UNM, BOSTON UNIVERSITY COLLABORATE TO TAKE SNAP SHOT OF CHEMICAL REACTION IN PROGRESS

July 1, 2003

UNM, BOSTON UNIVERSITY COLLABORATE TO TAKE SNAPSHOT OF CHEMICAL REACTION IN PROGRESS
Chemists work published in Science Magazine

University of New Mexico Chemistry Professor Debra Dunaway-Mariano and graduate student Guofeng Zhang teamed up with Boston University School of Medicine researchers to get the first glimpse of a chemical reaction as it is in the process of transforming to the chemical product.

Using X-ray crystallographic methods to take a snapshot of the molecule in its state of transition, the researchers have provided unequivocal proof for the existence of a long sought after chemical intermediate in phosphoryl transfer processes.

The research, which was recently featured in Science magazine, was so significant that it was treated as a Science Express paper meaning that independent of the field of science, the editors at Science magazine give their full attention to the paper and expedite the publishing process. A paper classified as such is sent out for review within two weeks and subsequently placed on the Internet. Between the time the paper is submitted and the availability to the public is approximately four weeks.

“They really gave this article special attention,” said Dunaway-Mariano. “That shows right there that this has big impact. It was an important finding. It’s out there in terms of recognition. One of the reasons why it was very important is because it is in the area of basic research. Often breakthroughs in basic research have long reaching effects in the applied sciences. For instance, the structure of the phosphorane intermediate will no doubt become the center of focus in drug design targeting phosphoryl transfer enzymes. Pharmaceutical companies develop new drugs based on structural mimicry, and phosphoryl transfer enzymes are the hottest of the hot new drug targets.”

“Pure luck” was how Dunaway-Mariano explained the remarkable finding.

“We were in the process of studying a biological phosphoryl reaction as it occurred in the presence of its natural protein catalyst,” said Dunaway-Mariano. “Protein catalysts, or enzymes, function in our bodies to speed up reactions. The enzyme closed (like a clam) over its chemical reactant, forcing it to a state of transition. We crystallized the molecular complex in this state, determined its structure and were surprised to find the pentacovalent phosphorane intermediate, which had eluded chemists for five decades.”

Dunaway-Mariano said reactions that occur in biological systems always require enzymes to serve as catalyst. There are no chemical reactions in the human body that occur spontaneously. The presence or absence of the enzyme determines whether the reaction is turned on or off. Basically, the human body is the organization of chemical reactions. These reactions must be very carefully controlled and timed. Medicines digested act on the enzymes that control the chemical reactions in our bodies or in our pathogens.

“Enzymes provide chemical reactants a deep crevice in which they can bind,” Dunaway-Mariano said. “The enzyme closes the entrance and squeezes down on the reactant. The enzyme relaxes once the product is formed so that it can swim away. Where we got lucky was that our enzyme formed crystals only from the closed state. The molecules were so tightly packed in the crystal that the enzyme could not open. In this closed state the phosphorane intermediate, a chemical species which is half-way between reactant and product, was frozen in time. In solution this phosphorane would be gone in less than a second. In the crystal it lasts indefinitely.”

Other scientists in the research include Karen Allen, associate professor, and Sushmita Lahiri, graduate student, both of Boston University.

The key in the research was that to take a picture, something had to stand still in time.

“The luck part in this process was the fact that the species we were looking for was trapped inside a crystal,” Dunaway-Mariano said. “This made it stable in time. As long as it was trapped inside this crystal, you could take pictures of it. Most reactions occur in a solution or some type of a solvent. We were able to get this trapped in a crystal and that’s what enabled it too live long enough so we could
take a picture of it and get an X-ray diffraction pattern to see it.”

The discovery of the pentacovalent phosphorane species addresses a question that chemists have been fighting over for more than 50 years, says Dunaway-Mariano.

“Finally there is a definitive result,” Dunaway-Mariano said. “We know now that phosphoryl transfer reactions take place through a pentacovalent phosphorane intermediate. It was extremely pleasing for scientists to actually see this intermediate following decades of arguing back and forth as to its existence while trying every experiment that they could think of to prove their position.

“It’s a chemistry concept that had been the subject of debate for at least half a century. And then, all of a sudden there’s a definitive picture (an actual photograph) of the species people have been arguing about. It’s something everybody wanted to see, but never got the chance to see it.”

Dunaway-Mariano came to UNM after 18 years of university service in the Washington D.C. area. She says the pleasant environment at UNM fosters the kind of open mind needed to perform research of this nature.

“It’s very pleasant here, my students and colleagues are wonderful and these are the essential ingredients of good science,” she said.

Dunaway-Mariano says people should expect to see more great research coming out of the chemistry department at UNM and the enzyme catalyzed reaction trapping is an example.

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