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| - | ==AChE monovalent inhibitors (continuation of the page [[AChE inhibitors and substrates]])==
| + | #REDIRECT [[AChE_inhibitors_and_substrates#Treatment_of_Alzheimer.27s_disease]] |
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| - | <applet load='2ack' size='500' frame='true' align='left'
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| - | scene='2ack/Com_view/1' />
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| - | '''6) Edrophonium (EDR)''' is stacked between the aromatic rings of <scene name='2ack/Com_view/2'>W84 and F330</scene>, near the ''Tc''AChE <scene name='2ack/Com_view/3'>catalytic triad</scene> which consists of <font color='magenta'><b>'''S200'''</b></font>, <font color='magenta'><b>'''E327'''</b></font>, and <font color='magenta'><b>'''H440'''</b></font> ([[2ack]]).
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| - | <applet load='1gqr' size='500' frame='true' align='right'
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| - | scene='1gqr/Com_view/1' />
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| - | '''7) Rivastigmine (Exelon)''' is a carbamate inhibitor of AChE, and it is currenly used in therapy of Alzheimer's disease. Rivastigmine (colored yellow) interacts with ''Tc''AChE <font color='lime'><b>(colored lime)</b></font> at the <scene name='1gqr/Active_site/4'>active-site gorge</scene>. The carbamyl moiety of rivastigmine is <scene name='1gqr/Active_site/9'>covalently bound</scene> to the active-site S200 Oγ. The second part of rivastigmine (the leaving group), NAP ((−)-S-3-[1-(dimethylamino)ethyl]phenol) is also held in the active-site gorge, but it is <scene name='1gqr/Active_site/6'>separated</scene> from the carbamyl moiety, hence, carbamylation took place. The <scene name='1gqr/Active_site/7'>crystal structure</scene> of ''Tc''AChE/<font color='magenta'><b>NAP (colored magenta)</b></font> is known ([[1gqs]]). The <font color='violet'><b>''Tc''AChE active-site residues</b></font> which are interacting with NAP are <font color='violet'><b>colored violet</b></font>. NAP is located in a similar region of ''Tc''AChE active site, but with different orientation than that of the NAP part (colored yellow) in the ''Tc''AChE/rivastigmine complex. Only H440 and F330 significantly change their side-chain conformations. <scene name='1gqr/Active_site/8'>Overlap</scene> of the ''Tc''AChE active sites in 4 different structures (<font color='lime'><b>''Tc''AChE</b></font>/rivastigmine, <font color='violet'><b>''Tc''AChE</b></font>/<font color='magenta'><b>NAP</b></font>, <font color='cyan'><b>native ''Tc''AChE</b></font> ([[2ace]]), and ''Tc''AChE/'''VX''' ([[1vxr]], ''Tc''AChE colored white and VX black) reveals that the conformation of H440 in the ''Tc''AChE/NAP structure is very similar its conformation in the native ''Tc''AChE ([[2ace]]), but the distance between H440 Nδ and E327 Oε is significantly longer in the ''Tc''AChE/rivastigmine and the ''Tc''AChE/'''VX''' complexes. This structural change disrupts the catalytic triad consisting of S200, E327, H440. This could explain the very slow kinetics of AChE reactivation after its inhibition by rivastigmine.
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| - | <applet load='AC5.pdb' size='500' frame='true' align='left'
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| - | scene='2j3q/Active_site/1' />
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| - | '''8)''' The ''Tc''AChE active site consists of two binding subsites. One of them is the "catalytic anionic site" (CAS), which involves the catalytic triad <scene name='2j3q/Active_site/2'>Ser200, His440, and Glu327</scene> <font color='orange'><b>(colored orange)</b></font> and the conserved residues <scene name='2j3q/Active_site/3'>Trp84 and Phe330</scene> which also participate in ligand recognition. Another conserved residue <scene name='2j3q/Active_site/4'>Trp279</scene> <font color='cyan'><b>(colored cyan)</b></font> is situated at the second binding subsite, termed the "peripheral anionic site" (PAS), ~14 Å from CAS. <scene name='2j3q/Active_site/6'>Thioflavin T</scene> is a good example of the PAS-binding AChE inhibitors. <scene name='2j3q/Active_site/7'>Superposition</scene> of the crystal structure of the <font color='red'><b>edrophonium</b></font>/''Tc''AChE (mentioned above as a CAS-binding inhibitor) ([[2ack]]) on the <font color='magenta'><b>thioflavin T</b></font>/''Tc''AChE complex structure ([[2j3q]]) shows that these ligands' positions do not overlap. Of note is that Phe330, which is part of the CAS, is the single residue interacting with <font color='magenta'><b>thioflavin T</b></font>. This residue is the only one which significantly <scene name='2j3q/Active_site/8'>changes its conformation</scene> to avoid clashes in comparison to other CAS residues of the <font color='red'><b>edrophonium</b></font>/''Tc''AChE complex.
