Boost Fund: Towards Alkaloids: Monooxygenases from Plants in Reaction Cascades

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Natural products from plants have been utilized by mankind since thousands of years. Those ingredients that are related to health issues have been of special interest. Hence it is not surprising that natural products are still the main direct or indirect source for new pharmacological entities. However, while plants are a renewable natural resource, the secondary metabolites involved, for example in plant defence or signalling processes, are often of limited availability. At the same time, the demand for the scalable production of plant natural product-based pharmaceutical drugs is growing. With increasing structural complexity, a de novo synthesis is rendered impractical: with numerous synthetic steps involved and, consequently, large amounts of waste accumulating, even the most elegant sequences will fail to be applied.

Microbial production is a promising alternative that is based on inexpensive renewable feed stocks. The fast growth rates of microbes allow short production times. Moreover they perform multi-step syntheses in a “one pot” manner thereby reducing the amount of waste produced. The challenge lies in heterologous expression of whole metabolic pathways and their optimization towards natural product analogues. Furthermore, while rather complex synthases are regularly successfully applied, reaction cascades involving synthetically highly versatile monooxygenases remain especially demanding. The mono-oxygenases are largely responsible for imparting structural and functional diversity to plant natural products. These NAD(P)H-dependent enzymes have a relatively low activity, a comparatively low stability, and often a low coupling efficiency between NAD(P)H consumption and product formation, leading to the formation of hydrogen peroxide and other reactive oxygen species which limits their performance in production processes.

In this joint project these challenges will be tackled by deve-loping in the preliminary phase an efficient multi-enzyme cascade for the production of strictosidine from 7-deoxyloganinic acid, a key intermediate for a vast number of monoterpenoid indole alkaloids which are for instance used as powerful antitumor drugs like vinblastine and vincristine. In order to reach the outlined ambitious goals of the strictosidine project, a joint effort of groups with different expertise is essential: Molecular biologists, biochemists, chemists as well as biochemical engineers will work together creating a toolbox available for the current project on one given alkaloid and beyond. All participants are internationally visible experts in their respective field with experience in working in coordinated programs.

The scientific activities of the Bioeconomy Science Center were financially supported by the Ministry of Innovation, Science and Resesarch within the framework of the NRW Strategieprojekt BioSC (No. 313/323‐400‐002 13).