Discovery and Biosynthesis of Terpenoid Natural Products

Terpenoids, as the largest family of secondary metabolites in nature, exhibit remarkable structural diversity and a wide range of biological activities, making them an important resource reservoir for new drug development. This research is dedicated to deciphering the biosynthetic mechanisms of terpenoid molecules, providing fundamental support for drug development.

Terpene synthases and oxidases are key enzymes that determine the structure and function of terpenoids. A comprehensive understanding of the structure and mechanism of these enzymes not only reveals the molecular basis of terpenoid diversity in nature and provides novel enzymatic tools for synthetic biology and biocatalysis. By elucidating the catalytic mechanisms of these key enzymes, we can achieve artificial intervention and redesign of natural product biosynthetic pathways, creating molecules with novel skeletons or activities. Our research group has achieved a series of breakthroughs in the structural resolution and catalytic mechanism research of terpenoid cyclases and oxidases.

Synthetic Biology to Overproduce High-Value Terpenoids

High-value functional terpenoid molecules often possess complex structures and superior pharmacological activities, but their natural sources are scarce, and traditional extraction methods can hardly meet industrial production demands. Synthetic biology provides an innovative approach to solve this bottleneck, enabling green, efficient, and sustainable production by reconstructing biosynthetic pathways in microbial hosts.

Compared to traditional chemical synthesis, biosynthesis processes occur under mild conditions, reducing the use of harmful solvents and waste generation, in line with green chemistry principles. More importantly, through modern enzyme engineering and metabolic engineering approaches, we can achieve precise regulation of synthetic pathways, not only improving target product yields but also generating analogues that are rare or non-existent in nature, expanding compound library diversity. This research direction closely combines basic scientific research with industrial applications, promising to drive innovative applications of biomanufacturing technology in the pharmaceutical field. Our research group has successfully constructed several efficient terpenoid precursor supply platforms, achieving microbial synthesis of various high-value terpenoid molecules.

Chemoenzymatic Synthesis and Drug Development of Pentacyclic Triterpenoids

Pentacyclic triterpenoids are widely distributed in plants and fungi, exhibiting various biological activities such as anti-tumor, anti-inflammatory, and anti-viral properties, making them important drug leads. However, their structural complexity makes it difficult to achieve efficient and selective structural modifications through traditional chemical synthesis methods.

The chemoenzymatic synthesis combines the efficiency of chemical synthesis with the high selectivity of biocatalysis, providing a unique strategy for modifying complex natural products. This innovative method offers significant advantages in drug molecule optimization: it can selectively modify sites that are difficult to acheive by traditional chemical methods; it can be carried out under mild conditions, avoiding the use of toxic reagents; and it can generate unique derivative libraries, expanding the structural diversity of lead compounds. Through this strategy, the pharmacodynamic properties of pentacyclic triterpenoids can be systematically optimized, their pharmacokinetic properties improved, ultimately developing novel drugs with clinical application prospects. Our research group are developing multiple chemoenzymatic strategies for selective modification of pentacyclic triterpenoids, constructing multiple novel derivatives with significant biological activities.