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.
Elizabeth A. Thomson | MIT News Office
Synthetic nanoparticles achieve the complexity of protein molecules
24.01.2017 | Carnegie Mellon University
Immune Defense Without Collateral Damage
24.01.2017 | Universität Basel
For the first time ever, a cloud of ultra-cold atoms has been successfully created in space on board of a sounding rocket. The MAIUS mission demonstrates that quantum optical sensors can be operated even in harsh environments like space – a prerequi-site for finding answers to the most challenging questions of fundamental physics and an important innovation driver for everyday applications.
According to Albert Einstein's Equivalence Principle, all bodies are accelerated at the same rate by the Earth's gravity, regardless of their properties. This...
An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...
Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
19.01.2017 | Event News
10.01.2017 | Event News
09.01.2017 | Event News
24.01.2017 | Earth Sciences
24.01.2017 | Life Sciences
24.01.2017 | Physics and Astronomy