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Project Description

Tropane alkaloid has a long history in traditional medicine since it can be found and extracted from many types of plants. It is most commonly found in Solanaceae plants, which are distributed all over the world, such as Asia, Europe and North Africa. Before tropane alkaloid was isolated from the plants, it was used to make extracts, ointments and herbs. In ancient Babylonia, physicians used nightshades containing tropane alkaloids as analgesics to relieve toothaches. Single compound tropane alkaloids were not isolated from plants until the 19th century. Producing greater effects, they are now used in a variety of drugs.

Tropane alkaloids including atropine and scopolamine are used in anticholinergic drugs, analgesics, anesthetics, and can be used to treat intestinal disorders and neurological disorders such as Parkinson’s disease. The extensive use of tropane alkaloids has increased the market demand, and they have been classified as essential drugs by the World Health Organization (WHO). However, the demand for tropane alkaloid drugs is higher than the production, which makes them expensive and difficult to access. We conducted an online questionnaire about tropane alkaloids, and more than 400 people responded. Among them, 67% of the respondents have used drugs containing tropane alkaloids, and 12% of the respondents noted that the increase in the price of tropane alkaloids has made it more difficult to purchase. Since tropane alkaloids are derived from plants, large-scale agriculture and complex manufacturing process are required to isolate the compound. Furthermore, unsystematic harvesting and harmful farming techniques have caused significant environmental damage, resulting in soil degradation and water pollution.

To solve the problem of insufficient supply of tropane alkaloids and reduce ecological damage, fēvere factory used genetically engineered yeast to produce putrescine, which can be chemically modified to produce tropane alkaloids. Although yeast already has the pathway to produce putrescine, we genetically engineered two pathways to produce putrescine in order to increase its efficiency and production. We improved the pathway that the yeast already has by increasing the gene expression of SPE1, which is responsible for the production of putrescine. We also inserted the AsADC and SPEB genes from oats into yeast to construct another more efficient pathway to produce putrescine. The plasmid containing three genes was inserted into the yeast, and its effectiveness was tested using LC-MS/MS. The results revealed that the genetically engineered yeast was able to significantly increase the production of putrescine compared with normal yeast.

Our newly designed yeast has great potential in the production of tropane alkaloids and helps meet the growing demand for tropane alkaloid drugs. The improved efficiency and yield of tropane alkaloids help reduce costs and make them more accessible to the public. The genetically engineered yeast may also replace the traditional extraction method of tropane alkaloids which requires large-scale farming. This method is not only cheaper, but also environmentally friendly since it does not require farmland or disruptive farming practices. Yeast can not only be used to produce tropane alkaloids, our project also shows the great potential of genetically engineered yeast to produce essential pharmaceutical compounds and make other high-cost drugs more accessible to the public.

Reference

1. Srinivasan, P., Smolke, C.D. Biosynthesis of medicinal tropane alkaloids in yeast. Nature 585, 614–619 (2020).

2. Srinivasan, P., Smolke, C.D. Engineering a microbial biosynthesis platform for de novo production of tropane alkaloids. Nat Commun 10, 3634 (2019).

3. Yin L I , Cao Z . MICROBIAL METABOLIC ENGINEERING:GATEWAY TO DEVELOP BLUEPRINTS FOR CELL FACTORIES[J]. Journal of Chemical Industry & Engineering, 2004, 55(10):1573-1580.

4. Ping Y , Li X , You W , et al. De Novo Production of the Plant-Derived Tropine and Pseudotropine in Yeast[J]. ACS Synthetic Biology, 2019, 8(6).

5. Tyagi A K , Tabor C W , Tabor H . Ornithine decarboxylase from Saccharomyces cerevisiae. Purification, properties, and regulation of activity[J]. Journal of Biological Chemistry, 1982, 256(23):12156-12163.

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