Plant-derived natural products have been used to treat human and animal ailments for millenia, and they remain a major source of new drugs for the treatment of human diseases in the 21st century. CNAP uses state of the art technologies to aid rapid discovery and development of natural products that can be used to develop drugs for pain relief and the treatment of diseases ranging from malaria to cancer.
CNAP Artemisia Research Project
The CNAP Artemisia Research Project developed improved non-GM varieties of the medicinal plant Artemisia annua with increased artemisinin yields, and ultimately Hyb8001r was selected as the best hybrid for commercial production. Ongoing research and development is focused on a wider understanding of Artemisia biology, particularly in understanding the mechanism of artemisinin biosynthesis.
Malaria claims almost a million lives every year but there is renewed global determination to halt it. New plant varieties will improve the supply of artemisinin for use in artemisinin combination therapies (ACTs), making these vital malaria medicines more accessible to patients in developing countries.
CNAP researchers published the first genetic map of Artemisia annua in the leading journal Science in 2010.
Scientists led by Professor Ian Graham in CNAP at the University of York and colleagues at GlaxoSmithKline (GSK) Australia discovered a complex gene cluster responsible for the synthesis of the medicinal compound noscapine. This discovery, published in Science in 2012, reveals that the pathway for synthesis of noscapine is controlled by a complex gene cluster of ten genes encoding five different enzyme classes, and at that time was the most complex gene cluster ever found in plants. The discovery has revealed the previously unknown biochemical pathway for noscapine synthesis. It will also greatly accelerate the breeding of high-noscapine poppy varieties.
The breakthrough came when the scientists discovered that poppy varieties that produce noscapine express a number of genes that are absent in varieties that are noscapine free. They then analysed the inheritance pattern of these genes in hundreds of offspring from crosses between noscapine and non-noscapine varieties. When they saw that all of these genes are inherited together, they realised they could be looking at an incredibly complex gene cluster. The identity and arrangement of genes in the cluster was determined by cloning and DNA sequencing.
When the 2012 Science paper was published Professor Ian Graham said: "We were amazed to find that this gene cluster encodes for almost the entire biosynthetic pathway for noscapine. With this one discovery we have been able to produce an outline of the pathway and define a number of the steps involved - something that normally takes years."
In June 2015 scientists led by Professor Ian Graham in CNAP at the University of York and colleagues at GSK Australia reported a key genetic discovery that paves the way for more effective painkillers. The discovery, published in 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.
The breakthrough came when the 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 team 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 (CNAP), based in the Department of Biology, 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.
Secret to making renewable energy from wood? The digestive system of the gribble may hold the key!
2 new Networks in Industrial Biotechnology awarded! Congratulations to Ian Graham and Simon McQueen-Mason, who will each lead a phase II NIBB.
Poppy genome decoded DNA code of the opium poppy genome determined.
Strengthening links with India: 2 major new research projects Funding secured by CNAP PIs.
CNAP, Department of Biology, University of York, Wentworth Way, York YO10 5DD, UK