Plant-derived secondary metabolites have proven to be a rich source of pharmaceuticals. From 1981 to 2010, over 65% of the 1355 new chemical entities introduced worldwide were natural products or natural product derivatives. The benzylisoquinoline alkaloids (BIAs) represent a diverse class of secondary metabolites (2500 known structures) with a broad range of pharmacological activities. Efforts to develop new chemical entities sourced or derived from plant secondary metabolites have largely faltered, because (a) the complexity and stereochemistry of natural products is difficult to access via synthetic chemistry and (b) the yiel of natural products extracted directly from plants can be insufficient to capture the full range of natural products present in a particular species. The goal of our Phase I work is to do a proof-of-concept demonstration that we can (a) make a microbial chassis for the production of the BIA key intermediate (S)-reticuline based on the naturally occurring pathway found in some plants and (b) show that the chassis can be used to make a small set of BIAs derived from reticuline. Future effort will be based on this BIA chassis strain and will focus on the development of specialized strains targeting a particular molecule or natural product scaffold.
Public Health Relevance Statement: Public Health Relevance: Plants have proven to be a rich source of pharmaceuticals with natural products or natural product derivatives representing over 65% of pharma compounds developed in the past 30 years. Often these natural products are found in quantities too small for meaningful study. In order to expand the library of prospective compounds, we are developing microbial strains that produce a broad range of plant alkaloid natural products (over 2500 members) that are relevant for treating infections, inflammation, chronic pain, Parkinson's disease, and likely have other yet unknown uses.
Project Terms: Alkaloids; Anabolism; Analgesics; anti-cancer therapeutic; antimicrobial; base; Benzylisoquinolines; Biological Factors; Cell Culture Techniques; Cells; Chemicals; chronic pain; Codeine; Databases; design and construction; Development; Dopamine; Engineering; Escherichia coli; Family; Future; gene synthesis; genetic manipulation; Ginkgo biloba; Goals; HIV; hypertension treatment; Individual; Infection; Inflammation; innovation; Libraries; member; Methods; microbial; microorganism; Mixed Function Oxygenases; Morphine; Organism; p-hydroxyphenylpyruvate; Parkinson Disease; Pathway interactions; Pharmacologic Substance; Phase; Plant alkaloid; Plants; Private Sector; Production; prospective; public health relevance; Public Sector; reticuline; scaffold; Source; stereochemistry; Structure; Synthesis Chemistry; synthetic biology; Tetrahydropapaveroline; Therapeutic; Work; Yeasts
