Toward Sustainable Paclitaxel Bioproduction: Plant Biology, Biosynthesis and Platform Engineering

Area of Science:

• Biochemistry
• Molecular Biology
• Chemical Engineering

Background:

• Paclitaxel (Taxol) is a vital anticancer chemotherapy agent derived from Taxus species.
• Its complex structure and limited supply due to precursor scarcity hinder widespread clinical use.
• The biosynthetic pathway involves 19-23 enzymatic steps, with key mechanistic questions, like oxetane ring formation, remaining.
• Heterologous biosynthesis is challenged by poor cytochrome P450 (CYP) expression and insufficient metabolic flux.

Purpose of the Study:

• To synthesize recent advances in understanding and engineering paclitaxel biosynthesis.
• To identify critical bottlenecks in complete heterologous production.
• To discuss strategies for overcoming these challenges.

Main Methods:

• Review of multi-omics approaches for pathway elucidation.
• Analysis of genomic and regulatory insights from Taxus species.
• Assessment of metabolic engineering strategies in microbial hosts (E. coli, S. cerevisiae) and plant-based platforms.
• Focus on CYP-mediated oxygenation and oxetane ring formation mechanisms.

Main Results:

• Significant progress in elucidating the paclitaxel biosynthetic pathway, particularly CYP-mediated steps.
• Genomic and regulatory data from Taxus species provide insights into pathway control.
• Metabolic engineering efforts show promise in microbial and plant systems, despite challenges.
• Key bottlenecks identified include unresolved enzymatic steps, CYP expression, flux, and scale-up.

Conclusions:

• Overcoming challenges in enzymatic steps, CYP expression, and metabolic flux is crucial for efficient heterologous paclitaxel production.
• Integrating advances in pathway elucidation, genomics, and metabolic engineering is key.
• Developing robust plant-based and microbial production platforms offers a sustainable solution for paclitaxel supply.