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Newly discovered enzymes found in the cinchona tree play a crucial role in the production of the malaria drug quinine and other important alkaloids. This opens up possibilities for the biotechnological production of these active ingredients.
For centuries, the process by which the cinchona tree produces its valuable alkaloids, including the life-saving quinine used to treat malaria, was shrouded in mystery. Now, a research team from the Max Planck Institute for Chemical Ecology in Jena, together with colleagues from the University of Georgia, has uncovered the secret. In a new study, the scientists demonstrate how the plant sequentially builds up the complex molecular framework characteristic of quinine. The researchers identified the enzymes responsible for catalyzing the chemical reactions that take place inside the plant. The study opens up new avenues for the sustainable and efficient laboratory production of natural substances such as quinine and related active ingredients.
The 350-year history of quinine, from Quechua bark to chemotherapy drug – with an important milestone in Jena
For over 350 years, quinine and other extracts from the cinchona tree (Cinchona spp.) were the only effective medicines against malaria, a tropical fever caused by single-celled parasites of the genus Plasmodium and transmitted by Anopheles mosquitoes. The name 'cinchona tree' actually originates from South America and comes from the Quechua term quina-quina, meaning 'bark of barks'. Powdered quina-quina was probably brought to Europe by Jesuits in the 17th century as an effective fever remedy. It was not until the beginning of the 19th century that quinine was identified as the active ingredient in cinchona bark, which was then isolated through an extraction process involving alcohol. “Quinine was one of the first active ingredients to be isolated from natural resources. It was also the first pure chemotherapeutic agent. It is still used to treat malaria today, for example in tropical Central Africa, where malaria is a common cause of illness and death," says Blaise Kimbadi Lombe, a postdoctoral researcher in the Department of Natural Product Biosynthesis at the Max Planck Institute for Chemical Ecology in Jena, Germany, and one of the lead authors of the study. He himself comes from the Democratic Republic of the Congo, a country located in Central Africa.
Cinchona alkaloids, which include quinine, a bitter substance found in beverages such as tonic water and Bitter Lemon, or quinidine, a remedy for cardiac arrhythmia, have a long history. In addition to their medical significance, Cinchona alkaloids are also used as catalysts in many chemical processes. Jena has played a particularly important role in quinine research, as it was at Friedrich Schiller University in Jena that the chemist Paul Rabe first described quinine's molecular structure in 1908.
The long search for the key to the biosynthesis of Cinchona alkaloids
Alkaloids from the cinchona tree are highly valuable, with an estimated annual economic value of US$2 billion. However, the industrial production process involves extracting and purifying these compounds from Cinchona plants grown on large-scale tropical plantations. The question of how the Cinchona tree produces these active ingredients has therefore been a major focus of research for over 100 years. Solving this mystery has been complicated by several factors. These include the complexity and uniqueness of the Cinchona alkaloid structure, limited knowledge of the intermediate products, which makes it difficult to predict what types of enzymes might be involved in the pathway, and inadequate analytical methods. There have also been challenges arising from cultivating the red cinchona tree in greenhouses and under sterile conditions.
Previous studies in Jena elucidated the first part of the metabolic pathway and identified the intermediate product, corynantheal. Further experiments demonstrated that this intermediate is converted by the plant into the final Cinchona alkaloids. However, the mechanism of this conversion and the enzymes involved remained unknown. "Specifically, we wanted to know: How does the conversion of the corynantheal skeleton occur, and which enzymes catalyze the process? Can these enzymes be used to easily, quickly and controllably produce cinchona alkaloids in a model organism? And can these enzymes be used to produce new cinchona alkaloid analogues that do not occur in nature?” explains Tingan Zhou, a doctoral student in the Department of Natural Product Biosynthesis, describing the aim of the study.
