Early Steps in Alkaloid Biosynthesis

Lead Research Organisation: John Innes Centre
Department Name: Contracts Office


Understanding the enzymes that catalyze natural product biosynthesis may enable production inmore tractable host organisms, and may also allow reprogramming of biosynthetic pathways to produce "unnatural" natural products with potentially improved pharmacological activities. Many biosynthetic pathways of natural products found in higher plants remain largely uncharacterized. Our laboratory seeks to understand, and ultimately harness, the metabolic pathways that direct the biosynthesis of plant-derived terpene indole alkaloids. This family of natural products, which comprises approximately 3000 members, is a particularly diverse group of molecules with a range of chemical structures and medicinal uses. We propose to study the mechanism of the few enzymes that have been cloned, isolate and clone as yet uncharacterized enzymes, and determine whether these enzymes can accept alternate substrates that would yield novel alkaloid structures. Short term efforts are currently focus on the mechanism of the first two enzymes of the pathway (strictosidine synthase and strictosidine glucosidase) and determine whether these enzymes can utilize alternate substrates that result in modified alkaloid structures. Understanding the mechanism of these enzymes may also provide clues as to how to modulate substrate specificity. Longer term efforts will focus on identifying a downstream enzyme that immediately follows strictosidine glucosidase in the pathway, and that plays a role in controlling the divergence from the corynanthe type alkaloids to the more complex Iboga and Aspidosperma alkaloids. Harnessing this complex metabolic pathway may enable the economical production of valuable medicinal compounds and allow nature's biosynthetic machinery to be hijacked for the production of unnatural alkaloids of our own design.


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