AChE inhibitors and substrates (Part II)

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==AChE monovalent inhibitors (continuation)==
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#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)''' ([[2ack]]) is stacked between the aromatic rings of <scene name='2ack/Com_view/2'>W84 and F330</scene>, near ''Tc''AChE <scene name='2ack/Com_view/3'>catalytic triad</scene> which consists of '''S200''', '''E327''', and '''H440'''.
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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. The <scene name='1gqr/Active_site/4'>active-site gorge</scene> of ''Tc''AChE complexed with rivastigmine ([[1gqr]]). The carbamyl moiety of rivastigmine is <scene name='1gqr/Active_site/5'>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 was <scene name='1gqr/Active_site/6'>separated</scene> from the carbamyl moiety, so the carbamylation took place. The <scene name='1gqr/Active_site/7'>crystal structure</scene> of ''Tc''AChE with <font color='magenta'><b>NAP alone (colored magenta)</b></font> (without carbamyl moiety) also was determined ([[1gqs]]). The <font color='violet'><b>''Tc''AChE active-site residues</b></font> which are important in interaction with NAP are <font color='violet'><b>colored violet</b></font>. NAP alone is located in the relatively similar region of ''Tc''AChE active site, but with unliked orientation in comparison to <font color='yellow'><b>NAP part</b></font> of rivastigmine. Only H440 and F330 significantly changed their side-chain conformations. <scene name='1gqr/Active_site/8'>Alignment</scene> of the ''Tc''AChE active sites in 4 different complexes (with rivastigmine, NAP alone, ACh ([[2ace]]), and the additional AChE inhibitor '''VX''' ([[1vxr]]) revealed that the conformation of H440 in the NAP alone/''Tc''AChE is very similar to that of native ''Tc''AChE ([[2ace]]), but the distance between H440 Nδ and E327 Oε is significantly increased in rivastigmine/''Tc''AChE and VX/''Tc''AChE complexes. This structural change disrupts the catalytic triad consisting of E327, H440, and S200. This could explain for 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='right'
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scene='2j3q/Active_site/1' />
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'''8)''' The ''Tc''AChE active site consists of two binding subsites. First of them is the "catalytic anionic site" (CAS), which involves 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 ligands 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 edrophonium (mentioned above CAS-binding inhibitor) in complex with ''Tc''AChE ([[2ack]]) on thioflavin T/''Tc''AChE structure ([[2j3q]]) demonstrates that these ligands do not overlapped. Of note, that Phe330, which is part of the CAS, is a single residue interacting with thioflavin T. Only this residue significantly <scene name='2j3q/Active_site/8'>changes its conformation</scene> to avoid clashes in comparison to other CAS residues of the edrophonium/''Tc''AChE complex.
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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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'''9)''' <scene name='2vja/Common/3'>OTMA</scene> is a nonhydrolyzable substrate analogue of AChE. The hydrolyze is impossible since OTMA possesses <scene name='2vja/Common/4'>carbon</scene> instead <scene name='2vja/Common/5'>ester oxygen</scene> of 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). Of note, OTMA binds not only at CAS, but also at PAS. The 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) at this subsite. 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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==References==
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<ref group='xtra'>PMID:8989325</ref> <ref group='xtra'>PMID:8415649</ref>
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<ref group='xtra'>PMID:15563167</ref> <ref group='xtra'>PMID:10089512</ref>
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<ref group='xtra'>PMID:16076210</ref> <ref group='xtra'>PMID:10476864</ref>
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<ref group='xtra'>PMID:12517147</ref> <ref group='xtra'>PMID:1678899</ref>
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<ref group='xtra'>PMID:10606746</ref> <ref group='xtra'>PMID:11888271</ref>
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<ref group='xtra'>PMID:18701720</ref> <ref group='xtra'>PMID:11863435</ref>
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<ref group='xtra'>PMID:18512913</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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Current revision

  1. REDIRECT AChE_inhibitors_and_substrates#Treatment_of_Alzheimer.27s_disease

Proteopedia Page Contributors and Editors (what is this?)

Alexander Berchansky, Wayne Decatur, David Canner, Michal Harel

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