Biomedical Engineering Reference
In-Depth Information
Rivastigmine
Galanthamine
Phe 330
Phe 330
Trp 84
Phe 331
Trp 84
His 440
Peripheral anionic site
Phe 331
His 440
Glu 327
Glu 327
Gly 115
Glu 199
Ser 200
Glu 199
Ser 200
Phe 298
Donepezil
Sarin
Phe 330
Glu 327
Trp 279
Trp 84
Glu 327
His 440
Glu 199
Ser 200
Tyr 70
Tyr 121
Phe 331
His 440
Glu 327
Phe 330
Asp 72
Phe 330
Glu 199
Trp 84
Ser 200
Ser 200
His 440
Trp 84
Glu 199
(A)
(B)
FIGURE 16.6 AChE structure and AChEI-binding modes. (A) The 3D structure of AChE. The localization
of the PAS and the residues constituting the catalytic anionic site and the esteratic site in the enzyme are indi-
cated. (B) The active site of AChE in crystal structures of the enzymes complexes with AChEIs. The binding
modes of reversible inhibitors rivastigmine, galanthamine, and donepezil to the AChE and the phosphorus
AChE conjugate formed after interaction with the irreversible inhibitor sarin.
the anionic site, respectively (exemplii ed by rivastigmine in Figure 16.6B). However, in contrast to
the very fast (microseconds) hydrolysis of acetate from the Ser 200 residue following the hydrolysis
of ACh, the dissociation of the carbamate group is very slow (minutes) (Figure 16.7B). Thus, the
inhibition exerted by this AChEI class arises from the active site in AChE being occupied and
unable to bind ACh for a considerable time after the initial binding of the inhibitor. In particular,
for rivastigmine ( 16.13 ) the duration of this reactivation phase is considerable, and the compound is
often termed a “pseudo-irreversible” inhibitor.
Other AChEIs, such as tacrine ( 16.9 ) and galanthamine ( 16.15 ), act like “true” inhibitors, as they
are not hydrolyzed by AChE but instead compete with ACh for the active site in the enzyme, inter-
acting with residues in both the anionic and esteratic subsites (Figure 16.6B). Donepezil ( 16.10 ),
on the other hand, targets the gorge connecting the active site with the surface of the enzyme, the
dimethoxy-indanone and benzyl piperidine moieties of the inhibitor interacting with Trp 279 in the
PAS and with Trp 84 and Phe 330 in the anionic subsite of the active site, respectively (Figure 16.6B).
Bisquaternary inhibitors, such as decamethonium ( 16.22 ), bind in a similar fashion, and the remark-
ably enhanced potencies displayed by bivalent ligands such as 16.20 is also attributed to their ability
to target two binding sites in AChE. Finally, propidium ( 16.23 ) and fasciculin-2, a 61-amino acid
peptide isolated from the venom of Dendroaspis (mamba) species, inhibit AChE noncompetitively
by binding exclusively to the PAS.
Irreversible organophosphorus AChEIs such as 16.7 and 16.8 all act at the active site of AChE, as
they form covalently attached phosphorus conjugates with the Ser 200 residue in the esteratic subsite
of the enzyme, thereby disrupting its catalytic mechanism (Figures 16.6B and 16.7C). Treatment of
the phosphorus AChE conjugate with so-called reactivators, oxime-based medical antidotes such as
pralidoxime ( 16.24 ) and obidoxime ( 16.25 ), can restore AChE function, but being unable to pass the
blood-brain barrier (BBB) they cannot reverse the central effects of organophosphate poisoning.
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