Chinese scientists have deciphered the biosynthetic pathway of a rare, naturally occurring anticancer drug, and reproduced it for the first time – in tobacco.
Paclitaxel – sold under the brand name Taxol – is a well-known anticancer compound. First discovered in the Pacific yew tree in 1962, paclitaxel is an FDA-approved anticancer drug used to treat breast, ovarian and lung cancer. The drug disturbs the division of cancer cells and in turn blocks cell cycle progression.
But despite the success of paclitaxel in clinical applications, it is extremely difficult to obtain. It makes up only about 0.004 per cent of the tree’s bark.
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The scarcity means that treating a patient with ovarian cancer, for instance, requires between three to 12 yew trees that are more than a century old, resulting in large numbers of yew trees being cut down.
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Adding to their scarcity is the fact that yew trees grow slowly. In China, where the tree is on the verge of extinction, the Pacific yew tree is classified as a first-level rare and protected species, on par with the giant panda.
The effectiveness and rarity of the tree has led to extensive research into alternative and sustainable production methods, including semi-synthesis from intermediates and cultivation of plant cell cultures that could reduce the need to cut down yew trees.
The chemical structure of paclitaxel, however, is extremely complex. Missing knowledge about the genes involved in several steps of paclitaxel’s biosynthesis has made it difficult to engineer the full pathway.
There may be a way around those challenges, thanks to the insights of two Chinese professors. Yan Jianbin with Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, and Lei Xiaoguang with the College of Chemistry and Molecular Engineering at Peking University, have suggested a new understanding of the synthesis pathway of paclitaxel.
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The researchers were able to artificially constitute a biosynthetic pathway for the key precursor of paclitaxel in tobacco. Their findings were published in the peer-reviewed journal Science on Thursday.
“The reaction steps [to produce paclitaxel] can be divided into three critical processes, including the formation of a skeleton, the biosynthesis of a highly functionalised intermediates called baccatin III based on the skeleton, and the attachment of a side chain,” Yan said in the paper.
The final step may be the most elusive. While it has been widely investigated for half a century, the complete biosynthetic pathway of baccatin III remained a mystery.
Then, the team found a distinctive chemical logic in the formation of a core structure called the “oxetane ring” and proved the process could be realised in a tobacco plant.
Biosynthesis of baccatin III typically requires at least 13 enzymes. But after the researchers introduced two key enzymes, they were able to cut the number of enzymes needed for the biosynthesis to nine.
What made the two key enzymes special is their versatility – a quality called functional promiscuity – meaning a single enzyme might catalyse several reactions at the same time.
Yan and his team investigated further, trying to determine if those nine genes formed the critical pathway that creates baccatin III.
“We attempted to co-express the two new genes with other known genes involved to determine whether we can artificially reconstruct the biosynthesis pathway in tobacco,” Yan said in the paper.
“Results show baccatin III could hardly be detected when any of the nine genes were absent. The outcome indicates that the nine genes constitute the core pathway in baccatin III biosynthesis. Some enzymes that were previously thought important might be unnecessary” he added.
The research offers a path through a stubborn bottleneck to biosynthesis of the precursor of paclitaxel. The pathway could be introduced into tobacco through gene engineering, which provides a chance for future production, according to researchers.
Yan said their future work would focus on clarifying the specific catalytic orders and versatility of the nine enzymes they had identified, as well as finding the rate that determines the steps for metabolic engineering optimisation.
The final challenge for researchers is to achieve batch manufacturing of paclitaxel. “With more effort from a broad field of scientists, including natural product chemists, plant physiologists, and synthetic biologists, green and efficient manufacturing of paclitaxel may be achieved via synthetic biology in the future,” Yan said the paper.
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