Recent Advances in the Biosynthesis and Biotechnological Production of Taxol

Yuxun Zhu; Feiyan Liang; Pengpei Chai; Sotirios C. Kampranis; Yong Zhao

doi:10.1016/j.eng.2025.12.018

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Recent Advances in the Biosynthesis and Biotechnological Production of Taxol

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Abstract

Taxol (paclitaxel), a widely used chemotherapeutic agent, was originally isolated from the bark of Taxus brevifolia. However, its extremely low natural abundance has prompted the development of alternative production methods. Currently, the predominant commercial strategy relies on semi-synthesis from a more abundant precursor, 10-deacetyl-baccatin III, extracted from the needles of various Taxus species. Advances in synthetic biology are opening promising new avenues for more sustainable and scalable Taxol production. Recent progress, including the discovery of a nuclear transport factor 2 (NTF2)-like protein FoTO1, the characterization of a series of oxetane-forming P450 enzymes, and the identification of taxoid-2 ′-oxoglutarate-dependent dioxygenase (T2 ′ OGD) and taxoid-3 ′-N-benzoyl-transferase (T3 ′ NBT) responsible for C2 ′ a-hydroxylation and 3 ′-N benzoylation, has greatly advanced our understanding of the Taxol biosynthetic pathway and enabled its reconstitution in both plant and microbial hosts. In this review, we summarize recent progress in defining the Taxol biosynthetic pathway and highlight synthetic biology strategies with the greatest potential to support reliable and sustainable production of this essential anticancer agent.

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Taxol / Biosynthetic pathway / Synthetic biology / Metabolic engineering

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Yuxun Zhu, Feiyan Liang, Pengpei Chai, Sotirios C. Kampranis, Yong Zhao. Recent Advances in the Biosynthesis and Biotechnological Production of Taxol. Engineering 202512018 DOI:10.1016/j.eng.2025.12.018

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References

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[1]	Stock CC, Reilly HC, Buckley SM, Clarke DA, Rhodas CP. Azaserine, a new tumour-inhibitory substance: studies with crocker mouse sarcoma 180. Nature 1954; 173(4393):71-2.

[2]	Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly in vitro by Taxol. Nature 1979; 277(5698):665-7.

[3]	Schiff PB, Horwitz SB. Taxol stabilizes microtubules in mouse fibroblast cells. Proc Natl Acad Sci 1980; 77(3):1561-5.

[4]	Amos LA, Lowe J. How Taxol stabilises microtubule structure. Chem Biol 1999; 6(3):R65-9.

[5]	Amato I. Chemists vie to make a better Taxol. Science 1992; 256(5055):311.

[6]	Nadeem M, Rikhari HC, Kumar A, Palni LMS, Nandi SK. Taxol content in the bark of Himalayan yew in relation to tree age and sex. Phytochemistry 2002; 60(6):627-31.

[7]	Schneider F, Samarin K, Zanella S, Gaich T. Total synthesis of the complex taxane diterpene canataxpropellane. Science 2020; 367(6478):676-81.

[8]	Danishefsky SJ, Masters JJ, Young WB, Link JT, Snyder LB, Magee TV, et al. Total synthesis of baccatin III and Taxol. J Am Chem Soc 1996; 118(12):2843-59.

[9]	Nicolaou KC, Yang Z, Liu JJ, Ueno H, Nantermet PG, Guy RK, et al. Total synthesis of Taxol. Nature 1994; 367(6464):630-4.

[10]	Hu YJ, Gu CC, Wang XF, Min L, Li CC. Asymmetric total synthesis of Taxol. J Am Chem Soc 2021; 143(42):17862-70.

[11]	Watanabe T, Oga K, Matoba H, Nagatomo M, Inoue M. Total synthesis of Taxol enabled by intermolecular radical coupling and Pd-catalyzed cyclization. J Am Chem Soc 2023; 145(47):25894-902.

[12]	Baloglu E, Kingston D. A new semisynthesis of paclitaxel from baccatin III. J Nat Prod 1999; 62(7):1068-71.

[13]	Galanie S, Thodey K, Trenchard IJ, Filsinger Interrante M, Smolke CD. Complete biosynthesis of opioids in yeast. Science 2015; 349(6252):1095-100.

