Long Postulated Enzyme Thebaine Synthase Potentiates Efficient Biosynthesis of Opioids by Increasing Thebaine Titers >20-fold in Engineered Yeast Strains
BUDAPEST, Hungary, May 29, 2018 /PRNewswire/ — Intrexon Corporation (NYSE: XON), a leader in the engineering and industrialization of biology to improve the quality of life and health of the planet, and Epimeron, Inc., a world-class provider of gene discovery and biosynthetic pathway optimization, today announced the isolation and recombinant expression of a novel gene from the opium poppy (Papaver somniferum) encoding the enzyme, thebaine synthase. The existence of this enzyme is essential to increase the rate of the final step in thebaine synthesis. This breakthrough allows biosynthesis of several important active agents and intermediates including thebaine, codeine and morphine, and is particularly noteworthy as the existence of this enzyme was not previously verified. The discovery was published in Nature Chemical Biology.
Microbial production of active pharmaceutical ingredients (APIs) holds the promise to replace current methods required to isolate these APIs and their intermediates from plant sources. Fermentation in microbes has potential to provide better consistency, greater supply-chain security, and avoids the resource-intensive isolation that often leads to quality and quantity variability in end products, leading to a lower cost of goods. Intrexon and Epimeron are collaborating to build a commercially scalable fermentative production system for the high quality, cost-effective, and secure manufacturing of opiate APIs and intermediates. In addition, the companies are working to develop other breakthrough technologies essential for efficient commercial production of opiates by yeast fermentation.
Thebaine is the first opiate alkaloid along the biosynthetic pathway for the narcotic analgesics morphine and codeine in opium poppy. In addition, using thebaine as a starting point greatly simplifies the synthesis of widely prescribed pharmaceuticals, including the analgesics oxycodone and hydrocodone along with the receptor antagonists buprenorphine and naltrexone, which are used for addiction treatment. However, thebaine is a complex opiate making efficient synthesis both important and difficult.
“Until now, the existence of a final enzyme in thebaine production was only speculative. Our discovery of the gene and its remarkable performance in engineered microbes was made possible by the strong partnership between Epimeron and Intrexon, coupled with the world-leading expertise in opiate alkaloid biochemistry at the University of Calgary,” stated Professor Peter Facchini, PhD, Chief Scientific Officer of Epimeron.
Chris Savile, PhD, Senior Director, Commercial Operations and the project leader at Intrexon commented, “A longstanding dilemma in thebaine biosynthesis has involved the precise mechanism of the final step in the poppy. Formation of the necessary precursor intermediate occurs spontaneously, but it’s very slow – too slow for use in a commercial manufacturing process. The publication establishes the natural synthetic pathway. Of particular significance, we show that inclusion of this novel enzyme in engineered yeast strains increases thebaine titers by greater than twenty-fold.”
The thebaine synthesis effort represents the leading program in Intrexon’s collaboration with Genopaver, LLC, a company focused on the fermentative production of alkaloids through genetically modified cell-lines and substrate feeds.
The article, titled “A pathogenesis-related 10 protein catalyzes the final step in thebaine biosynthesis”, is available online in Nature Chemical Biology here.
About Intrexon Corporation
Intrexon Corporation (NYSE: XON) is Powering the Bioindustrial Revolution with Better DNA™ to create biologically-based products that improve the quality of life and the health of the planet. Intrexon’s integrated technology suite provides its partners across diverse markets with industrial-scale design and development of complex biological systems delivering unprecedented control, quality, function, and performance of living cells. We call our synthetic biology approach Better DNA®, and we invite you to discover more at www.dna.com or follow us on Twitter at @Intrexon, on Facebook, and LinkedIn.
Epimeron Inc. is working to enable the commercialization of high-value bioproducts by making key discoveries in plant genomics for our Synthetic Biology partners. At Epimeron Inc., newly discovered genetic elements and biochemical strategies are translated into the appropriate commercial host organism. Epimeron Inc. seeks to partner and work together to enhance the success of manufacturing programs.
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