Mini drug-producing biofactories built in yeast

Washington, August 17 : California Institute of Technology scientists in the U.S. say that mini biofactories in yeast may be useful for churning out large quantities of drugs, including antiplaque toothpaste additives, antibiotics, nicotine, and even morphine.

Christina D. Smolke, an assistant professor of Chemical Engineering, has revealed that she and graduate student Kristy Hawkins have genetically modified common baker's yeast (Saccharomyces cerevisiae) so that it contains the genes for several plant enzymes.

The researchers say that the enzymes enable the yeast to produce a chemical called reticuline, which is a precursor for many different classes of benzylisoquinoline alkaloid (BIA) molecules-a large group of chemically intricate compounds, such as morphine, nicotine, and codeine, which are naturally produced by plants.

BIA molecules exhibit a wide variety of pharmacological activities like antispasmodic effects, pain relief, and hair growth acceleration. Other BIAs have shown anticancer, antioxidant, antimalarial, and anti-HIV potential.

"There are estimated to be thousands of members in the BIA family, and having a source for obtaining large quantities of specific BIA molecules is critical to gaining access to the diverse functional activities provided by these molecules," says Smolke, whose lab focuses on using biology as a technology for the synthesis of new chemicals, materials, and products.

However, the natural plant sources of BIAs accumulate only a small number of the molecules, usually "end products" like morphine and codeine that, while valuable, cannot be turned into other compounds, thus limiting the availability of useful new products.

Smolke and Hawkins added the genes for other enzymes, from both plants and humans, to their reticuline-producing yeast.

This allowed the yeast to efficiently generate large quantities of the precursors for sanguinarine, a toothpaste additive with antiplaque properties; berberine, an antibiotic; and morphine.

The researchers are now trying to engineer the yeast so that they will turn these precursor molecules into the final, pharmacologically useful molecules.

"But even the intermediate molecules that we are producing can exhibit important and valuable activities, and a related area of research will be to examine more closely the pharmacological activities of these metabolites and derivatives now that pure sources can be obtained," says Smolke, who estimates that her system could be used for the large-scale manufacture of BIA compounds in one to three years.

The researchers are also planning to extend their research to the production of BIAs that do not normally exist in nature.

"If one thinks of these molecules as encoding functions that are of interest to us, the ability to produce nonnatural alkaloids will provide access to more diverse functions and activities. By expanding to nonnatural alkaloids, we can search for molecules that provide enhanced activities, new activities, and not be limited by the activities that have been selected for in nature," says Smolke.

"Our work has the potential to result in new therapeutic drugs for a broad range of diseases. This work also provides an exciting example of the increased complexity with which we are engineering biological systems to address global societal challenges," she says.

ANI