[14]	Luo X, Reiter MA, d’Espaux L, Wong J, Denby CM, Lechner A, et al. Complete biosynthesis of cannabinoids and their unnatural analogues in yeast. Nature 2019; 567(7746):123-6.

[15]	Zhao Y, Hansen NL, Duan YT, Prasad M, Motawia MS, Møller BL, et al. Biosynthesis and biotechnological production of the anti-obesity agent celastrol. Nat Chem 2023; 15(9):1236-46.

[16]	Zhang J, Hansen LG, Gudich O, Viehrig K, Lassen LMM, Schrübbers L, et al. A microbial supply chain for production of the anti-cancer drug vinblastine. Nature 2022; 609(7926):341-7.

[17]	Xiong X, Gou J, Liao Q, Li Y, Zhou Q, Bi G, et al. The Taxus genome provides insights into paclitaxel biosynthesis. Nat Plant 2021; 7(8):1026-36.

[18]	Cheng J, Wang X, Liu X, Zhu X, Li Z, Chu H, et al. Chromosome-level genome of Himalayan yew provides insights into the origin and evolution of the paclitaxel biosynthetic pathway. Mol Plant 2021; 14(7):1199-209.

[19]	Jiang B, Gao L, Wang H, Sun Y, Zhang X, Ke H, et al. Characterization and heterologous reconstitution of Taxus biosynthetic enzymes leading to baccatin III. Science 2024; 383(6683):622-9.

[20]	Li C, Yin X, Wang S, Sui S, Liu J, Sun X, et al. A cytochrome P450 enzyme catalyses oxetane ring formation in paclitaxel biosynthesis. Angew Chem Int Ed 2024; 63(31):e202407070.

[21]	Yang C, Wang Y, Su Z, Xiong L, Wang P, Lei W, et al. Biosynthesis of the highly oxygenated tetracyclic core skeleton of Taxol. Nat Commun 2024; 15(1):2339.

[22]	Zhao Y, Liang F, Xie Y, Duan YT, Andeadelli A, Pateraki I, et al. Oxetane ring formation in Taxol biosynthesis is catalyzed by a bifunctional cytochrome P450 enzyme. J Am Chem Soc 2024; 146(1):801-10.

[23]	McClune CJ, Liu J-C-T, Wick C, De La Peña R, Lange BM, Fordyce PM, et al. Discovery of FoTO1 and Taxol genes enables biosynthesis of baccatin III. Nature 2025; 643:582-92.

[24]	Liang F, Xie Y, Zhang C, Zhao Y, Motawia MS, Kampranis SC. Elucidation of the final steps in Taxol biosynthesis and its biotechnological production. Nat Synth 2025; 4:1212-22.

[25]	Xie L, Gao J, Zhou YJ. Synthetic biology for Taxol biosynthesis and sustainable production. Trends Biotechnol 2024; 42(6):674-6.

[26]	Zhang Y, Wiese L, Fang H, Alseekh S, Perez de Souza L, Scossa F, et al. Synthetic biology identifies the minimal gene set required for paclitaxel biosynthesis in a plant chassis. Mol Plant 2023; 16(12):1951-61.

[27]	Zhong J, Wang Y, Chen Z, Yalikun Y, He L, Liu T, et al. Engineering cyanobacteria as a new platform for producing Taxol precursors directly from carbon dioxide. Biotechnol Biof Biop 2024; 17(1):99.

[28]	Chen Q, Xin Q, Dong S, Ge X, Men X, Zhang H. Recent advances and perspectives in biosynthesis of paclitaxel: key enzymes and intermediates. Int J Biol Macromol 2025; 331(1):148049.

[29]	Hezari M, Lewis NG, Croteau R. Purification and characterization of taxa-4(5),11(12)-diene synthase from pacific yew (Taxus brevifolia) that catalyzes the first committed step of Taxol biosynthesis. Arch Biochem Biophys 1995; 322(2):437-44.

[30]	Lin X, Hezari M, Koepp AE, Floss HG, Croteau R. Mechanism of taxadiene synthase, a diterpene cyclase that catalyzes the first step of Taxol biosynthesis in pacific yew. Biochemistry 1996; 35(9):2968-77.

