Unlocking the Chemical Diversity of Plant Natural Product Pathways: Dehydrogenases in Alkaloid Biosynthesis

点击翻译按钮获取中文摘要

Plants, microbes and insects produce complex small molecules, called "natural products". Given the energy that the organism must expend to produce these molecules, natural products clearly must confer some evolutionary advantage on the producing organism. Therefore, most natural products have some type of biological activity. For our purposes, this means that these metabolites are a rich resource for a wide range of applications, including the development of pharmaceuticals, insecticides, herbicides, biomaterials and bioenergy sources. We are especially interested in a class of natural products known as the alkaloids, which are produced by a wide range of plants and insects. One group of alkaloids, called the "monoterpene indole alkaloids" contains a large assortment of alkaloid compounds, where each is produced from the same starting material. The well-known compounds strychnine (a poison), quinine (an anti-malarial), camptothecin (anticancer) and vinblastine (anticancer) are monoterpene indole alkaloids. However, to effectively utilise the compounds that Nature provides, we must develop robust methods for large-scale production of them. Additionally, it would be valuable to have methods to modify the structures of these compounds so we can test additional derivatives for improved biological activity. This means we need to understand the biochemical processes- the biosynthesis- that the plant uses to construct these molecules. With this knowledge, we can reprogram or genetically engineer plants or microbial organisms such as baker's yeast to overproduce these valuable compounds. Moreover, if we identify and understand the biocatalysts that the plant uses to synthesise these molecules, we can potentially recombine plant biosynthetic pathways in new ways to make novel molecules with potentially improved biological activities. In this proposal, we describe how we will discover how nature synthesises some of the monoterpene indole alkaloids. We will identify the genes that are responsible for biosynthesis in several important alkaloids. In preliminary work, we have already identified two of these genes. We will then place these genes into a strain of baker's yeast that we have developed. This strain will then be able to produce the alkaloids from scratch.