MIT chemist discovers secret behind nature's medicines

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.

Source: MIT

Related stories:

A molecular switch turns on the flame in 'nature's blowtorch'
Uncontrolled reaction of organic compounds with oxygen is easy: we call it fire. But nature often needs to do oxidations very specifically, adding oxygen to a particular carbon atom in a complicated molecule without disturbing anything else. Usually, this job falls to an enzyme called cytochrome P450. Because cytochrome P450 can catalyze molecular oxidations with pinpoint accuracy, it has been called "nature's blowtorch," and its job is analogous to that of a welder doing a tricky repair in a highly flammable wooden house. It needs to do the repair without burning itself or the house.
Scientists solve structure of gene regulator that plays key role in cancer
Scientists at The Wistar Institute have collaborated on a major advance in understanding a gene regulator that contributes to some of the deadliest cancers in humans. The culmination of 10 years’ work, their research paves the way for the development of new cancer therapies.
One shot of gene therapy spreads through brain in animal study
By targeting a site in a mouse brain well connected to other areas, researchers successfully delivered a beneficial gene to the entire brain—after one injection of gene therapy. If these results in animals can be realized in people, researchers may have a potential method for gene therapy to treat a host of rare but devastating congenital human neurological disorders, such as Tay-Sachs disease.
Extreme environment biology research may help solve lignocellulosic ethanol puzzle
Buried beneath a sulfurous cauldron in European seas lies a class of microorganisms known as “extremophiles,” so named because of the extreme environmental conditions in which they live and thrive. Almost as radical, perhaps, is the idea that these organisms and their associated enzymes could somehow unlock the key to a new transportation economy based on a renewable biofuel, lignocellulosic ethanol.
New molecule involved in the body's processing of dietary fat identified
UCLA investigators have identified a new molecule that may help regulate the delivery of fats to cells for energy and storage. Published in the April issue of the journal Cell Metabolism, the finding could lead to a better understanding of how we utilize fats from the foods we eat.
New 'biofuel cell' produces electricity from hydrogen in plain air
A pioneering “biofuel cell” that produces electricity from ordinary air spiked with small amounts of hydrogen offers significant potential as an inexpensive and renewable alternative to the costly platinum-based fuel cells that have dominated discussion about the “hydrogen economy” of the future, British scientists reported here today.
A Ruler of Gold and DNA
Scientists from the U.S. Department Energy’s Lawrence Berkeley National Laboratory and the University of California at Berkeley have developed a ruler made of gold nanoparticles and DNA that can measure the smallest of life’s phenomena, such as precisely where on a DNA strand a protein attaches itself.
Intelligently designed molecular evolution
Evolutionary paths to new therapeutic drugs, as well as a wide assortment of other enzyme products, have been created through, of all things, intelligent design. A team of researchers with the Lawrence Berkeley National Laboratory (Berkeley Lab) and the University of California at Berkeley have developed a technique in which the evolution of an important class of proteins is steered towards a desired outcome.

News discussion:

General Science news