麻豆淫院

Stanford University researchers report the discovery of eight previously unknown genes that, when expressed in tobacco leaves, reconstitute the Taxol precursor baccatin III at levels matching its natural abundance in yew needles. The find could accelerate the manufacture of a much-needed cancer drug.

Yew trees of the genus Taxus serve as the natural reservoir for paclitaxel, a potent chemotherapeutic sold as Taxol. Within these slow-growing conifers, the highest concentrations of late-stage intermediates such as baccatin III accumulate in the bark where they reach only 0.001鈥�0.050% of dry weight, and to an even lesser extent in the needles of younger shoots.

Direct extraction of paclitaxel from yew yields so little material that manufacturers instead semi-synthesize paclitaxel from the more abundant intermediate, baccatin III. Even this industry standard method is highly inefficient compared to other modern drug manufacturing methods.

Adding to the dilemma, bark harvests impose severe ecological and economic costs, since removal of the protective outer layers often kills the tree, whereas needles can be collected more sustainably but contain lower concentrations of the desired compounds. A fully sustainable biosynthetic solution is needed.

Between the late 1990s and 2006, researchers characterized 12 enzymes in the Taxol biosynthetic pathway. Since then, progress has stalled, still short of the complete production system with an untold number of missing steps left.

In the study, "Discovery of FoTO1 and Taxol genes enables biosynthesis of baccatin III," in Nature, researchers developed multiplexed perturbation 脳 single-nucleus (mpXsn) transcriptomics to resolve Taxus metabolic modules.

A total of 17,143 single-nucleus transcriptomes spanning 272 tissue samples, cell types, developmental stages and elicitor conditions from Taxus media needles were profiled and condensed into 2,901 pseudo-bulk cell states.

Top candidates were functionally tested by transient expression in Nicotiana benthamiana tobacco leaves, with metabolic products analyzed via gas chromatography鈥搈ass spectrometry and nuclear magnetic resonance.

Eight previously uncharacterized genes emerged from these screens, including a nuclear transport factor 2鈥搇ike protein, FoTO1, that improves fidelity of the first oxidation step. Several more enzymes discovered fulfilled crucial steps in the transformation of substrate into baccatin III. Two of the missing enzymes shared a catalytic function despite being independently evolved.

According to the authors, "The identities of the new Taxol genes shed light on why they remained unknown for so long. Pathway reconstitution required unanticipated gene families and functionalizations."

The mpXsn method overcame transcriptomic resolution limits in a large, complex genome. More than just a genomic insight, the method essentially laid bare the natural process leading to a complete paclitaxel, a major conceptual advance in both studying hidden gene functions and Taxol production.

Newly identified enzymes offer a potential alternative to Yew tree sourcing of baccatin III, paving the way for sustainable large-scale biomanufacturing of paclitaxel.

Beyond paclitaxel biosynthesis, the mpXsn platform will be useful for studying gene sets of interest in other non-model organisms.

Eukaryotes, especially, pose major challenges for functional genomics and gene-guided discovery, because they generally lack the comprehensive gene clusters that are found in prokaryotes.

Methods such as mpXsn, which affordably capture precise gene covariance across hundreds of transcriptional states, might help to overcome this long-standing challenge in functional genomics.

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