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| - | '''9)''' Organophosphorus acid anhydride (OP) nerve agents are potent inhibitors which rapidly phosphonylate AChE and then may undergo an internal dealkylation reaction (called "aging") to produce an OP-enzyme conjugate that cannot be reactivated.
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| - | [[Image:Soman_reaction.png | left | thumb | 800px | Reaction between Ser200OG and Soman, assuming an in-line attack by the OG, followed by spontaneous dealkylation of the O-pinacolyl group.]]
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| - | <applet load='Soman1.pdb' size='500' frame='true' align='right' scene='2wfz/Al/1' />
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| - | Acetylcholinesterase (AChE) hydrolysizes the neurotransmitter <scene name='2wfz/Al/2'>acetylcholine (ACh)</scene>, producing <scene name='2wfz/Al/3'>choline and an acetate</scene> group. <scene name='2wfz/Al/2'>ACh</scene> directly binds catalytic <scene name='2wfz/Al/4'>Ser200</scene> (via its nucleophilic Oγ atom). <scene name='2wfz/Al/5'>Soman</scene>, O-(1,2,2-trimethylpropyl) methylphosphonofluoridate (<font color='violet'><b>fluorine atom is colored violet</b></font> and <font color='darkmagenta'><b>phosphorus atom is colored darkmagenta</b></font>), is one of the most toxic organophosphate compounds (OPs). Soman inhibits AChE by <scene name='2wfz/Al/6'>covalent binding</scene> to catalytic Ser200, <scene name='2wfz/Al/7'>mimicking ACh</scene>. This process <scene name='2wfz/Al/8'>(phosphonylation)</scene> implicates nucleophilic attack of the Ser200 nucleophilic Oγ atom on the phosphorus atom of soman, with concomitant departure of its fluoride atom. After that AChE catalyzes the <scene name='2wfz/Al/9'>dealkylation ("aging")</scene> of the soman or other OP. This causes irreversible inhibition of AChE, "aged" soman/AChE conjugate can not be reactivated. However, before “aging”, at the step of <scene name='2wfz/Al/8'>phosphonylation</scene>, AChE can be <scene name='2wfz/Al/11'>reactivated</scene> by nucleophiles, such as pralidoxime (2-PAM), resulting in <scene name='2wfz/Al/12'>cleavage</scene> of the phosphonyl adduct from Ser200 Oγ.
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| - | At the <scene name='2wfz/Ali/3'>active site of the nonaged soman/TcAChE conjugate</scene> ('''2wfz''') the catalytic His440 forms hydrogen bonds with Ser200 Oγ and Glu327 Oε1 via its Nε2 and Nδ1 nitrogens, respectively. The O2 atom of soman is within hydrogen bonding distance of His440 Nε2. Soman O1 mimicks carbonyl oxygen of ACh. A water molecule 1001 interacting with soman O2 is represented as a <font color='red'><b>red ball</b></font>. The active site residues of the nonaged soman/TcAChE are colored <font color='yellow'><b>yellow</b></font>. The O2 atom of the <scene name='2wfz/Ali/4'>dealkylated (aged) soman</scene> ([[2wg0]]) forms a salt bridge with His440 Nε2. The active site residues of the aged soman/TcAChE are colored <font color='pink'><b>pink</b></font>. <scene name='2wfz/Ali/5'>Alignment</scene> of the structures of the nonaged ('''2wfz''') and aged ([[2wg0]]) conjugates reveals a small, but important, change within the active site - the imidazole ring of His440 is tilted back to a native-like conformation after dealkylation. The water molecule 1001, which interacts with soman O2 in the nonaged crystal structure, is not within hydrogen bonding distance of O2 in the aged crystal structure. 2-PAM binds poorly to the nonaged phosphonylated enzyme (its electron density was not found) and binds in an <scene name='2wfz/Ali/7'>unfavorable and nonfunctional conformation</scene> after soman aging to ''Tc''AChE ([[2wg1]]).
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| - | <br /><applet load="1som" size="350" color="white" frame="true" align="right" spinBox="true"
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| - | caption="1som, resolution 2.20Å" scene="1som/Ache_soman/1"/> <br />
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| - | To understand the basis for irreversible inhibition, the structure of the aged conjugate obtained by reaction of ''Torpedo californica'' AChE (''Tc''AChE) with [http://en.wikipedia.org/wiki/Soman O-pinacolylmethylphosphonofluoridate] (soman) was solved by X-ray crystallography to 2.2Å resolution ([[1som]]). The highest positive difference density peak corresponded to the OP phosphorus and was located within covalent bonding distance of the active-site serine (S200). The <scene name='1som/Soman_active_site/3'>OP-oxygen atoms</scene> are within hydrogen-bonding distance of four potential donors from catalytic subsites of the enzyme, suggesting that electrostatic forces significantly stabilize the aged enzyme. The methyl group of soman occupies the <scene name='1som/Soman_acyl_binding/2'>acyl binding pocket</scene>, bounded by Trp233, Phe288, and Phe290. The active sites of aged sarin-TcAChE ([[1cfj]]) and soman-TcAChE were essentially identical and provided structural models for the negatively charged, tetrahedral intermediate that occurs during deacylation with the natural substrate, acetylcholine.