[31]	Wang YF, Shi QW, Dong M, Kiyota H, Gu YC, Cong B. Natural taxanes: developments since 1828. Chem Rev 2011; 111(12):7652-709.

[32]	Sagwan-Barkdoll L, Part III AA. Taxadiene-5a-ol is a minor product of CYP725A4 when expressed in Escherichia coli. Biotech App Biochem 2017; 65(3):294-305.

[33]	Jennewein S, Long RM, Williams RM, Croteau R. Cytochrome P450 taxadiene 5a-hydroxylase, a mechanistically unusual monooxygenase catalyzing the first oxygenation step of Taxol biosynthesis. Chem Biol 2004; 11(3):379-87.

[34]	Köksal M, Jin Y, Coates RM, Croteau R, Christianson DW. Taxadiene synthase structure and evolution of modular architecture in terpene biosynthesis. Nature 2011; 469(7328):116-20.

[35]	Guerra-Bubb J, Croteau R, Williams RM. The early stages of Taxol biosynthesis: an interim report on the synthesis and identification of early pathway metabolites. Nat Prod Rep 2012; 29(6):683-96.

[36]	Hefner J, Rubenstein SM, Ketchum REB, Gibson DM, Williams RM, Croteau R. Cytochrome P450-catalyzed hydroxylation of taxa-4(5),11(12)-diene to taxa-4(20),11(12)-dien-5a-o1: the first oxygenation step in Taxol biosynthesis. Chem Biol 1996; 3(6):479-529.

[37]	Jennewein S, Rithner CD, Williams RM, Croteau RB. Taxol biosynthesis: taxane 13a-hydroxylase is a cytochrome P450-dependent monooxygenase. Proc Natl Acad Sci USA 2001; 98(24):13595-600.

[38]	Schoendorf A, Rithner CD, Williams RM, Croteau RB. Molecular cloning of a cytochrome P450 taxane 10b-hydroxylase cDNA from Taxus and functional expression in yeast. Proc Natl Acad Sci USA 2001; 98(4):1501-6.

[39]	Jennewein S, Rithner CD, Williams RM, Croteau R. Taxoid metabolism: taxoid 14b-hydroxylase is a cytochrome P450-dependent monooxygenase. Arch Biochem Biophys 2003; 413(2):262-70.

[40]	Chau M, Croteau R. Molecular cloning and characterization of a cytochrome P450 taxoid 2a-hydroxylase involved in Taxol biosynthesis. Arch Biochem Biophys 2004; 427(1):48-57.

[41]	Chau M, Jennewein S, Walker K, Croteau R. Taxol biosynthesis: molecular cloning and characterization of a cytochrome p450 taxoid 7b-hydroxylase. Chem Biol 2004; 11(5):663-72.

[42]	Edgar S, Li FS, Qiao K, Weng JK, Stephanopoulos G. Engineering of taxadiene synthase for improved selectivity and yield of a key Taxol biosynthetic intermediate. ACS Synth Biol 2017; 6(2):201-5.

[43]	Iohannes S, Jackson D. Tackling redundancy: genetic mechanisms underlying paralog compensation in plants. New Phytol 2023; 240:1381-9.

[44]	Walker K, Croteau R. Taxol biosynthesis: molecular cloning of a benzoyl-CoA: taxane 2a-o-benzoyltransferase cDNA from Taxus and functional expression in Escherichia coli. Proc Natl Acad Sci USA 2000; 97(25):13591-6.

[45]	Jing L, Zhi M, Mizuno M, Tanaka T, Iinuma M. Two taxane diterpenes from Taxus mairei. Phytochemistry 1988; 27(11):3674-5.

[46]	Appendino G, Cravotto G, Enriù R, Gariboldi P, Barboni L, Torregiani E, et al. Taxoids from the roots of Taxus × media cv. Hicksii. J Nat Prod 1994; 57(5):607-23.

[47]	Ondari ME, Walker KD. The Taxol pathway 10-O-acetyltransferase shows regioselective promiscuity with the oxetane hydroxyl of 4-deacetyltaxanes. J Am Chem Soc 2008; 130(50):17187-94.

