HerbalEGram: Volume 8, Number 2, February 2011

Scientists Gain New Insight Into How Opium Poppies
Produce Morphine

Scientists at the Donald Danforth Plant Science Center, a nonprofit research institute in St. Louis, Missouri, have made great strides in understanding the atomic structure of an enzyme from the opium poppy’s biosynthetic pathway. Opium poppy (Papaver somniferum) is an important medicinal plant from which the widely used analgesic alkaloids morphine and codeine are derived.¹

Toni Kutchan, PhD, whose lab at the center specializes in biosynthetic pathways, and Thomas Smith, PhD, who runs a structural biology lab at the center, partnered in the research, and their findings were published in the Journal of Biological Chemistry in December of 2010.² Dr. Kutchan’s team started by crystallizing one of the enzymes at work in the plant’s production of morphine: salutaridine reductase (SalR). Dr. Smith’s team then performed X-ray crystallography to determine the atomic structure of the enzyme.¹

SalR was crystallized in order to give the scientists a better view. “A repetitive, fixed order has to be brought into the enzyme structure in order to be able to solve its structure; otherwise one sees only a blur of atoms that are moving around in solution,” said Dr. Kutchan (e-mail, January 27, 2011). Crystallizing an enzyme is a process of trial and error, and sometimes even when the conditions are right, the resulting crystals can be too small to diffract X-rays, according to Dr. Kutchan.

It took approximately 2 years to generate crystals that were adequate for testing, said Dr. Kutchan, who has been captivated by “how plants make drugs” for decades (personal communication, January 24, 2011). The goal of her lab, as expressed on the Danforth website, is to “elucidat[e] the biosynthetic pathways of selected medicinal compounds in plants and [develop] improved sources of these chemicals. According to Dr. Smith, SalR was chosen as the first enzyme from the opium synthetic pathway to be investigated by the teams because of its stability. “This was like the low-hanging fruit,” said Dr. Smith."³

X-ray crystallography revealed that a “flap covering the active site” of the enzyme appears to squeeze down to catalyze a more efficient chemical reaction upon substrate molecules.¹ As explained in the Journal of Biological Chemistry article, this flap probably functions as a gatekeeper of sorts, “eliminating the possibility for SalR to metabolize flat-shaped compounds, such as steroids.”² As a result, the enzyme remains specialized for the morphine-production process.²

Scientific breakthroughs pertaining to the atomic structure of plant enzymes have the potential to lead to the creation of new pharmaceuticals and nutraceuticals, in addition to reducing the manufacturing costs of established plant-derived drugs. “A big part of the cost [of manufacturing pharmaceuticals] is purification,” said Dr. Kutchan, explaining that the enrichment of a plant’s compound production would keep purification expenditures low. Using atomic-level enzyme information, scientists can work toward engineering plants that will produce increased amounts of certain compounds, such as morphine.

Michael Tempesta, PhD, founder and managing partner of Phenolics, LLC, remarked that while a greater morphine yield per plant could be advantageous, it could also be exploited for corrupt reasons, e.g., illegal drugs (e-mail, January 21, 2011). On the other hand, detailed information about opium poppy’s atomic structure may provide an opportunity to thwart illegal opium production, according to Dr. Tempesta: “Development of a compound to block the production of morphine in the plant [could have the effect of] potentially rendering the illicit poppy-growing industries unable to produce a meaningful crop.”

“Plants are so malleable now, in terms of genetic manipulation,” said Dr. Smith. Both he and Dr. Kutchan confirmed that their labs are already investigating the atomic structures of additional opium poppy enzymes, the names of which will be concealed until the researchers publish their findings.

References

1.   Critical knowledge about opium’s atomic structure discovered by Danforth Center researchers [press release]. St. Louis, MO: Donald Danforth Plant Science Center; January 17, 2011.

2.     Higashi Y, Kutchan T, Smith T. The atomic structure of salutaridine reductase from the opium poppy papavar somniferum. J Biol Chem. Dec 17, 2010;285(51). Available at:  www.jbc.org/content/early/2010/12/17/jbc.M110.168633.full.pdf+html. Accessed January 20, 2011.

3.     Donald Danforth Plant Science Center. Laboratories: Toni Kutchan. Donald Danforth Plant Science Center website. Available at: www.danforthcenter.org/science/laboratories/toni_kutchan/. Accessed January 24, 2011.