Current advances in the biotechnological synthesis of betulinic acid: new findings and practical applications

Betulinic acid (BA), a penta-cyclic triterpenoid found as a ubiquitous secondary metabolite throughout the plant kingdom, has aroused tremendous interests due to its different pharmacological properties, which lead to large market demand. However, the content of BA in plant is low for phytoextraction. Although chemical semi-synthesis or biotransformation of BA from betulin with high conversion efficiency is achieved, it still relies on phytoextraction from the bark of medicinal trees. To circumvent this issue, the biotechnological synthesis of BA in engineered yeasts has been developed. In this review, the pharmacological properties of BA are first summarized, including antitumor, anti-HIV, antiprotozoal, anti-inflammatory, apoptosis activator and anti-metabolic syndrome. Then, the traditional phytoextraction, semi-synthesis and biotechnological synthesis of BA are discussed. Particularly, current advances in its biotechnological synthesis and strategies to improve BA production are focused. Moreover, potential strategies for further promotion of BA yield, including the introduction of artificial isopentenol utilization pathway, semi-rational mutagenesis of lupeol synthase and cytochrome P450, and subcellular morphology and compartmentalization, are discussed.