Benzylisoquinoline alkaloid biosynthesis

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A large and diverse array of natural products, also known as specialized metabolites, are responsible for the many colours, flavors, fragrances, and aromas found in plants. These compounds also serve as natural attractors of pollinating insects, effective pest deterrents, and provide plants with important lines of antimicrobial defense. The potent biological activity of plant specialized metabolites has led to the medicinal use of many compounds, among the longest standing and arguably the most important being the painkilling properties of morphine and codeine obtained from the opium poppy. Remarkably, the farming of opium poppy plants has remained the world's only commercial source of opiate painkillers for many thousands of years. Morphine was first isolated more than 200 years ago and a slow, methodical scientific process eventually led to an understanding of the >15 chemical steps that convert the simple amino acid tyrosine to the complex molecular morphine in the plant. Recent advances in several powerful biotechnologies have dramatically accelerated the rate of scientific discovery in biology, including the isolation of all predicted genes responsible for the formation of morphine in opium poppy. Over the past 20 years, my laboratory has contributed many of the key genetic, biochemical and cellular discoveries involving the biosynthesis not only of morphine, but also several other related alkaloids produced by opium poppy with different pharmacological properties, such as the cough suppressant and anticancer drug noscapine, the muscle relaxant papaverine, and the antimicrobial sanguinarine. The availability of genetic resources and biochemical knowledge has allowed scientists and engineers to begin the process of transferring the complex cellular machinery from the opium poppy plant to other organisms, including simple baker's yeast. The production of opiate pharmaceuticals by fermentation in yeast as opposed to the farming of plants has several advantages. Yeast grows faster and fermentation systems can be quickly scaled up if demand increases. Plants are vulnerable to environmental uncertainties, such as climate, pathogens and pests. Yeast is also easier to genetically manipulate, which could lead to the generation of new drugs. The global supply of legal opiates, including the availability of the dugs in Canada, also affected by political, social and economic factors. The proposed research aims to capitalize on several recent breakthrough discoveries made in my laboratory to advance our knowledge of morphine and noscapine biosynthesis. Missing parts and unresolved biological processes represent significant obstacles to the realization of important new technologies required to ensure a safe and stable supply of indispensable painkillers and other important drugs. The overarching objective is to fill key gaps in our knowledge of morphine and noscapine metabolism.**