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| - | <applet load='AC1.pdb' size='500' frame='true' align='left'
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| - | scene='2vja/Common/1' />
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| - | '''10)''' <scene name='2vja/Common/3'>OTMA</scene> is a nonhydrolyzable substrate analogue of AChE. Its hydrolysis is impossible as OTMA possesses <scene name='2vja/Common/4'>carbon</scene> atom instead of the <scene name='2vja/Common/5'>ester oxygen</scene> in the AChE natural substrate ACh. Similarly to ACh, OTMA covalently binds to the ''Tc''AChE ([[2vja]]) <scene name='2vja/Active_site/1'>Ser200</scene> Oγ at the CAS. At this subsite OTMA also interacts with <scene name='2vja/Active_site/2'>Trp84, Phe330</scene> (cation-π interactions); <scene name='2vja/Active_site/3'>Glu199</scene> (electrostatic interaction); <scene name='2vja/Active_site/4'>Gly118, Gly119, and Ala201</scene>(hydrogen bonds). OTMA binds not only at CAS, but also at PAS. A second OTMA molecule interacts with <scene name='2vja/Active_site/5'>Trp279, Tyr70</scene> (cation-π interactions), and <scene name='2vja/Active_site/6'>Tyr121</scene> (weak hydrogen bond). Thus, this dual binding mode of OTMA with ''Tc''AChE (to CAS and PAS) could be prototypical for [[AChE bivalent inhibitors]].
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| - | '''Please see also our pages [[AChE bivalent inhibitors]] and [[AChE bivalent inhibitors (Part II)]].'''
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| - | ==Selected 3D Structures of AChE ==
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| - | * [[2ace]] This is the original solved structure for '''Torpedo Californica'''
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| - | * [[1ea5]] This is one of the highest quality representative X-ray structures in the PDB.
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| - | * [[1eve]] The E2020 (Aricept) complex.
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| - | * [[1ax9]] Endrophonium complex.
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| - | * [[1vot]] Complex with Huperzine, a Chinese folk medicine.
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| - | * [[1fss]] Complex with snake venum toxin Fasciculin-II.
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| - | * [[1acj]] Complex with tacrine.
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| - | * [[1e66]] Complex with huprine X.
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| - | * [[1dx6]] Complex with galanthamine.
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| - | * [[1w6r]] Complex with galanthamine iminium derivative.
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| - | * [[2ack]] Complex with edrophonium.
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| - | * [[1vzj]] Structure of the tetramerization domain of acetylcholinesterase.
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| - | * [[1gqr]] Complex with rivastigmine.
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| - | * [[1gqs]] Complex with NAP alone.
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| - | * [[1vxr]] Complex with VX.
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| - | * [[2vja]] Complex with OTMA.
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| - | * [[1som]] Complex with soman.
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| - | * [[1cfj]] Complex with sarin
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| - | ==References==
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| - | <ref group='xtra'>PMID:8989325</ref> <ref group='xtra'>PMID:8415649</ref><ref group='xtra'>PMID:15563167</ref><ref group='xtra'>PMID:10089512</ref><ref group='xtra'>PMID:16076210</ref> <ref group='xtra'>PMID:10476864</ref><ref group='xtra'>PMID:12517147</ref><ref group='xtra'>PMID:1678899</ref><ref group='xtra'>PMID:10606746</ref><ref group='xtra'>PMID:11888271</ref><ref group='xtra'>PMID:18701720</ref> <ref group='xtra'>PMID:11863435</ref><ref group='xtra'>PMID:18512913</ref> <ref group='xtra'>PMID:10353814</ref>
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| - | <references group='xtra'/>
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| - | [[Category: catalytic triad]]
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| - | [[Category: Cholinesterase]]
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| - | [[Category: Acetylcholinesterase]]
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| - | [[Category: AChE inhibitors]]
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| - | [[Category: inhibitor]]
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| - | [[Category: cholinesterases]]
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| - | [[Category: acetylcholine]]
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| - | [[Category: cation-pi]]
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| - | [[Category: Alzheimer's disease]]
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| - | [[Category: ISPC, Israel Structural Proteomics Center.]]
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