Researchers produce cocaine from genetically modified tobacco

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Cocaine, a typical alkaloid extracted from the leaves of coca (Erythroxylum novogranatense), is increasingly being used in therapy as a local mucosal anesthetic. However, the biochemical pathway causing the synthesis of the molecule by the plant was still partly unknown, leading to the massive use of coca leaves. In a new study, researchers may have revolutionized the therapeutic use of cocaine by discovering the specific enzymes that cause its synthesis. They managed to obtain this substance by genetically modifying tobacco plants under controlled conditions and in controlled quantities.

For centuries, coca leaves have been traditionally used by indigenous South Americans for their stimulant properties, as well as their analgesic and anesthetic effects. However, the severe addiction and illegal trade associated with the substance has made it more widely known to the general public due to its adverse health effects.

However, researchers have recently discovered that cocaine can be used for various operations on the mucous membranes, in particular in ophthalmology. When directly instilled into the eye, this substance would have unprecedented potency (much greater than that of a traditional local anesthetic) in making the patient’s eye instantly insensitive to pain, thus avoiding the need for general anesthesia. It will also be a powerful analgesic that can be used to relieve traumatic pain.

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In order to study the use of cocaine in medicine, researchers have largely determined its biosynthetic pathway. But the final piece of the puzzle, the chemical precursor that completes the chemical process from 4-(1-methyl-2-pyrrolidinyl)-3-oxobutanoic acid or MPOA to the tropane alkaloid (cocaine), has not yet been identified.

Researchers at the Botanical Institute in Kunming, China, found the missing pieces, including two enzymes known as EnCYP81AN15 and EnMT4. By adding them to the biochemical process, the researchers were able to synthesize cocaine from genetically modified tobacco, and also intend to induce a biosynthetic pathway in microorganisms such as Escherichia coli or Saccharomyces cerevisiae.

Respond only to a medical request

By genetically modifying Nicotiana benthamiana, a plant in the tobacco family, Chinese researchers were able to obtain about 400 nanograms of cocaine per milligram of dried leaves. In comparison, coca leaves produce 25 times more. Tobacco cocaine would thus be far from satisfying widespread demand, but the complete biosynthetic pathway could be reproduced by organisms that are widely distributed in nature and grow rapidly, such as the bacterium Escherichia coli or the yeast Saccharomyces cerevisiae.

The new study, detailed in ACS Publications, does indicate that two enzymes selectively mediate the oxidative cyclization of S-MPOA to form an unstable ecgonone intermediate, which is then methylated to form the optically active methylecgonone (or tropane alkaloid). Thus, in their study, the scientists established this biosynthetic pathway in Nicotiana benthamiana.

In addition, the production of cocaine by other plant organisms offers no advantage to the illicit trade, since it is much cheaper to grow coca and extract cocaine from the leaves. Thus, the induction of a biosynthetic pathway from other plants is more suitable for the pharmaceutical sector, since it will allow the development of compounds with similar properties (to cocaine from coca), but with unique characteristics, destined for the medical sector.

Production on other plants will also eventually allow the pharmaceutical industry to move away from the production of coca leaves and control the production of a substance intended for patients. This alternative has the potential to have a significant impact on the cocaine supply chain and possibly allow it to be further regulated.

However, it should be kept in mind that the use of cocaine, even in the medical field, remains limited due to the possible addiction that patients can develop. Therefore, more research will be required before this substance can be freely used in a medical environment and in a controlled manner.

ACS publications.

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