FoTO1和Taxol基因的发现使浆果赤霉素III的生物合成成为可能，这一成果由斯坦福大学Elizabeth S. Sattely小组经过不懈努力而取得。这一研究成果发表在2025年6月11日出版的国际学术期刊《自然》上。

在Taxthem庞大且富含酶的基因组中，研究人员预计紫杉醇途径将难以通过传统的RNA测序和共表达分析来解决。为了提高途径鉴定转录分析的分辨率，课题组开发了一种策略，课题组称之为多重扰动单核（mpXsn）转录图谱跨越组织、细胞类型、发育阶段和激发条件的细胞状态。他们的数据表明，紫杉醇生物合成基因分离成不同的表达模块，表明连续的亚通路。这些模块解析了7个新基因，允许在烟叶中重新合成和分离出17个基因的浆果赤霉素III（紫杉醇的原生前体），其含量与红杉针叶中的自然丰度相当。

值得注意的是，研究人员发现核转运因子2（NTF2）样蛋白FoTO1对于促进第一次氧化过程中所需产物的形成至关重要，从而解决了紫杉醇途径重构的长期瓶颈。与一个新的β-苯丙氨酸-辅酶a连接酶一起，这里发现的8个基因使3' -N-debenzoyl-2' -脱氧紫杉醇的生物合成成为可能。更广泛地说，该团队建立了一种可推广的方法来有效地扩展共表达分析的能力，以匹配大型、未表征基因组的复杂性，促进高价值基因集的发现。

据介绍，植物制造复杂而有效的治疗分子，但从天然生产者或通过化学合成获得这些分子是困难的，这限制了它们在临床中的应用。一个突出的例子是抗癌治疗紫杉醇（以紫杉醇的品牌出售），它是从紫杉树（红豆杉品种）中提取的。确定完整的紫杉醇生物合成途径将使这种药物的异源合成成为可能，但尽管经过了半个世纪的研究，这一目标仍未实现。

附：英文原文

Title: Discovery of FoTO1 and Taxol genes enables biosynthesis of baccatin III

Author: McClune, Conor James, Liu, Jack Chun-Ting, Wick, Chloe, De La Pea, Ricardo, Lange, Bernd Markus, Fordyce, Polly M., Sattely, Elizabeth S.

Issue&Volume: 2025-06-11

Abstract: Plants make complex and potent therapeutic molecules1,2, but sourcing these molecules from natural producers or through chemical synthesis is difficult, which limits their use in the clinic. A prominent example is the anti-cancer therapeutic paclitaxel (sold under the brand name Taxol), which is derived from yew trees (Taxus species)3. Identifying the full paclitaxel biosynthetic pathway would enable heterologous production of the drug, but this has yet to be achieved despite half a century of research4. Within Taxus’ large, enzyme-rich genome5, we suspected that the paclitaxel pathway would be difficult to resolve using conventional RNA-sequencing and co-expression analyses. Here, to improve the resolution of transcriptional analysis for pathway identification, we developed a strategy we term multiplexed perturbation×single nuclei (mpXsn) to transcriptionally profile cell states spanning tissues, cell types, developmental stages and elicitation conditions. Our data show that paclitaxel biosynthetic genes segregate into distinct expression modules that suggest consecutive subpathways. These modules resolved seven new genes, allowing a de novo 17-gene biosynthesis and isolation of baccatin III, the industrial precursor to Taxol, in Nicotiana benthamiana leaves, at levels comparable with the natural abundance in Taxus needles. Notably, we found that a nuclear transport factor 2 (NTF2)-like protein, FoTO1, is crucial for promoting the formation of the desired product during the first oxidation, resolving a long-standing bottleneck in paclitaxel pathway reconstitution. Together with a new β-phenylalanine-CoA ligase, the eight genes discovered here enable the de novo biosynthesis of 3’-N-debenzoyl-2’-deoxypaclitaxel. More broadly, we establish a generalizable approach to efficiently scale the power of co-expression analysis to match the complexity of large, uncharacterized genomes, facilitating the discovery of high-value gene sets.

DOI: 10.1038/s41586-025-09090-z

Source: https://www.nature.com/articles/s41586-025-09090-z