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New Class of Proteins Discovered at WSU

PULLMAN, Wash. — This week’s “Science” magazine features a major article by Washington State University Professor of Biochemistry Norman G. Lewis and co-workers on their discovery of the first member of an apparent new class of proteins.

These proteins help explain how nature controls free- radical chemistry, something scientists in laboratories have had difficulty doing.

The findings have potentially broad applications, extending even to human medicine.

Nature’s control of free-radical chemistry is a mystery because scientists have had enormous difficulty in controlling these reactions.

“Always various mixtures have formed instead,” says WSU’s Lewis. “Free-radical reactions are often blamed for the onset of various medical disorders, such as cancers, as well as for the unwanted degradation of synthetic materials.

“On the other hand, nature uses this bio-chemistry extensively and exquisitely to link almost 40 percent of its organic constituent in the biosphere,” Lewis said.

The WSU group discovered a protein that they believe helps guide free-radical coupling reactions to give only a specific product, in their case pinoresinol.

Pinoresinol is a lignan that is an important precursor of several cancer-preventing and cancer-treating lignans.

“The importance of this discovery goes far beyond making this lignan,” Lewis says. Many other substances in nature are made by free-radical reactions. These include wood, cork, the skin pigment melanin, the outer skeleton of insects, and fungal fruiting bodies such as mushrooms.

Each of these substances may have its own guiding protein to insure it is made in an orderly fashion.

“Our problem was knowing what to look for,” says Laurence Davin. Davin is program director for Lewis’s lab and co-author of the paper published in “Science”. Co-workers Huai-Bin Wang, Anastasia Crowell, Diana Bedgar, Diane Martin and Simo Sarkanen also were co-authors on the article.

Now that the first protein has been found, the search for others should be easier.

This class of proteins, which they term “dirigent proteins” from the Latin “dirigere” (to align or guide), should prove valuable in the laboratory.

“Until now, the kind of reaction we’re looking at for pinoresinol, getting a specific product rather than a mixture, is something that the chemist hasn’t been able to do in the lab,” says Davin. It gives scientists a way to make lignans the same way the plant does.

Davin helps coordinate the project that resulted in the discovery of dirigent proteins, using forsythia to study how plants make lignans. In plants, some lignans are part of a plant’s defenses against a variety of organisms. Other lignans are used to fight cancers and viruses in humans, or to provide protection against the onset of cancers and other diseases.

Pinoresinol is made in a three-step process. First two molecules of an alcohol are modified by an enzyme, then they are aligned by the dirigent protein and linked. Without the dirigent protein, the product will at best be a combination of pinoresinol, each a mirror image of the other and each functionally distinct.

Forsythia makes only the one pinoresinol form it needs. But laboratory test tube assemblies before the discovery of the dirigent protein resulted in a mixture not only of the two forms of pinoresinol, but also including three other mirror image pairs. The desired pinoresinol was only one of the eight products in the tube, and had to be separated and purified from the mixture.

“We knew that the forsythia had something that no laboratory had,” says Davin. But even though they knew the something was there, it proved difficult to find.

Now that they have identified the first dirigent protein, Lewis and his colleagues are looking for others in plants. They expect to find them in many different plant species, and they expect to find different dirigents in any one species, such as forsythia. That’s because forsythia makes a variety of lignans precisely, not just pinoresinol, and the protein that helps make pinoresinol does not help make any other lignan they’ve yet examined.

“Science” is the official publication of the American Association for the Advancement of Science. The four-page article reporting the lab’s discovery is entitled “Stereoselective Bimolecular Phenoxy Radicl Coupling by an Auxiliary (Dirigent) Protein Without an Active Center.”

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