The cinchona tree contains various medicinally active substances, including the antimalarial drug quinine. Now researchers have discovered how the plant produces these ingredients. The results open up the possibility of producing quinine and co efficiently in the laboratory in the future instead of relying on the cultivation of cinchona trees. In addition, it might be possible to produce new types of medicines that are based on the structure of natural products and modify them.
The plant substance quinine has been used against malaria for centuries. Although synthetic drugs are now available, the natural product continues to play an important role as it leads to less resistance. Quinine is obtained from the bark of the cinchona tree (Cinchona spp.), which is native to South America. So far, the trees have been cultivated on tropical plantations specifically for this purpose, their bark is harvested and the active ingredients are isolated in a complex industrial process. Although biotechnological production would be more efficient and sustainable, it has not yet been possible. The reason: “Despite the importance of cinchona alkaloids, it was largely unknown how plants produce these structurally complex molecules,” reports a team led by Blaise Kimbadi Lombe from the Max Planck Institute for Chemical Ecology in Jena.
Max Planck Institute for Chemical Ecology/Angela Overmeyer
Synthesis route traced
Now Lombe and his colleagues have revealed the secret of the cinchona tree. To do this, they traced step by step how the plant synthesizes its ingredients using various intermediate products. The first intermediate product was already known, an alkaloid called Corynantheal. “Specifically, we wanted to know: How does the conversion of the Corynantheal framework occur and which enzymes catalyze this process? Can these enzymes be used to produce cinchona alkaloids in a model organism in a simple, rapid and controlled manner? And can these enzymes be used to produce new cinchona alkaloid analogues that do not occur in nature?” explains Lombe’s colleague Tingan Zhou.
In search of answers, the researchers labeled the precursors of quinine with isotopes so that they could trace their path and transformations. In this way, they identified three additional, previously unknown intermediate products on the way to the finished active ingredients. Using genetic analysis, they also found the enzymes that are responsible for converting these intermediate products.
Basis for biotechnological production
“The discovery of the genes required for the individual steps enables the biosynthetic conversion of known starting materials into quinine and other important components of the cinchona tree,” report the researchers. If they transferred the genes into a modified tobacco plant as a model organism, it produced the desired substances. “Our study is further evidence that nature is the best chemist,” says Lombe’s colleague Sarah O’Connor. “The enzymes discovered open up a wide range of perspectives, including the biotechnological production of medically or chemically valuable compounds.”
In addition to quinine, other medically or economically important active ingredients from the cinchona tree can also be produced in this way, including quinidine, an agent against cardiac arrhythmias, and cinchonidine, which is used as a catalyst in many chemical processes. Other variations that do not occur in nature with a similar molecular structure that could also serve as medicines would also be conceivable. “Our findings not only solve a long-standing biochemical puzzle, but also form the basis for the sustainable production of cinchona alkaloids,” summarizes the team.
Source: Blaise Kimbadi Lombe (Max Planck Institute for Chemical Ecology, Jena) et al., Nature, doi: 10.1038/s41586-026-10227-x