Back to the plant: overcoming roadblocks to the microbial production of pharmaceutically important plant natural product
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METABOLIC ENGINEERING AND SYNTHETIC BIOLOGY - REVIEW
Back to the plant: overcoming roadblocks to the microbial production of pharmaceutically important plant natural products Natali Ozber1 · Jacinta L. Watkins1 · Peter J. Facchini1 Received: 29 May 2020 / Accepted: 30 July 2020 © Society for Industrial Microbiology and Biotechnology 2020
Abstract Microbial fermentation platforms offer a cost-effective and sustainable alternative to plant cultivation and chemical synthesis for the production of many plant-derived pharmaceuticals. Plant alkaloids, particularly benzylisoquinoline alkaloids and monoterpene indole alkaloids, and recently cannabinoids have become attractive targets for microbial biosynthesis owing to their medicinal importance. Recent advances in the discovery of pathway components, together with the application of synthetic biology tools, have facilitated the assembly of plant alkaloid and cannabinoid pathways in the microbial hosts Escherichia coli and Saccharomyces cerevisiae. This review highlights key aspects of these pathways in the framework of overcoming bottlenecks in microbial production to further improve end-product titers. We discuss the opportunities that emerge from a better understanding of the pathway components by further study of the plant, and strategies for generation of new and advanced medicinal compounds. Keywords Opiates · Alkaloids · Cannabinoids · Plant secondary metabolism · Synthetic biology
Introduction Plants have been used as medicines since ancient civilizations and, with the aid of modern science, have remained the commercial source of high-value pharmaceutical products in the present-day. Plant-derived pharmaceuticals consist of more than 60% of approved antibiotics and anticancer drugs and are considered essential medications to meet basic health needs [1, 2]. One of the plants which has been cultivated since ancient times is opium poppy (Papaver somniferum) in which medicinal value is attributed to the accumulation of benzylisoquinoline alkaloids (BIAs), including morphine, codeine and thebaine. Morphine and codeine are used as analgesics for the treatment of moderate to severe pain, whereas thebaine is used as a feedstock for production of semi-synthetic analgesics including hydrocodone * Peter J. Facchini [email protected] Natali Ozber [email protected] Jacinta L. Watkins [email protected] 1
Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada
(Vicodin®), hydromorphone (Dilaudid®), oxycodone (OxyContin®), and oxymorphone (Numorphan®). Naloxone (Narcan®) and naltrexone are used for the treatment of opiate overdose and addiction. Catharanthus roseus (also known as Madagascar periwinkle) is another plant valued for the pharmaceutical compounds it produces, the monoterpene indole alkaloids (MIAs). ‘Vinca’ type MIAs produced in C. roseus include the anticancer drugs vinblastine (Velban®) and vincristine (Oncovin®), as well as precursors for the semi-synthesis of vinorelbine (Navelbine®) and vindesine (El
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