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A tobacco plant was engineered to produce cocaine in its leaves: ScienceAlert

A tobacco plant was engineered to produce cocaine in its leaves: ScienceAlert

Used by humans as a stimulant and anesthetic for thousands of years, the drug commonly known as cocaine was carefully crafted by species of the coca plant (Erythroxyl) more tens of millions of years in an arms race against hungry insects.

Knowing exactly how plants pull off this feat of chemical engineering would be a big win for the pharmaceutical industry while helping biologists better understand the evolution of similar pesticides across the plant kingdom.

Yet the sheer complexity of producing this chemical is one of nature’s best-kept secrets, one that scientists have spent the better part of a century unraveling.

Today, researchers at the Kunming Institute of Botany in China have finally uncovered the final major steps in the biosynthetic process.

Not only did they more or less map out the biochemical pathway of cocaine production, but the researchers also reconstructed the entire chain inside a humble tobacco plant for good measure.

The process of forcing tobacco to produce cocaine is unlikely to ever improve current production methods, or provide serious progress on new ways to produce stimulants.

But a similar method involving bacteria or yeast could one day revolutionize the way we design and industrialize pharmaceuticals.

Cocaine is one of a class of organic molecules called tropane alkaloids. A whole family of plants have developed methods of making these chemicals to thwart herbivores, and in turn, we humans have taken advantage of the side effects they have on our own biology.

Hyoscyamine, for example, is a tropane alkaloid. Crafted by Deadly Nightshade (Atropa belladonna), we’ve used hyoscyamine medicinally to dilate our pupils, paralyze our sputum glands during surgery, and treat our beating hearts for over a century.

The history of cocaine use could be longerfrom chewing coca leaves for an energy boost since ancient times to its use as a topical anesthetic in modern surgery to its psychoactive effects as an illicit recreational drug.

Chemically speaking, cocaine has a lot in common with hyoscyamine, with a recent discovery that both emerge from the same precursor – a molecule called 4-(1-methyl-2-pyrrolidinyl)-3-oxobutanoic acid (or MPOA in abbreviated).

The structural difference between the two molecules is subtle but essential, but how Erythroxyl attenuates the crucial transformation of MPOA into cocaine has so far remained a mystery.

Fortunately, the low contrast in molecular structures was enough for researchers to limit their search to a particular group of proteins, leading to the discovery of a pair of enzymes called EnCYP81AN15 and EnMT4.

The molecular origami each is responsible for not only fulfills crucial steps on how cocaine comes from a convoluted chemical production chain, but strengthens the relationship between two pharmacologically significant plant compounds.

There are still a few small holes in the map, although the researchers are confident that well-known enzymes from biochemistry could easily do the job.

To demonstrate this, they plugged six cocaine-producing genes into the tobacco plant, Nicotiana benthamianaletting the genetic hybrid fill in the gaps using its own versions of the suspected enzymes.

Sure enough, the modified tobacco plants did generate cocaine, which pretty much proves the team had a working knowledge of how cocaine is made.

Putting aside questions about how this might impact its illicit manufacture – if at all – the knowledge could have profound implications for the pharmaceutical industry, allowing researchers to modify the formula and potentially discover new bioactive compounds with much more efficiency.

Cocaine derivatives, such as cocaine hydrochloride, have been approved for use by the FDA as local anesthetics as recently like 2020demonstrating that this centuries-old stimulant is far from being a vestige of history.

This research was published in Journal of the American Chemical Society.

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