Genetic discovery uncovers key tool for morphine production in poppies

Date: June 25, 2015

Source: University of York

Summary:

Scientists have made a key genetic discovery in poppies, paving the way for more effective painkillers.

Poppies. Scientists have revealed the long sought after gene that is seen as a critical gateway step in the synthesis of the morphinan class of alkaloids, which include the painkiller drugs morphine and codeine.

Credit: © phodo1 / Fotolia

Scientists at the University of York and GlaxoSmithKline (GSK) Australia have made a key genetic discovery in poppies, paving the way for more effective painkillers.

The discovery, published in the latest issue of Science, reveals the long sought after gene that is seen as a critical gateway step in the synthesis of the morphinan class of alkaloids, which include the painkiller drugs morphine and codeine.

The gene, called STORR, is only found in poppy species that produce morphinans. The STORR gene evolved when two other genes encoding oxidase and reductase enzymes came together millions of years ago. The resulting gene fusion plays a key role in production of morphine.

Scientists hope this will enable the breeding of bespoke poppy varieties, including those that produce the anti-cancer compound noscapine. Discovery of the STORR gene completes the set of genes needed for genetic engineering of morphine production in microbes such as yeast. Whether or not this can compete commercially with plant based production remains to be seen.

The breakthrough came when scientists identified poppy plants that were not able to produce morphine or codeine but instead accumulated another compound called (S)-reticuline. These plants were found to carry mutations in the STORR gene. These mutations cause a roadblock in the pathway to morphine production in poppy plants. The scientists were able to show that the non-mutated wild type gene can overcome the roadblock, by expressing it in yeast cells.

Professor Ian Graham, who led the research in the Centre for Novel Agricultural Products, based in the Department of Biology at the University of York, said: "Plants produce an amazing array of natural chemicals. Discovery of this STORR gene fusion provides us with new insight into how poppy plants have evolved to produce the most effective painkillers known to man."

The naturally occurring opiates of the morphinan class of alkaloids include morphine, codeine and thebaine. Morphine and codeine can be directly used as analgesic painkillers. Thebaine is widely used as the starting point for synthesis of a number of semi-synthetic opiates including hydrocodone, hydromorphone, oxycodone, and oxymorphone. Thebaine is also used to synthesise the opioid antagonist naloxone, which is used to counter the effects of opiate overdose.

Dr Thilo Winzer, lead author on the Science publication, said: "Opium poppy is one of the most important medicinal plants. The formation of the fusion protein was probably a key evolutionary event in its ability to synthesise pharmaceutically important morphinan alkaloids."

The discovery of the STORR gene completes the suite of genes thought to be required for production of morphinans in microbial systems. Plants remain a proven and efficient production system delivering Kg amounts per hectare of active pharmaceutical ingredients (API) at relatively low cost. Discovery of the STORR gene may enable an alternative supply route to be evaluated.

Tim Bowser, Head of R&D for GSK Australia's Opiates Division, said: "The discovery of the STORR gene provides us with a new tool for molecular plant breeding, making it faster and easier. GSK are using this discovery to develop bespoke commercial poppy varieties."

Story Source:

The above post is reprinted from materials provided by University of York.Note: Materials may be edited for content and length.

Journal Reference:

Thilo Winzer, Marcelo Kern, Andrew J. King, Tony R. Larson, Roxana Teodor, Samantha Donninger, Yi Li, Adam A. Dowle, Jared Cartwright, Rachel Bates, David Ashford, Jerry Thomas, Carol Walker, Tim A. Bowser, and Ian A. Graham. Morphinan biosynthesis in opium poppy requires a P450-oxidoreductase fusion protein. Science, 25 June 2015 DOI: 10.1126/science.aab1852

Cite This Page:

University of York. "Genetic discovery uncovers key tool for morphine production in poppies." ScienceDaily. ScienceDaily, 25 June 2015. <www.sciencedaily.com/releases/2015/06/150625143714.htm>.

Vitamin A supplementation may cause immune system to 'forget' past infections

New research suggests that vitamin A inhibits trained immunity, leading to tolerance of the innate immune cells upon stimulation with mitogens, antigens

Date: June 30, 2015

Source: Federation of American Societies for Experimental Biology

Summary:

Although vitamin A supplementation can have profound health benefits when someone is deficient, new evidence is emerging to show that vitamin A supplementation above and beyond normal levels may have negative health consequences. A new research report may help to explain why too much vitamin A can be harmful.

Although vitamin A supplementation can have profound health benefits when someone is deficient, new evidence is emerging to show that vitamin A supplementation above and beyond normal levels may have negative health consequences. A new research report published in the July 2015 issue of the Journal of Leukocyte Biology may help to explain why too much vitamin A can be harmful. Too much vitamin A shuts down the body's trained immunity, opening the door to infections to which we would otherwise be immune. This study adds to the arguments that vitamin A supplementation should only be done with clear biological and clinical arguments. Furthermore, it also suggests that low vitamin A concentrations in certain situations may even be "normal."

"This study helps to explain the mechanisms of anti-inflammatory effects of vitamin A and by doing so opens the door to identifying novel ways to modulate the immune response and restore its function in situations in which it is dysregulated," said Mihai G. Netea, M.D., Ph.D., a researcher involved in the work from the Department of Internal Medicine at Radboud University Medical Center in Nijmegen, The Netherlands.

To make this discovery, Netea and colleagues stimulated immune cells, isolated from volunteers, with Vitamin A and saw that the cells produced fewer cytokines, key proteins that help ward off microbes, upon stimulation with various mitogens and antigens. Furthermore, the cells were also stimulated with various microbial structures, which resulted in long-term activation or training of the cells. When the same experiments were performed in the presence of vitamin A, the microbial structures were no longer able to activate the immune cells.

"The interface of nutrition and immunity is an area of considerable importance, especially in an age when dietary supplements and vitamins are quite common," said John Wherry, Ph.D., Deputy Editor of the Journal of Leukocyte Biology. "These new findings shed light on an importance balance in vitamin A levels for optimal immunity. These studies have implications for how we think about daily vitamins, but also for the developing world, where improving diet could have dramatic benefits on how the immune system is trained to respond to different infections."

Story Source:

The above post is reprinted from materials provided by Federation of American Societies for Experimental Biology. Note: Materials may be edited for content and length.

Journal Reference:

Rob J. W. Arts, Bastiaan A. Blok, Reinout van Crevel, Leo A. B. Joosten, Peter Aaby, Christine Stabell Benn, and Mihai G. Netea. Vitamin A induces inhibitory histone methylation modifications and down-regulates trained immunity in human monocytes. J. Leukoc. Bio., June 2015 DOI: 10.1189/jlb.6AB0914-416R

Cite This Page:

Federation of American Societies for Experimental Biology. "Vitamin A supplementation may cause immune system to 'forget' past infections: New research suggests that vitamin A inhibits trained immunity, leading to tolerance of the innate immune cells upon stimulation with mitogens, antigens." ScienceDaily. ScienceDaily, 30 June 2015. <www.sciencedaily.com/releases/2015/06/150630121406.htm>.