Secrets of Natural Cocaine Production Revealed

Discovery of crucial step could aid pain-drug development, study says.

A closeup of the coca plant relative, Erythroxylum australe.

A mysterious but crucial step that coca plants use to build cocaine has been discovered, according to a group of biochemists.

Despite the drug's infamy, cocaine is chemically similar to a host of anesthetics and stimulants used legally every day. Understanding how cocaine is made in the coca plant might therefore lead to new anesthetic drugs without the addictive qualities, the study authors say.

"Plants can't run away, so they have to be the planet's best chemists to survive," said study co-author John D'Auria, a biochemist at the Max Planck Institute for Chemical Ecology in Germany.

"They make chemicals other organisms simply cannot make, including cocaine."

But to maximize a chemical's benefits to humans, he said, "we need to have some idea how the plants are making it. If you understand the biochemistry, you might take away the bad properties and keep the anesthetic ones."

Ancient Medicine

South Americans have cultivated coca for about 8,000 years.

"Coca is important in terms of a cash crop for South America and the source of an infamous street drug, but it also has a strong medicinal history," D'Auria said.

Indigenous tribes that cultivated coca chewed its leaves for religious rituals as well as for hunger and thirst suppression.

Yet today little is known about how the plant actually creates cocaine, in part because of its highly illicit nature—few, if any, U.S. labs are permitted to grow coca or study cocaine, which is part of a group of compounds called tropane alkaloids.

To probe the mysteries of cocaine, D'Auria and his team began by studying a highly similar yet legally grown family of flowering plants called Solanaceae, also known as the potato or nightshade family.

Although cocaine is part of a different family, many Solanaceae plants also produce tropane alkaloids, some of which have been made into medicines that dilate pupils, wrangle motion sickness, and treat peptic ulcers.

But D'Auria's team eventually realized that coca plants weren't using the same enzymes as Solanaceae plants to build their tropane alkaloid molecules.

That's surprising, he said, because the alkaloids are complex molecules that take many stages to create, and evolution typically conserves the best solutions rather than reinventing them.

"Another thing is that the roots of Solanaceae make tropane alkaloids. Coca does it in the leaves, which is a huge difference," D'Auria said. "That means nature has found two very different ways to make very similar compounds, which I think is extremely impressive."

To pinpoint one of cocaine's production steps, D'Auria and his colleagues ground up the coca leaves and searched for enzyme activity they thought might help prepare molecules of cocaine, which looks like two carbon-based rings bridged by bonds with oxygen.

The team eventually found an enzyme—and the gene that codes for it—that prepares cocaine's main ring to merge with benzoic acid, the plant's second-to-last step in building the drug.

Next Steps

The researchers are now gearing up to publish a study on the final step in the cocaine-building process, and they hope to retrace the earlier steps until the whole pathway is mapped.

Biochemist Toni Kutchan, who studies medicinal compounds at the Donald Danforth Plant Science Center, said the work wasn't a revalation but noted its importance in unraveling cocaine synthesis.

"This is one of many steps, so I'll be interested to see what they reveal in the next study," she said.

Kutchan also said she'd like to know why the coca plant began making such a complex molecule in the first place.

Study co-author D'Auria hinted that cocaine's natural purpose may be to kill bugs.

Previous work found that a high amount of cocaine in cultivated coca plants—as much as 10 percent of young leaves' dry weight—acts as an insecticide. More studies of the crop's wild ancestors, he said, could help solve the riddle.

"We are absolutely interested in this and are working on the question," D'Auria said, adding that his team is now studying six relatives of coca in the lab, and "we are working on obtaining the insect herbivores which are known to feed on them."

The new study about how plants make cocaine was published online last week in the journal Proceedings of the National Academy of Sciences.