[48]	Hodgson H, Stephenson MJ, Kikuchi S, Martin LBB, Liu JCT, Casson R, et al. Plants utilize a protection/deprotection strategy in limonoid biosynthesis: a “missing link” carboxylesterase boosts yields and provides insights into furan formation. J Am Chem Soc 2024; 146(43):29305-10.

[49]	Walker KD, Klettke K, Akiyama T, Croteau R. Cloning, heterologous expression, and characterization of a phenylalanine aminomutase involved in Taxol biosynthesis. J Biol Chem 2004; 279(52):53947-54.

[50]	Walker K, Fujisaki S, Long R, Croteau R. Molecular cloning and heterologous expression of the C-13 phenylpropanoid side chain-CoA acyltransferase that functions in Taxol biosynthesis. Proc Natl Acad Sci USA 2002; 99(20):12715-20.

[51]	Ramírez-Estrada K, Altabella T, Onrubia M, Moyano E, Notredame C, Osuna L, et al. Transcript profiling of jasmonate-elicited Taxus cells reveals a β-phenylalanine-CoA ligase. Plant Biotechnol J 2016; 14(1):85-96.

[52]	Kingston DGI. The shape of things to come: structural and synthetic studies of Taxol and related compounds. Phytochemistry 2007; 68(14):1844-54.

[53]	Sanchez-Muñoz R, Perez-Mata E, Almagro L, Cusido RM, Bonfill M, Palazon J, et al. A novel hydroxylation step in the taxane biosynthetic pathway: a new approach to paclitaxel production by synthetic biology. Front Bioeng Biotechnol 2020; 8:410.

[54]	Markolovic S, Wilkins SE, Schofield CJ. Protein hydroxylation catalyzed by 2-oxoglutarate-dependent oxygenases. J Biol Chem 2015; 290(34):20712-22.

[55]	Walker K, Long R, Croteau R. The final acylation step in Taxol biosynthesis: cloning of the taxoid C13-side-chain N-benzoyltransferase from Taxus. Proc Natl Acad Sci USA 2002; 99(14):9166-71.

[56]	Long RM, Lagisetti C, Coates RM, Croteau RB. Specificity of the N-benzoyl transferase responsible for the last step of Taxol biosynthesis. Arch Biochem Biophys 2008; 477(2):384-9.

[57]	Cusidó RM, Palazón J, Bonfill M, Navia-Osorio A, Morales C, Piñol MT. Improved paclitaxel and baccatin III production in suspension cultures of Taxusmedia. Biotechnol Progr 2002; 18(3):418-23.

[58]	Sabater-Jara AB, Onrubia M, Moyano E, Bonfill M, Palazón J, Pedreño MA, et al. Synergistic effect of cyclodextrins and methyl jasmonate on taxane production in Taxus x media cell cultures. Plant Biotechnol J 2014; 12(8):1075-84.

[59]	Perez-Matas E, Hidalgo-Martinez D, Moyano E, Palazon J, Bonfill M. Overexpression of BAPT and DBTNBT genes in Taxus baccata in vitro cultures to enhance the biotechnological production of paclitaxel. Plant Biotechnol J 2024; 22(1):233-47.

[60]	Fu J, Xu W, Huang W, Wang B, Li S, Zhang J, et al. Importation of taxadiene synthase into chloroplast improves taxadiene production in tobacco. Planta 2021; 253(5):107.

[61]	Li J, Mutanda I, Wang K, Yang L, Wang J, Wang Y. Chloroplastic metabolic engineering coupled with isoprenoid pool enhancement for committed taxanes biosynthesis in Nicotiana benthamiana. Nat Commun 2019; 10(1):4850.

[62]	De La Peña R, Sattely ES. Rerouting plant terpene biosynthesis enables momilactone pathway elucidation. Nat Chem Biol 2021; 17(2):205-12.

[63]	Ajikumar PK, Xiao WH, Tyo KEJ, Wang Y, Simeon F, Leonard E, et al. Isoprenoid pathway optimization for Taxol precursor overproduction in Escherichia coli. Science 2010; 330(6000):70-4.

[64]	Malci K, Santibáñez R, Jonguitud-Borrego N, Santoyo-Garcial J, Kerkhoven E, Rios-Solis L. Improved production of Taxol® precursors in S. cerevisiae using combinatorial in silico design and metabolic engineering. Microb Cell Fact 2023; 22:243.

