Ironjustic
Thu, Apr-27-06, 16:17
http://www.eurekalert.org/pub_releases/2006-04/miot-mcd-
042606.php
Public release date: 26-Apr-2006 [ Print Article | E-mail
Article | Close Window ]
Contact: Elizabeth Thomson thomson@mit.edu 617-258-5402
Massachusetts Institute of Technology
MIT chemist discovers secret behind nature's medicines
CAMBRIDGE, Mass.--MIT scientists have just learned another
lesson from nature. After years of wondering how organisms
managed to create self-medications, such as anti-fungal
agents, chemists have discovered the simple secret.
Scientists already knew that a particular enzyme was able to
coax a reaction out of stubborn chemical concoctions to
generate a large family of medically valuable compounds
called halogenated natural products. The question was, how do
they do it?
Chemists would love to have that enzyme's capability so they
could efficiently reproduce, or slightly re-engineer, those
products, which include antibiotics, anti-tumor agents, and
fungicides.
Thanks to MIT chemistry Associate Professor Catherine L.
Drennan's recent crystallography sleuthing, the secret to the
enzyme's enviable prowess has come to light and it appears
almost anti-climactic. It's simply a matter of the size of one
of its parts.
"If an enzyme is a gun that fires to cause a reaction, then we
wanted to know the mechanism that pulls the trigger," Drennan
said. "In chemistry, we often have to look at 'molecules in,
molecules out.' With halogenated natural products, though, we
couldn't figure out how it happened, because the chemicals are
so nonreactive. Now that we have the enzyme's structure and
figured out how it works, it makes sense. But it's not what we
would have predicted."
To make halogenated natural products, enzymes catalyze the
transformation of a totally unreactive part of a molecule, in
this case a methyl group. They break specific chemical bonds
and then replace a hydrogen atom with a halide, one of the
elements from the column of the periodic table containing
chlorine, bromine and iodine. In the lab, that's a very
challenging task, but nature accomplishes it almost
nonchalantly. The trick involves using a turbo-charged enzyme
containing iron.
A clue to how these enzymes operate emerged from a 2005 study
by Christopher T. Walsh of Harvard Medical School, Drennan's
collaborator and co-author of the study published in the March
16 issue of Nature. Looking at the SyrB2 enzyme that the
microorganism Pseudomonas syringae uses to produce the
antifungal agent syringomycin, he discovered it had a single
iron atom in the protein's active site, the part responsible
for the chemical reaction.
Drennan and her graduate student Leah C. Blasiak, who was
first author of the study, crystallized SyrB2 and then used
X-ray crystallography to discover the physical structure of
the protein. The X-rays scatter off the crystal, creating
patterns that can be reconstructed as a three-dimensional
model for study.
Normally, iron-containing enzymes have three amino acids that
hold the iron in the active site. In this enzyme, however,
one of the typical amino acids was substituted with a much
shorter one.
That smaller substitute leaves more room in the active site --
enough space for the halide, in this case a chloride ion, to
casually slip inside and bind to the iron, without the grand
theatrics chemists had anticipated. After the iron and the
chloride bind, the protein closes down around the active site,
effectively pulling the trigger on the gun.
"We were surprised," Drennan said. "The change in activity
required for an enzyme to be capable of catalyzing a
halogenation reaction is so radical that people thought there
must be a really elaborate difference in their structures. But
it's just a smaller amino acid change in the active site.
Things are usually not this simple, but there's an elegant
beauty in this simplicity," and it may be what gives other
enzymes the prowess required for making other medicinally
valuable halogenated natural products, too.
###
The research was partially funded by the National Institutes
of Health.
