibition is almost irreversible.

Fasciculin is a snake toxin. It is a little protein of 7kDa which inhibits AChE in binding the peripheric site, preventing the substrate from passing through the narrower portion of the gorge towards the catalytic site. This inhibition is almost irreversible.

The toxin is the one used in cristallisation of the Human acetylcholinesterase (in green on the picture).

===Inhibitors used as treatments===

We can find a lot of inhibitors such as Alzheimer's disease drugs treatment. Actually, Alzheimer disease is a neurodegenerative disease in which ACh is less present. An inhibition approach can be used to increase the remaining of ACh in the synaptic cleft by inhibiting the action of AChE. These ~~treatment~~ include rivastigmine, donepezil and tacrine. However, ~~those~~ drugs ~~don't~~ cure this disease, but only delay its development.

We can find a lot of inhibitors such as in Alzheimer's disease drugs treatment. Actually, Alzheimer's disease is a neurodegenerative disease in which ACh is less present. An inhibition approach can be used to increase the remaining of ACh in the synaptic cleft by inhibiting the action of AChE. These treatments include rivastigmine, donepezil and tacrine. However, these drugs do not cure this disease, but only delay its development.

The molecule which has been the most studied is tacrine. A monomer of tacrine binds strongly at the peripheral site, preventing the subtrate from entry. When tacrine is in the dimer shape, it can bind the catalytic and peripheral sites of AChE.

The molecule which has been the most studied is tacrine. A monomer of tacrine binds strongly to the peripheral site, preventing the subtrate from entry. When tacrine is in the dimer shape, it can bind the catalytic and peripheral sites of AChE.

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@@ Line 11: / Line 11: @@
 [[Image: Sites de l'AChE.jpg|400 px|]]
-The peripheral site is a transitional  binding site of the substrate. It provides a region rich in aromatic amino acids that guide the ligands (ACh or other agonists) by setting an array of low-affinity binding sites. This hydrophobic region trapps ACh and transfers it to the deep catalytic site.
+The peripheral site is a transitional  binding site of the substrate. It provides a region rich in aromatic amino acids that guide the ligands (ACh or other agonists) by setting an array of low-affinity binding sites. This hydrophobic region traps ACh and transfers it to the deep catalytic site.
 The catalytic site of AChE consists of two subsites: the "esteratic" site and "the anionic" site.
-In the "esteratic site" a catalytic triad consisting of <scene name='Sandbox_1b41/Esteratic_site/2'>E334, H447, S203</scene> forms a planar array that ressembles the catalytic triad of serine proteases.
+In the "esteratic site" a catalytic triad consisting of <scene name='Sandbox_1b41/Esteratic_site/2'>E334, H447, S203</scene> forms a planar array that resembles the catalytic triad of serine proteases.
-S203 is activated (it becomes nucleophilic) by E334 and H447. This activation allows the following reaction: the acylation between hydroxyl group of S203 and ACh oxygen (or other agonists). A covalent bond between the enzyme and the substrate creates an oxyanion. This oxyanion then reacts with two glycins setting up hydrogen bond.
+S203 is activated (it becomes nucleophilic) by E334 and H447. This activation allows the following reaction: the acylation between hydroxyl group of S203 and ACh oxygen (or other agonists). A covalent bond between the enzyme and the substrate creates an oxyanion. This oxyanion then reacts with two glycins setting up a hydrogen bond.
 In the "anionic" site, the <scene name='Sandbox_1b41/Anionic_site/1'>W86</scene> binds trimethylammonium group of ACh.
-Further to these steps the substrat is well positioned to be hydrolysed into acetic acid and cholin.
+Further to these steps the substrate is well positioned to be hydrolysed into acetic acid and cholin.
 [[Image: Hydrolyse ACh par AChE.jpg|500 px|]]
@@ Line 28: / Line 28: @@
 ===Fasciculin II===
-Fasciculin is a snake toxin. It's a little protein of 7kDa which inhibits AChE in bindind the peripheric site, preventing the substrate from passage through the narrower portion of the gorge towards the catalytic site. This inhibition is almost irreversible.
+Fasciculin is a snake toxin. It is a little protein of 7kDa which inhibits AChE in binding the peripheric site, preventing the substrate from passing through the narrower portion of the gorge towards the catalytic site. This inhibition is almost irreversible.
 The toxin is the one used in cristallisation of the Human acetylcholinesterase (in green on the picture).
 ===Inhibitors used as treatments===
-We can find a lot of inhibitors such as Alzheimer's disease drugs treatment. Actually, Alzheimer disease is a neurodegenerative disease in which ACh is less present. An inhibition approach can be used to increase the remaining of ACh in the synaptic cleft by inhibiting the action of AChE. These treatment include rivastigmine, donepezil and tacrine. However, those drugs don't cure this disease, but only delay its development.
+We can find a lot of inhibitors such as in Alzheimer's disease drugs treatment. Actually, Alzheimer's disease is a neurodegenerative disease in which ACh is less present. An inhibition approach can be used to increase the remaining of ACh in the synaptic cleft by inhibiting the action of AChE. These treatments include rivastigmine, donepezil and tacrine. However, these drugs do not cure this disease, but only delay its development.
-The molecule which has been the most studied is tacrine. A monomer of tacrine binds strongly at the peripheral site, preventing the subtrate from entry. When tacrine is in the dimer shape, it can bind the catalytic and peripheral sites of AChE.
+The molecule which has been the most studied is tacrine. A monomer of tacrine binds strongly to the peripheral site, preventing the subtrate from entry. When tacrine is in the dimer shape, it can bind the catalytic and peripheral sites of AChE.