AChE inhibitors and substrates (Part II)

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==AChE monovalent inhibitors (continuation of the page [[AChE inhibitors and substrates]])==
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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 the ''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. 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 with <font color='magenta'><b>NAP alone (colored magenta)</b></font> (without carbamyl moiety) 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'>Alignment</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 edrophonium (mentioned above as a CAS-binding inhibitor) in complex with ''Tc''AChE ([[2ack]]) on thioflavin T/''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 thioflavin T. 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 edrophonium/''Tc''AChE complex.
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<applet load='AC1.pdb' size='500' frame='true' align='right'
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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. Its hydrolysis is impossible since OTMA possesses <scene name='2vja/Common/4'>carbon</scene> instead of <scene name='2vja/Common/5'>ester oxygen</scene> as is seen 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. 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). 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><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>
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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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