How is cocaine produced in plants?
Cocaine is one of the most commonly used (and abused) plant-derived drugs in the world, but we have little modern information about how plants produce this complex alkaloid. Researchers from the Max Planck Institute for Chemical Ecology in Jena, Germany, have just discovered the key reactions of cocaine formation in coca plants in South America and identified responsible enzymes. This enzyme has been shown to belong to the family of aldo-keto-reductase proteins, revealing some exciting new insights into the evolution of cocaine biosynthesis.
Alkaloids constitute a very large group of natural nitrogenous compounds that have different effects on the human body. A large number of plant-produced alkaloids have strong pharmacological effects and can be used as toxins, stimulants, drugs or recreational drugs, including caffeine, nicotine, morphine, quinine, strychnine, atropine and cocaine. Atropine and the addictive drug cocaine used to dilate the pupil of the eye are both tropane alkaloids, which have two distinct, interconnected five- and seven-membered rings.
It is known that species in the seven plant family produce tropane alkaloids, including cruciferae (Brassica oleracea), Solanaceae (Solanaceae or Potatoaceae), and Astragalaceae (Cucco). These examples are not closely related to each other. For example, suppose the last common ancestor of the family A. sylvestris and Solanaceae lived about 120 million years ago. But how similar are the biosynthetic pathways of tropane alkaloids in these families? Is there an original tropane alkaloid pathway lost in evolution in most other plant families? Alternatively, the paraffin alkaloid biosynthesis occurs independently on several different occasions.
Although the formation of cocaine has not been studied in the past 40 years, the biosynthesis of the related alkane alkaloid from the belladonna (Solanaceae) has matured. In the penultimate step, the ketone function is reduced to an alcohol residue. This key response is catalyzed by an enzyme of the short chain dehydrogenase/reductase (SDR) protein family in belladonna. Among the enzymes in this group, there are many dehydrogenases that degrade alcohol.
To find the corresponding enzymes in cocaine biosynthesis, the team's PhD student Jan Jirschitzka searched for the SDR-like protein in the genome of coca plants. However, all of the SDR genes he cloned and expressed did not have any activity on the key response to cocaine formation. Therefore, he used a more classical approach - identifying cocaine synthetase activity in coca leaf extracts, purifying responsible proteins, isolating peptides, and - after partial sequencing - cloning the corresponding genes.
This enzyme was named methyl ketone degrading enzyme (MecgoR). AKR enzymes are known in plants as well as mammals, amphibians, yeast, protozoa and bacteria. For example, they are involved in the formation of steroid hormones. The second result is that the MecgoR gene and protein are highly active in the young leaves of coca plants, but not in the roots. On the other hand, atropine is synthesized only at the roots of belladonna, from where it is transported to the green organs of plants. Based on these results, Max Planck researchers concluded that the tropane alkaloid pathway in coca and belladonna evolved completely independently.
The elucidation of the MecgoR catalytic step in cocaine biosynthesis represents a major success, but researchers are now continuing to study other important steps in the cocaine pathway. It is also of interest to understand how cocaine is stored in leaf tissue in such a high amount. This alkaloid can account for 10% of the dry weight of immature coca leaf, which is an amazing amount of any particular alkaloid accumulation.
