PACLITAXEL 遗传生物合成的新进展:T1βOH TAXANE 羟化酶的鉴定。

IF 6.8 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
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引用次数: 0

摘要

在寻求创新癌症疗法的过程中,紫杉醇仍然是临床肿瘤学的基石。然而,在最后一种紫杉醇羟化酶表征之后的几十年里,其复杂的生物合成途径,尤其是复杂的氧合步骤,一直是一个谜。所涉及的酶的高度分化和杂交性带来了巨大的挑战。在这项研究中,我们采用了一种创新的方法,结合硅学方法和功能基因分析,来揭示这一难以捉摸的途径。我们利用潜在配体库进行了分子对接研究,发现 TB574 是紫杉醇生物合成途径中潜在的缺失酶,并显示出良好的相互作用。利用作为新型微生物细胞工厂联合体的工程化酿酒葡萄孢菌株进行补充性体内试验,不仅验证了 TB574 在形成难以捉摸的紫杉醇中间体 T5αAc-1β,10β-diol 过程中的关键作用,而且还以前所未有的产量实现了紫杉醇前体的生物合成,包括 T5αAc-1β,10β-diol 的产量,约为 40 毫克/升。这一成果前景广阔,为进一步探索利用微生物群的新型代谢工程方法提供了新的方向。总之,我们的研究不仅进一步研究了以前未表征的酶在紫杉醇生物合成中的作用,而且为全面了解紫杉醇的生物合成及其异源生产开辟了一条道路。T1βOH 的表征强调了未来利用异源系统生产紫杉醇以改善癌症治疗和药品生产的重大飞跃,从而为提高癌症疗法的疗效和药品生产的效率带来了巨大希望。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A novel step towards the heterologous biosynthesis of paclitaxel: Characterization of T1βOH taxane hydroxylase

In the quest for innovative cancer therapeutics, paclitaxel remains a cornerstone in clinical oncology. However, its complex biosynthetic pathway, particularly the intricate oxygenation steps, has remained a puzzle in the decades following the characterization of the last taxane hydroxylase. The high divergence and promiscuity of enzymes involved have posed significant challenges. In this study, we adopted an innovative approach, combining in silico methods and functional gene analysis, to shed light on this elusive pathway. Our molecular docking investigations using a library of potential ligands uncovered TB574 as a potential missing enzyme in the paclitaxel biosynthetic pathway, demonstrating auspicious interactions. Complementary in vivo assays utilizing engineered S. cerevisiae strains as novel microbial cell factory consortia not only validated TB574's critical role in forging the elusive paclitaxel intermediate, T5αAc-1β,10β-diol, but also achieved the biosynthesis of paclitaxel precursors at an unprecedented yield including T5αAc-1β,10β-diol with approximately 40 mg/L. This achievement is highly promising, offering a new direction for further exploration of a novel metabolic engineering approaches using microbial consortia. In conclusion, our study not only furthers study the roles of previously uncharacterized enzymes in paclitaxel biosynthesis but also forges a path for pioneering advancements in the complete understanding of paclitaxel biosynthesis and its heterologous production. The characterization of T1βOH underscores a significant leap forward for future advancements in paclitaxel production using heterologous systems to improve cancer treatment and pharmaceutical production, thereby holding immense promise for enhancing the efficacy of cancer therapies and the efficiency of pharmaceutical manufacturing.

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来源期刊
Metabolic engineering
Metabolic engineering 工程技术-生物工程与应用微生物
CiteScore
15.60
自引率
6.00%
发文量
140
审稿时长
44 days
期刊介绍: Metabolic Engineering (MBE) is a journal that focuses on publishing original research papers on the directed modulation of metabolic pathways for metabolite overproduction or the enhancement of cellular properties. It welcomes papers that describe the engineering of native pathways and the synthesis of heterologous pathways to convert microorganisms into microbial cell factories. The journal covers experimental, computational, and modeling approaches for understanding metabolic pathways and manipulating them through genetic, media, or environmental means. Effective exploration of metabolic pathways necessitates the use of molecular biology and biochemistry methods, as well as engineering techniques for modeling and data analysis. MBE serves as a platform for interdisciplinary research in fields such as biochemistry, molecular biology, applied microbiology, cellular physiology, cellular nutrition in health and disease, and biochemical engineering. The journal publishes various types of papers, including original research papers and review papers. It is indexed and abstracted in databases such as Scopus, Embase, EMBiology, Current Contents - Life Sciences and Clinical Medicine, Science Citation Index, PubMed/Medline, CAS and Biotechnology Citation Index.
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