Towards plant synthetic biology: elucidating the novel enzymology of iridoid biosynthesis

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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 particularly interested in a class of natural products known as the iridoids, which are produced by a wide range of plants and insects. Many of these molecules have insecticidal activity, which can be used to protect plants from predation. Others have medicinal activity, acting as anti-cancer or anti-malarial agents. For example, the well-known compounds strychnine (a poison) and quinine (an anti-malarial) are derived from iridoids. Iridoids may also play a role in promoting human health. For example, the iridoids present in the Noni fruit are believed to contribute to the health-promoting properties of this food. However, to effectively utilise the compounds that Nature provides, we must develop robust methods for large-scale production of them. 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 bio-catalysts 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 the iridoids. We will identify the genes that are responsible for three important steps in iridoid biosynthesis. We will then place those three genes into baker's yeast, generating a strain of yeast that produces a simple iridoid compound. In longer term studies, we can add additional iridoid biosynthesis genes to this yeast strain to generate more complicated iridoid compounds that have industrial applications.