New research from the University of Calgary (Calgary, Canada) has identified two genes in the opium poppy that are involved in the synthesis of codeine and morphine. This discovery could simplify the pharmaceutical manufacturing of these two pain relievers.
The opium poppy has long been depended upon for its natural ability to create these two powerful pain-fighters. But despite widespread medical use, codeine must be derived from morphine, which still needs to be extracted from the seeds of the poppy plant. For decades, researchers have searched for a synthetic mechanism to manufacture these drugs, but have struggled to understand how the opium poppy generates these substances.
“The enzymes encoded by these two genes have eluded plant biochemists for a half-century," Peter Facchini, professor in the department of biological sciences at the University of Calgary, said in a press release. "In finding not only the enzymes but also the genes, we've made a major step forward. It is equivalent [to] finding a gene involved in cancer or other genetic disorders."
To find the exact genes that control the production of codeine and morphine, Facchini worked with post-doctoral researcher Jillian Hagel to evaluate 23,000 different genes in search of codeine o-dementhylase (codm) and thebaine 6-0-demethylase (t6odm). These genes produce the enzymes that the opium poppy uses to covert codeine into morphine. Called non-heme dioxygenases, codm and t6odm are the only genes known to catalyze the synthesis of codeine and morphine. By inhibiting the expression of t60dm and codm in the opium poppy, the researchers tested their discovery and found that virus-induced gene silencing successfully blocked the creation of the two substances.
Although codeine can be extracted directly from the plant, it is not found in the same abundance as morphine, because codeine must be created from the original morphine. In the human body, an enzyme in the liver reverses the synthesis of codeine and turns it back into morphine. Because of this, codeine and morphine have the same effects on the human brain. According to Facchini, the process of synthesizing and harvesting codeine will no longer be necessary if the genes he and Hagel discovered are used to make a knock-out version of the opium poppy that only creates codeine.
"We can potentially create plants that will stop production at codeine,” said Facchini. “We are also working toward the synthesis of codeine and other opiate drugs more efficiently and economically in controlled bioprocessing facilities. Our discovery now makes it possible to use microorganisms to produce opiate drugs and other important pharmaceuticals."
According to Facchini, these drugs are important because they generate a lot of revenue for the pharmaceutical industry. Canada is among the world’s top consumers of codeine, spending more than $100 million every year to import opiates.
"The evolution of these two genes in a single plant species has had such a huge impact on humanity over the past several thousand years,” said Facchini. “Our discovery allows this unique genetic power to be harnessed in many important ways." The researchers will now focus on using the codeine gene to produce the drugs in a yeast or bacteria vector.
The paper, “Dioxygenases catalyze the O-demethylation steps of morphine biosynthesis in opium poppy,” was published March 14 in Nature Chemical Biology.