TY  - JOUR
Y1  - 2024/09/01/
A1  - Escrich, A
A1  - Jonguitud-Borrego, N
A1  - Malci, K
A1  - Sanchez-Muñoz, R
A1  - Palazon, J
A1  - Rios-Solis, L
A1  - Moyano, E
PB  - Elsevier BV
EP  - 212
JF  - Metabolic Engineering
AV  - public
ID  - discovery10200105
SN  - 1096-7176
N1  - © 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/).
VL  - 85
N2  - 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, T5?Ac-1?,10?-diol, but also achieved the biosynthesis of paclitaxel precursors at an unprecedented yield including T5?Ac-1?,10?-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 T1?OH 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.
TI  - A novel step towards the heterologous biosynthesis of paclitaxel: Characterization of T1?OH taxane hydroxylase
KW  - Enzyme characterization
KW  -  Heterologous production
KW  -  Paclitaxel
KW  -  T1?OH
KW  -  Taxane hydroxylase
KW  -  Yeast consortia
KW  -  Paclitaxel
KW  -  Saccharomyces cerevisiae
KW  -  Mixed Function Oxygenases
KW  -  Molecular Docking Simulation
KW  -  Metabolic Engineering
KW  -  Taxoids
KW  -  Bridged-Ring Compounds
UR  - http://dx.doi.org/10.1016/j.ymben.2024.08.005
SP  - 201
ER  -