How the Cinchona tree produces its miraculous molecules: A scientific detective story
To understand how cinchona trees produce cinchona alkaloids, the scientists solved a complex puzzle similar to chemical detective work. First, they added specially labeled precursors to the leaves, stems, and roots of the red Cinchona tree (Cinchona pubescens) and tracked how these were converted into subsequent compounds, looking for "traces" of the label in the plant tissue. This allowed them to identify three previously unknown intermediate products as key pieces of the puzzle. Then, they searched for the enzymes that catalyze the conversions of these intermediates. Using gene and protein data from different parts of the plant, as well as comparisons with related plant species, the researchers found two enzymes that produce one of the newly discovered intermediate substances: malonyl-corynantheol. To test whether malonyl-corynantheol is part of the metabolic pathway, the scientists used a method to temporarily switch off the genes that make this compound, confirming that malonyl-corynantheol is a precursor for quinine and other Cinchona alkaloids.
One of the biggest challenges was finding the enzyme responsible for converting malonyl-corynantheol into a newly discovered intermediate product called cinchonium. After many unsuccessful attempts, the research team identified the appropriate gene by combining data on gene activity, proteins, and gene patterns from various plant species and parts. From its sequence, this enzyme appeared to be a transferase. It was a big surprise to the researchers that a transferase enzyme could carry out this unusual cyclisation reaction.
The researchers then showed that the cinchonium intermediate undergoes two more reactions to form the so-called “quinoline-quinuclidine scaffold”. “In a series of transformations catalyzed by two unrelated enzymes, the scaffold expands from an indole ring system to a quinoline ring system. We identified these enzymes as an oxoglutarate-dependent dioxygenase and a cytochrome P450,“ Blaise Kimbadi Lombe summarizes the biosynthetic process.
The research team then managed to use these enzymes to produce the known medicinal compounds as well as derivatives that could potentially be used for medicinal purposes.
From bark to lab: a breakthrough in sustainable drug production
“Our study is further proof that nature is the best chemist. The enzymes we have discovered open up a wide range of possibilities, including the biotechnological production of medically or chemically valuable compounds,” says the study’s leader Sarah O'Connor, director at the Max Planck Institute for Chemical Ecology and head of the Department of Natural Product Biosynthesis.
The scientists predict that the production of essential Cinchona alkaloids, which are currently obtained by extracting them from Cinchona bark, will eventually shift towards synthetic biology methods.
Dr. Blaise Kimbadi Lombe, Department of Natural Product Biosynthesis, Max Planck Institute for Chemical Ecology, Hans-Knöll-Straße 8, 07745 Jena, Germany, Phone +49 3641 57-1214, E-Mail blombe@ice.mpg.de
Tingan Zhou, Department of Natural Product Biosynthesis, Max Planck Institute for Chemical Ecology, Hans-Knöll-Straße 8, 07745 Jena, Germany, Phone +49 3641 57-1214, E-Mail tzhou@ice.mpg.de
Prof. Dr. Sarah O’Connor, Department of Natural Product Biosynthesis, Max Planck Institute for Chemical Ecology, Hans-Knöll-Straße 8, 07745 Jena, Germany, Phone +49 3641 57-1200, E-Mail oconnor@ice.mpg.de
Kimbadi Lombe, B.;* Zhou, T.;* Kang, G.; Wood, J. C.; Hamilton, J. P., Gase, K.; Nakamura, Y.; Alam, R. M.; Dirks, R. P.; Caputi, L.; Buell, C. R.; O’Connor, S. E. (2026). Biosynthesis of Cinchona Alkaloids. Nature, doi: 10.1038/s41586-026-10227-x.
https://www.nature.com/articles/s41586-026-10227-x
https://www.ice.mpg.de/548102/PR_Kimbadi-Lombe_Zhou Press information of the Max Planck Institute for Chemical Ecology
https://www.ice.mpg.de/112195/natural-product-biosynthesis Department of Natural Product Biosynthesis of the Max Planck Institute for Chemical Ecology
Tingan Zhou, Sarah O’Connor and Blaise Kimbadi Lombe
Source: Angela Overmeyer
Copyright: Max Planck Institute for Chemical Ecology
Seedling and bark of a cinchona tree
Source: Angela Overmeyer
Copyright: Max Planck Institute for Chemical Ecology
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Tingan Zhou, Sarah O’Connor and Blaise Kimbadi Lombe
Source: Angela Overmeyer
Copyright: Max Planck Institute for Chemical Ecology
Seedling and bark of a cinchona tree
Source: Angela Overmeyer
Copyright: Max Planck Institute for Chemical Ecology
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