Bio-Engineered Yeast Cranks Out Pharmaceuticals

Chemical engineers at the California Institute of Technology have used various plant genes to genetically modify common baker’s yeast to produce large quantities of drugs, including antibiotics, nicotine, and even morphine.

Writing about their work in Nature Chemical Biology, Caltech’s Christina D. Smolke and Kristy Hawkins explained how they genetically modified baker’s yeast (Saccharomyces cerevisiae) so that it contained the genes for several plant enzymes. The enzymes allow the yeast to produce a chemical called reticuline, which is a precursor for many different classes of benzylisoquinoline alkaloid (BIA) molecules. BIA molecules are 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, including antispasmodic effects, pain relief, and hair growth acceleration. Other BIAs have shown anti-cancer, 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. 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, can’t be turned into other compounds, thus limiting the availability of useful new products.

To their reticuline-producing yeast, Smolke and Hawkins added the genes for other enzymes, from both plants and humans, which allowed the yeast to efficiently generate large quantities of the precursors for sanguinarine, a toothpaste additive with anti-plaque properties; berberine, an antibiotic; and morphine.

The researchers are now in the process of engineering their 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 also plan to extend their research to the production of BIAs that don’texist in nature. “If one thinks of these molecules as encoding functions that are of interest to us, the ability to produce non-natural alkaloids will provide access to more diverse functions and activities. By expanding to non-natural 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. Our work has the potential to result in new therapeutic drugs for a broad range of diseases,” said Smolke.

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Source: California Institute of Technology

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