Isoprenoid metabolism in compositae

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Isoprenoid metabolism provides mechanisms to channel a ubiquitous precursor, isopentenyl pyrophosphate, into the synthesis of a diverse array of natural products. Although all organisms can produce isoprenoids as part of their primary metabolism, plants synthesize a secondary layer of isoprenoids to augment their adaptation fitness. More than 50,000 isoprenoids have been identified, and clear evidence exists that some isoprenoids are of central importance in plant physiology, development, and interactions with other organisms. Plant isoprenoids have been used by humans as pharmaceuticals, nutraceuticals, and industrial products, but the chemical synthesis of these commodities is often difficult due to their structural complexities. To control the isoprenoid metabolism in plants or in other heterologous systems, it is necessary to advance the basic knowledge of isoprenoid biosynthesis. I propose here to study the biochemistry, transport, and carbon-flow of sesquiterpene lactones (SLs) in the plant family Compositae, to which lettuce, sunflower and medicinal plant sweet wormwood (Artemisia annua) belong. Specific emphasis will be given to the biosynthesis of the anti-malarial drug, artemisinin (an SL endoperoxide derivative), in A. annua. The genes responsible for the SL C11,13-double-bond reduction and lactone ring synthesis will be identified and characterized, and the structure-function relationship in the sesquiterpene oxygenase will be analyzed using chimeric cytochrome P450 enzymes. The potential involvement of ATP-Binding Cassette-transporters in sesquiterpenoid transport will be critically evaluated in an engineered yeast system and plants. I will also investigate carbon-flow in the biosynthesis of SLs using sunflower trichomes as a model system. In the trichomes, the coordination of two distinct cell types (photosynthetic and non-photosynthetic) will be studied by labeled precursor-feeding assays, in situ immunolocalization of key enzymes, in situ RNA hybridization, and single-cell-type genomics. The proposed multi-facet analysis will elucidate how the SLs are synthesized and transported in the trichomes of the Compositae and will provide a rationale for SL flux engineering.