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“the average length of a drug shortage is 1.5 years”- Senate Committee on Homeland Security and Governmental Affairs
https://www.hsgac.senate.gov/wp-content/uploads/2023-03-20-HSGAC-Majority-Draft-Drug-Shortages-Report.pdf
“approximately 78% of API manufacturers are located outside of the U.S.” – FDA
https://www.fda.gov/about-fda/fda-basics/fact-sheet-fda-glance
“Up to 50 new drug shortages per year for the last decade.” – FDA
“2 billion people worldwide lack access to basic medicines.” – World Health Organization
https://cdn.who.int/media/docs/default-source/essential-medicines/fair-price/chapter-medicines.pdf?sfvrsn=adcffc8f_4&download=true
“40% of Western drugs are derived from plants.” – USDA
https://www.fs.usda.gov/wildflowers/ethnobotany/medicinal/index.shtml
Valentic T, Payne J, Smolke CD. 2020. Structure determination and engineering of a scoulerine 9-O-methyltransferase enables biosynthesis of novel alkaloids in yeast. ACS Catalysis. 10: 4497-509.
Abstract Benzylisoquinoline alkaloids (BIAs) are an important class of plant natural products with diverse pharmacological properties. Microbial platforms can produce BIAs through heterologous biosynthesis more efficiently than native plant hosts and allow for the generation of currently inaccessible BIA biosynthetic intermediates and unnatural derivatives. However, much remains unknown regarding the structures, substrate scopes, and mechanisms of many of the enzymes involved in BIA biosynthesis, which hampers efforts toward engineering these enzymes to produce alternative products or act in non-native biosynthetic contexts. Here, we present multiple crystal structures of two scoulerine 9-O-methyltransferase (S9OMT) variants from Thalictrum flavum which catalyze an essential step in the biosynthesis of berberine. The crystal structures revealed the structural basis for substrate and cofactor recognition by TfS9OMT and provide further insight into the structure and function of S9OMTs. A structural comparison of the TfS9OMT and T. flavum norcoclaurine 6OMT (Tf6OMT) crystal structures identified important residues for enzyme regiospecificity, which were confirmed via mutagenesis and in vitro assays. Several TfS9OMT mutants with expanded substrate scopes toward various 1-benzylisoquinoline substrates were generated. The rationally engineered TfS9OMT mutants with altered regiospecificity were tested in a yeast-based scoulerine production platform and enabled de novo production of tetrahydropalmatrubine and tetrahydropalmatine.
Srinivasan P, Smolke CD. 2020. Biosynthesis of medicinal tropane alkaloids in yeast. Nature: 585: 614-9.
Abstract Tropane alkaloids from nightshade plants are neurotransmitter inhibitors that are used for treating neuromuscular disorders and are classified as essential medicines by the World Health Organization1,2. Challenges in global supplies have resulted in frequent shortages of these drugs3,4. Further vulnerabilities in supply chains have been revealed by events such as the Australian wildfires5 and the COVID-19 pandemic6. Rapidly deployable production strategies that are robust to environmental and socioeconomic upheaval7,8 are needed. Here we engineered baker’s yeast to produce the medicinal alkaloids hyoscyamine and scopolamine, starting from simple sugars and amino acids. We combined functional genomics to identify a missing pathway enzyme, protein engineering to enable the functional expression of an acyltransferase via trafficking to the vacuole, heterologous transporters to facilitate intracellular routing, and strain optimization to improve titres. Our integrated system positions more than twenty proteins adapted from yeast, bacteria, plants and animals across six sub-cellular locations to recapitulate the spatial organization of tropane alkaloid biosynthesis in plants. Microbial biosynthesis platforms can facilitate the discovery of tropane alkaloid derivatives as new therapeutic agents for neurological disease and, once scaled, enable robust and agile supply of these essential medicines.