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Genetically Engineered E. coli Cranks Out Opiate Precursor

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    Though opiate drug use has been much maligned over the past several years, the need for medically relevant painkillers has not waned. Scientists have been continually on the hunt for improved production methods of opiate compounds, as extraction from poppy sap is inefficient and time-consuming.

    Now, a team of Japanese researchers from Ishikawa Prefectural University and Kyoto University has modified several genes from Escherichia coli to produce large quantities of the morphine precursor thebaine, which can be changed to make painkilling drug compounds. Moreover, the investigators found that their engineered E. coli produced 300 times more thebaine compared to a recently developed method involving yeast, in addition to having a much lower risk of unregulated production.

Prokaryotic expression system (E.coli expression system) is a classical expression system developed earlier and widely used in gene expression technology. In recent decades, E.coli expression system has been continuously developed and improved, and has been widely used by scientific research and industrial users to express various recombinant proteins. Compared with other expression systems, it is characterized by high expression level of target gene, short culture period, strong anti-pollution ability and low cost. Our researchers have established a mature E.coli expression service platform to provide the expression and purification of various recombinant proteins and their complexes in escherichia coli.

    “Morphine has a complex molecular structure; because of this, the production of morphine and similar painkillers is expensive and time-consuming,” explained co-author Fumihiko Sato, Ph.D., professor in the graduate school of biostudies at Kyoto University. “But with our E. coli, we were able to yield 2.1 milligrams of thebaine in a matter of days from roughly 20 grams of sugar, as opposed to 0.0064 mg with yeast.”

    The findings from this study were published recently in Nature Communications through an article entitled “Total biosynthesis of opiates by stepwise fermentation using engineered Escherichia coli.”

    Traditionally, morphine is extracted from poppy sap in a process that results in opiates such as thebaine and codeine. In order to streamline the production process, synthetic biologists had recently engineered the yeast genome so that it produced opiate alkaloids from sugar. However, there were ethical concerns that the pain-killing molecules could be produced easily and unregulated, provided that one has access to the necessary yeast strain. The authors of the current study suggest that such a risk is almost insignificant with the newly engineered E. coli strains.

    “Four strains of genetically modified E. coli are necessary to turn sugar into thebaine,” noted Dr. Sato. “E. coli are more difficult to manage and require expertise in handling. This should serve as a deterrent to unregulated production.”

    Previously, the Japanese team tweaked E. coli to synthesize reticuline, another morphine precursor that appears upstream in the transformation process from thebaine. In the new system, the team added genes from other bacteria and enzyme genes from opium poppies, Coptis japonica, and Arabidopsis. The researchers credit the strong activity of enzymes in the new system for their success in making thebaine and hope to achieve even further improvements.

    “By adding another two genes, our E. coli were able to produce hydrocodone, which would certainly boost the practicality of this technique,” Dr. Sato stated. “With a few more improvements to the technique and clearance of pharmaceutical regulations, manufacturing morphine-like painkillers from microbes could soon be a reality.”

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