--------------------------------------------------------------
-------------------
Who loves ya. Tom
Jesus Was A Vegetarian! http://jesuswasavegetarian.7h.com
Man Is A Herbivore!
http://pages.ivillage.com/ironjustice/manisaherbivore
DEAD PEOPLE WALKING
http://pages.ivillage.com/ironjustice/deadpeoplewalking
042606.php
Public release date: 26-Apr-2006 [ Print Article | E-mail
Article | Close Window ]
Contact: Elizabeth Thomson thomson@mit.edu 617-258-5402
Massachusetts Institute of Technology
MIT chemist discovers secret behind nature's medicines
CAMBRIDGE, Mass.--MIT scientists have just learned another
lesson from nature. After years of wondering how organisms
managed to create self-medications, such as anti-fungal
agents, chemists have discovered the simple secret.
Scientists already knew that a particular enzyme was able to
coax a reaction out of stubborn chemical concoctions to
generate a large family of medically valuable compounds
called halogenated natural products. The question was, how do
they do it?
Chemists would love to have that enzyme's capability so they
could efficiently reproduce, or slightly re-engineer, those
products, which include antibiotics, anti-tumor agents, and
fungicides.
Thanks to MIT chemistry Associate Professor Catherine L.
Drennan's recent crystallography sleuthing, the secret to the
enzyme's enviable prowess has come to light and it appears
almost anti-climactic. It's simply a matter of the size of one
of its parts.
"If an enzyme is a gun that fires to cause a reaction, then we
wanted to know the mechanism that pulls the trigger," Drennan
said. "In chemistry, we often have to look at 'molecules in,
molecules out.' With halogenated natural products, though, we
couldn't figure out how it happened, because the chemicals are
so nonreactive. Now that we have the enzyme's structure and
figured out how it works, it makes sense. But it's not what we
would have predicted."
To make halogenated natural products, enzymes catalyze the
transformation of a totally unreactive part of a molecule, in
this case a methyl group. They break specific chemical bonds
and then replace a hydrogen atom with a halide, one of the
elements from the column of the periodic table containing
chlorine, bromine and iodine. In the lab, that's a very
challenging task, but nature accomplishes it almost
nonchalantly. The trick involves using a turbo-charged enzyme
containing iron.
A clue to how these enzymes operate emerged from a 2005 study
by Christopher T. Walsh of Harvard Medical School, Drennan's
collaborator and co-author of the study published in the March
16 issue of Nature. Looking at the SyrB2 enzyme that the
microorganism Pseudomonas syringae uses to produce the
antifungal agent syringomycin, he discovered it had a single
iron atom in the protein's active site, the part responsible
for the chemical reaction.
Drennan and her graduate student Leah C. Blasiak, who was
first author of the study, crystallized SyrB2 and then used
X-ray crystallography to discover the physical structure of
the protein. The X-rays scatter off the crystal, creating
patterns that can be reconstructed as a three-dimensional
model for study.
Normally, iron-containing enzymes have three amino acids that
hold the iron in the active site. In this enzyme, however,
one of the typical amino acids was substituted with a much
shorter one.
That smaller substitute leaves more room in the active site --
enough space for the halide, in this case a chloride ion, to
casually slip inside and bind to the iron, without the grand
theatrics chemists had anticipated. After the iron and the
chloride bind, the protein closes down around the active site,
effectively pulling the trigger on the gun.
"We were surprised," Drennan said. "The change in activity
required for an enzyme to be capable of catalyzing a
halogenation reaction is so radical that people thought there
must be a really elaborate difference in their structures. But
it's just a smaller amino acid change in the active site.
Things are usually not this simple, but there's an elegant
beauty in this simplicity," and it may be what gives other
enzymes the prowess required for making other medicinally
valuable halogenated natural products, too.
###
The research was partially funded by the National Institutes
of Health.
--------------------------------------------------------------
-------------------
Who loves ya. Tom
Jesus Was A Vegetarian! http://jesuswasavegetarian.7h.com
Man Is A Herbivore!
http://pages.ivillage.com/ironjustice/manisaherbivore
DEAD PEOPLE WALKING
http://pages.ivillage.com/ironjustice/deadpeoplewalking