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.