Oct. 4, 2013

Researchers find enzymes are multitasking in opium poppy

Discovery could lead to better production of valuable painkilling drugs from plants and micro-organisms

Author

Mark Lowey

Peter Facchini, left, opium poppy expert and fellow researcher PhD student Scott Farrow.

Peter Facchini, left, opium poppy expert and fellow researcher PhD student Scott Farrow.

Riley Brandt

University of Calgary scientists have discovered that metabolic enzymes in opium poppies play a more important role than previously understood in enabling the plant to make morphine, codeine and other important compounds.

Researchers Peter Facchini and PhD student Scott Farrow also discovered a biochemical reaction that had not been known to occur in plants, a process they say might also happen in garden-variety poppies and other plants.

Their work, published this week as a cover story in the Journal of Biological Chemistry, sheds light on how the opium poppy – the world’s only source of the valuable painkillers – evolved the ability to make morphine and other compounds.

“The functions of what we thought were really specific genes and enzymes involved in morphine biosynthesis are actually much broader,” says Facchini, professor of biological sciences in the Faculty of Science and an internationally recognized expert on the opium poppy.

New research builds on 2010 discovery of genes, enzymes

Three years ago, Facchini’s laboratory reported the discovery of two unique genes – along with the enzymes they encode – that enable the opium poppy to synthesize morphine and codeine. Enzymes are protein molecules – highly selective catalysts that accelerate both the rate and specificity of metabolic reactions.

Facchini says the new finding demonstrates that those enzymes, and a third enzyme also discovered by his lab, have an unexpected and widespread role in the opium poppy.

“There are more branches of related alkaloid metabolism that lead to a lot of different compounds that have different pharmacological and important biological properties in opium poppy,” he says.

These new insights could one day enable pharmaceutical companies to manipulate the biochemical pathway and create varieties of opium poppy that produce higher levels of specific drugs, such as codeine or morphine.

Codeine is by far the most widely used opiate in the world and one of the most commonly used painkillers.  It can be extracted directly from opium poppy, although most of the painkiller is chemically synthesized from the much more abundant morphine found in the plant.

Canadians spend more than $100 million a year on codeine-containing pharmaceuticals and are among the world’s top consumers of the drug per capita.

New research shows certain enzymes play a widespread role in synthesis of morphine, codeine and other important painkilling compounds unique to the opium poppy.

Research shows certain enzymes play a role in synthesis of morphine, codeine and other painkillers.

Riley Brandt

Codeine manufacturing plants?

Facchini and Farrow suspect that the biochemical reactions they discovered also occur in garden-variety poppy species related to the opium poppy, as well as in other plants.

“The difference between related plants, in terms of their ability to make or not make morphine, might only be the activity of a single enzyme,” Facchini says. 

If so, it may eventually be possible to manipulate metabolic pathways so that other plants – or even yeast and bacteria – can produce morphine, codeine or thebaine, an “intermediate” compound obtained only from opium poppy and used to make the painkiller drug oxycodone. 

However, companies seeking to 'tweak’ opium poppy biochemistry should be cautious, Facchini says, because the related metabolic pathways produce compounds with anti-microbial activity designed to protect the plant.

“If you’re going to continue to rely on this plant as a ‘drug-production system’ and apply technological solutions to improving varieties, you better understand the biochemistry thoroughly,” Facchini says.

Farrow spent the last three years unravelling the biochemical reactions, performing in vitro (‘test tube’) analysis on many compounds using state-of-the-art mass spectrometry equipment.  

He also used a technique called virus-induced gene silencing to essentially knock out the genes’ morphine- and codeine-making enzymes, which confirmed their widespread role in the opium poppy’s physiological functions.

Prior to this discovery, the only similar biochemical reaction reported in the scientific literature was a human enzyme that breaks down the illegal drug ecstasy, although the enzyme itself hasn’t yet been identified.

Farrow is now investigating 20 other plant species genetically sequenced by Facchini’s lab to determine if the biochemical reaction also occurs in these plants.

A top-calibre student attracted to the university, Farrow holds a prestigious Alexander Graham Bell Canada Graduate Scholarship, an NSERC Postgraduate Scholarship, and an Alberta Innovates – Technology Futures Graduate Student Scholarship.

Major funding for the research was provided by Genome Canada and Genome Alberta.