[Editors] MIT chemist discovers secret behind nature's medicines

[Elizabeth Thomson]

MIT News Office
Massachusetts Institute of Technology
Room 11-400
77 Massachusetts Avenue
Cambridge, MA  02139-4307
Phone: 617-253-2700
http://web.mit.edu/newsoffice/www

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MIT chemist discovers secret behind nature's medicines
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For Immediate Release
WEDNESDAY, APR. 26, 2006
Contact: Elizabeth A. Thomson
Phone: 617-258-5402
Email: thomson at mit.edu

PHOTO AVAILABLE

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.

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Elizabeth A. Thomson
Assistant Director, Science & Engineering News
Massachusetts Institute of Technology
News Office, Room 11-400
77 Massachusetts Ave.
Cambridge, MA  02139-4307
617-258-5402 (ph); 617-258-8762 (fax)
<thomson at mit.edu>

<http://web.mit.edu/newsoffice/www>
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