Collaborative research: metabolic engineering of terpenoid indole alkaloids using transcriptional regulators in C. roseus hairy roots

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1066879/1064903 Shanks/GibsonPlants produce large numbers of chemicals that are useful as drugs for treating a variety of medical conditions. Unfortunately, these chemicals are often produced by plants in only trace amounts. As a result, large quantities of plant material must often be used to produce small amounts of drugs, making these drugs very expensive. An example of this problem is provided by a class of compounds produced by Catharanthus roseus (periwinkle), known as terpenoid indole alkaloids. Terpenoid indole alkaloids include chemicals such as vincristine and vinblastine, which are used to treat certain types of cancer, and ajmalicine, which is used to treat hypertension. As periwinkle produces these chemicals in only trace amounts, they can cost over one million dollars per pound. To reduce the costs of these drugs, it is critical to develop varieties of periwinkle that produce these drugs in higher amounts. Towards that end, the effects of increasing expression of the biosynthetic genes that are responsible for production of these drugs will be investigated. A two-fold strategy for increasing expression of these biosynthetic genes will be pursued. Part one of this strategy is to test the effects of reducing expression of repressor genes that decrease expression of the biosynthetic genes. Part two of this strategy is to decrease expression of the repressor genes while simultaneously increasing expression of activator genes that increase expression of the biosynthetic genes. The hypothesis being tested is that, by decreasing expression of repressors and increasing expression of activators, it should be possible to achieve a significant increase in expression of the biosynthetic genes. This increase in expression of the biosynthetic genes should then lead to increased production of terpenoid indole alkaloids, allowing those terpenoid indole alkaloids that are useful as drugs to be produced at a lower cost. Previously uncharacterized chemicals that accumulate in response to alterations in expression of the biosynthetic genes will also be analyzed. Characterization of these chemicals will both provide valuable information regarding the biochemical pathways by which terpenoid indole alkaloids are produced, as well as potentially providing information regarding additional chemicals that may be tested for use as drugs.