A novel step towards the heterologous biosynthesis of paclitaxel: Characterization of T1βOH taxane hydroxylase

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• dc.contributor.author Escrich Montañana, Ainoa
• dc.contributor.author Jonguitud-Borrego, Nestor
• dc.contributor.author Malci, Koray
• dc.contributor.author Sánchez Muñoz, Raúl, 1990-
• dc.contributor.author Palazón Barandela, Javier
• dc.contributor.author Rios-Solis, Leonardo
• dc.contributor.author Moyano Claramunt, Elisabet
• dc.date.accessioned 2024-11-13T07:08:21Z
• dc.date.available 2024-11-13T07:08:21Z
• dc.date.issued 2024
• dc.description.abstract 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.
• dc.description.sponsorship This research was supported by Agencia Estatal de Investigación REF: PID2020-113438RBI00/AEI/10.13039/501100011033; the YLSY program of the Ministry of National Education of Turkey; the Mexican government's dependence CONACyT (Mexican National Council for Science and Technology) CVU: 675492 and CVU: 537962; the Engineering and Physical Sciences Research Council (Grant number: EP/R513209/1); the Royal Society (Grant Number: RSG\R1\180345) and the British Council (Grant Number: 527429894). Ainoa Escrich was supported by a fellowship from the University Pompeu Fabra.
• dc.format.mimetype application/pdf
• dc.identifier.citation Escrich A, Jonguitud-Borrego N, Malcı K, Sanchez-Muñoz R, Palazon J, Rios-Solis L, et al. A novel step towards the heterologous biosynthesis of paclitaxel: Characterization of T1βOH taxane hydroxylase. Metab Eng. 2024 Sep;85:201-12. DOI: 10.1016/j.ymben.2024.08.005
• dc.identifier.doi http://dx.doi.org/10.1016/j.ymben.2024.08.005
• dc.identifier.issn 1096-7176
• dc.identifier.uri http://hdl.handle.net/10230/68508
• dc.language.iso eng
• dc.publisher Elsevier
• dc.relation.ispartof Metab Eng. 2024 Sep;85:201-12
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-113438RBI00
• dc.rights © 2024 The Authors. Published by Elsevier Inc. on behalf of International Metabolic Engineering Society. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Enzyme characterization
• dc.subject.keyword Heterologous production
• dc.subject.keyword Paclitaxel
• dc.subject.keyword T1βOH
• dc.subject.keyword Taxane hydroxylase
• dc.subject.keyword Yeast consortia
• dc.title A novel step towards the heterologous biosynthesis of paclitaxel: Characterization of T1βOH taxane hydroxylase
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion