Friedelin in plants: metabolism, synthase engineering and production strategies

Friedelin (FD) is a pentacyclic triterpenoid with significant pharmacological potential and serves as the biosynthetic precursor to the anti-obesity drug celastrol. Despite its value, FD availability is limited by low natural abundance and the stereochemical complexity of chemical synthesis. This article critically reviews the state-of-the-art in FD research, spanning natural distribution, extraction methodologies, and the molecular basis of its biosynthesis. The structural evolution of friedelin synthases (FDSs), contrasting the mechanisms of multifunctional versus single-function enzymes, was analyzed. Furthermore, a comprehensive roadmap for sustainable production, integrating “Push-Block-Regulate-Store” metabolic engineering strategies with novel insights into transcriptional regulation, was provided. It is proposed that the convergence of AI-driven enzyme design, transporter engineering, and CRISPR-based precision breeding will overcome current yield bottlenecks, enabling the industrial-scale biomanufacturing of FD and its derivatives.