Dr Blaise Kimbadi Lombe - Max Planck Institute for Chemical Ecology, Jena, Germany

Dr Blaise Kimbadi Lombe

Title: Biosynthesis of Cinchona Alkaloids

Abstract:The Cinchona alkaloids, which have been studied for more than 250 years, are plant-derived natural products that have had, collectively, an extraordinary impact in medicine and in basic science. Examples of Cinchona alkaloids include quinine, a historically important anti-malarial drug and bittering ingredient of tonic water, and cinchonidine, a chiral catalyst widely used in process chemistry. Surprisingly, it is still largely unknown how plants synthesize these famous compounds. This talk will report on the elucidation of the biosynthetic pathway of Cinchona alkaloids, along with the identification of responsible enzymes. A combination of isotopic labelling, gene silencing, single nuclei RNA sequencing, and comparative transcriptomics revealed the involvement of several unexpected biosynthetic transformations, including a previously unreported quaternary amine forming enzymatic cyclization. Moreover, we demonstrate the enzymes can be used to produce both natural and non-natural halogenated Cinchona alkaloids in Nicotiana benthamiana. Our work unlocks the long-standing mystery of how the distinctive scaffold of Cinchona alkaloids is biosynthesized, and highlights the prospects for access to these compounds and non-natural analogs through metabolic engineering approaches.