 |
Printable
PDF Version
X-Rays May Show The Way
To Better Alzheimer's
Drugs
Weizmann Institute
scientists explain how a
plant substance blocks a
key brain enzyme
involved in Alzheimer's
disease.
Galanthine (Galanthus
nivalis)
Huperzine A already
works to restore
acetylcholine levels by
inhibiting the enzyme,
Acetylcholinesterase
REHOVOT, Israel --
December 27, 1999 --
Weizmann Institute
researchers have
revealed the exact
nature of the 3-D
interaction between
galanthamine, a natural
substance extracted from
the common snowdrop (Galanthus
nivalis) and the brain
enzyme
acetylcholinesterase (AChE).
Their findings,
appearing in the
December 17 issue of the
Federation of European
Biochemical Societies (FEBS
Letters), may provide
crucial information in
designing a new family
of Alzheimer¹s drugs.
Alzheimer's disease is a
severe degenerative
disorder causing memory
loss and other cognitive
deficits in roughly 10
percent of the elderly.
One of its pathological
hallmarks is the
deterioration of nerve
cells releasing
acetylcholine a
neurotransmitter that
helps ferry "messages"
in the form of nerve
impulses between brain
cells. The acetylcholine
shortage that ensues is
compounded by the action
of acetylcholinesterase
(AChE), the enzyme which
breaks down
acetylcholine in the
body at an astonishing
rate of 20,000 molecules
per second.
Blocking acetylcholine
breakdown
While scientists have
yet to understand the
cause of the disease,
several Alzheimer¹s
drugs already exist,
including Aricept, HupA
(huperzine A), and
Cognex (tacrine). Their
underlying approach is
to attempt to restore
acetylcholine levels by
inhibiting AChE
activity.
Using X-ray
crystallography, Dr.
Harry Greenblatt of the
Weizmann Institute¹s
Department of Structural
Biology, has revealed
that galanthamine acts
in a similar manner,
replenishing
acetylcholine levels by
binding to AChE¹s active
site and shutting off
its "cutting machinery."
Greenblatt conducted the
research together with
Dr. Gitay Kryger, and
Professors Joel Sussman,
and Israel Silman, all
of the Weizmann
Institute, as well as
Dr. Terry Lewis of
Zeneca Agrochemicals, in
England. However,
according to Greenblatt,
parallel to boosting
acetylcholine levels,
galanthamine may go an
extra lap.
Dual-action power
"In addition to its
effect on AChE,
galanthamine also binds
to acetylcholine
receptors (proteins on
the surface of the nerve
cell which are activated
by acetylcholine) thus
directly stimulating
neuronal function," says
Greenblatt. "This dual
mode of action, coupled
with the evidence that
galanthamine has reduced
side-effects in
comparison to tacrine
make it a particularly
exciting candidate for
designing improved
potency drugs."
And this is where the
"blueprint" generated by
the Weizmann team may
prove highly beneficial.
One of the most
important steps toward
understanding how a
molecule works is to map
it out, explains Prof.
Sussman. For instance,
after Watson and Crick
demonstrated DNA's
structure through their
tinker-toy model, the
secret of genetic
replication became
suddenly, almost
intuitively, clear. In a
similar fashion, X-ray
crystallography can be
used to capture highly
accurate 'snapshots' of
natural complexes, such
as that of galanthamine
with AChE. ³By studying
these interactions, we
can see how modifying
certain chemical
properties can
potentially enhance
their binding, leading
to greater drug
efficacy," says Sussman.
The scientists worked
with high quality
crystals of AChE derived
from electric organ
tissue of the Torpedo
fish, one of the richest
sources of this enzyme.
The Torpedo AChE
crystals were soaked
with galanthamine, and
then exposed to a narrow
X-ray beam, producing a
diffraction pattern from
which a 3-D computer
image of the
AChE-galanthamine
complex could be
obtained.
Ancient defense
mechanisms--new
applications
The current Weizmann
study builds upon
previous Alzheimer¹s
disease research
completed by Sussman,
Silman and Dr. Michal
Harel, of the Structural
Biology Department.
Several years ago, they
were the first to
completely solve the
three-dimensional
structure of AChE,
showing that ithas a
deep, canyon-like chasm
known as the "aromatic
gorge", where
acetylcholine is broken
down. Later, the team
solved the structures of
complexes formed between
AChE and diverse
synthetic and natural
compounds, including the
synthetically produced
Aricept, fasciculin - a
snake venom toxin, and
huperzine A an extract
from a Chinese herb used
for centuries to treat
memory disorders. All of
these substances, as
well as the newly
examined galanthamine,
are joined by a common
denominator. Although
they differ in their
mode of association,
they inhibit AChE by
blocking its active site
located at the bottom of
the aromatic gorge. AChE
inhibition is also the
principle mode of action
of many pesticides.
While fasciculin clearly
has a predatory function
in the case of snake
venom, might the plant
products act in defense
against insects or
parasites? "This
question has not been
explored, says Sussman.
However, the fact that
unrelated plants from
different parts of the
world produce AChE
inhibitors is striking."
The Weizmann Institute
team is currently
collaborating with
France¹s Institut de
Chimie des Substances
Naturelles and Zeneca
Agrochemicals, with the
aim of applying the
knowledge gleaned from
these natural compounds
toward improved
Alzheimer's drugs and
"environment-friendly"
insecticides.
This study of the
galanthamine-AChE
binding was funded by
the European Union 4th
Framework Program in
Biotechnology, the U.S.
Army Medical and
Material Command, the
Weizmann Institute's
Kimmelman Center for
Biomolecular Structure
and Assembly, and the
Dana Foundation. The
generous support of Mrs.
Tania Friedman is
gratefully acknowledged.
The coordinates of the
complex between AChE and
galanthamine have been
deposited with the
Protein Data Bank (at
EBI, code 1dx6). Prof.
Israel Silman, a member
of the Weizmann
Institute's Neurobiology
Department, holds the
Bernstein-Mason Chair of
Neurochemistry. Prof.
Joel Sussman is the
former head of the
Protein Data Bank of the
Brookhaven National
Laboratory in Upton, New
York.
Printable
PDF Version
|