[65]	Kovacs K, Zhang L, Linforth RST, Whittaker B, Hayes CJ, Fray RG. Redirection of carotenoid metabolism for the efficient production of taxadiene [taxa-4(5),11(12)-diene] in transgenic tomato fruit. Transgenic Res 2007; 16(1):121-6.

[66]	Gao J, Gou Y, Huang L, Lian J. Reconstitution and optimization of complex plant natural product biosynthetic pathways in microbial expression systems. Curr Opin Biotechnol 2024; 87:103136.

[67]	Huang Q, Roessner CA, Croteau R, Scott AI. Engineering Escherichia coli for the synthesis of taxadiene, a key intermediate in the biosynthesis of Taxol. Bioorgan Med Chem 2001; 9(9):2237-42.

[68]	Wang J, Ji X, Yi R, Li D, Shen X, Liu Z, et al. Heterologous biosynthesis of terpenoids in Saccharomyces cerevisiae. Biotechnol J 2025; 20:e202400712.

[69]	Ding Y, Ning Y, Xin D, Fu Y. Dual cytoplasmic-peroxisomal compartmentalization engineering and multiple metabolic engineering strategies for high yield non-psychoactive cannabinoid in Saccharomyces cerevisiae. Biotechnol J 2024; 19:2300590.

[70]	Chen R, Gao J, Yu W, Chen X, Zhai X, Chen Y, et al. Engineering cofactor supply and recycling to drive phenolic acid biosynthesis in yeast. Nat Chem Biol 2022; 18(5):520-9.

[71]	Dusséaux S, Wajn WT, Liu YX, Ignea C, Kampranis SC. Transforming yeast peroxisomes into microfactories for the efficient production of high-value isoprenoids. Proc Natl Acad Sci USA 2020; 117(50):31789-99.

[72]	Yuan JF, Ching CB. Mitochondrial acetyl-CoA utilization pathway for terpenoid productions. Metab Eng 2016; 38:303-9.

[73]	Farhi M, Marhevka E, Masci T, Marcos E, Eyal Y, Ovadis M, et al. Harnessing yeast subcellular compartments for the production of plant terpenoids. Metab Eng 2011; 13(5):474-81.

[74]	Hammer SK, Avalos JL. Harnessing yeast organelles for metabolic engineering. Nat Chem Biol 2017; 13(8):823-32.

[75]	Dahl RH, Zhang F, Alonso-Gutierrez J, Baidoo E, Batth TS, Redding-Johanson AM, et al. Engineering dynamic pathway regulation using stress-response promoters. Nat Biotechnol 2013; 31(11):1039-46.

[76]	Qian S, Cirino PC. Using metabolite-responsive gene regulators to improve microbial biosynthesis. Curr Opin Chem Eng 2016; 14:93-102.

[77]	Gou YW, Li DF, Zhao MH, Li MX, Zhang JJ, Zhou YL, et al. Intein-mediated temperature control for complete biosynthesis of sanguinarine and its halogenated derivatives in yeast. Nat Commun 2024; 15(1):5238.

[78]	Yuan JF, Ching CB. Dynamic control of ERG 9 expression for improved amorpha-4,11-diene production in Saccharomyces cerevisiae. Microb Cell Fact 2015; 14:38.

[79]	Srinivasan P, Smolke CD. Biosynthesis of medicinal tropane alkaloids in yeast. Nature 2020; 585(7826):614-9.

[80]	Zhou K, Qiao K, Edgar S, Stephanopoulos G. Distributing a metabolic pathway among a microbial consortium enhances production of natural products. Nat Biotechnol 2015; 33(4):377-83.

[81]	Brooks SM, Marsan C, Reed KB, Yuan SF, Nguyen DD, Trivedi A, et al. A tripartite microbial co-culture system for de novo biosynthesis of diverse plant phenylpropanoids. Nat Commun 2023; 14(1):4448.

[82]	Chen RB, Chen XH, Chen Y, Yang JD, Chen WS, Zhou YJ, et al. De novo biosynthesis of plant lignans by synthetic yeast consortia. Nat Chem Biol 2025; 21:1487-96.