Natural products are closely related to the long-term development history of natural sciences, and also important sources of clinically used drugs, especially in anticancer and antiinfection aspects. Along with the developing of diseases, many new challenges in disease treatment have been met, making innovative drugs with new chemical structures and new mode-of-actions in urgent needs. In point of innovative drug development, natural products have been, and are still playing irreplaceable roles in drug-lead discovery. We focus our research interests on the discovery and biosynthesis of natural pharmaceutical molecules, and carry out several main researches below:

1. Discovery of new natural pharmaceutical molecules. After several years’efforts, we have constructed a bacteria library with >4,000 bacteria including >3,400 marine bacteria isolated from marine sponges, corals, and sea deposits, and >700 terrestrial bacteria isolated from medicinal plants and soils. By means of chemotype analyses, genome mining, and heterologous expression of gene clusters, we discover new natural products from the bacteria library, and screen for pharmaceutical molecules under the guidance of biological assays.

2. Characterization of catalytic functions and mechanisms of key biosynthetic enzymes in natural product biosynthesis. The central issue in natural product biosynthesis is characterizing the catalytic functions and mechanisms of biosynthetic enzymes. We characterize enzymatic functions by gene-deletion and reconstitution of catalysis in vitro, and uncover the catalytic mechanisms based on enzyme structures (crystal structures, cryo-EM structures, and solution NMR structures), site-directed mutagenesis, reaction energy calculation, etc. Our group have gained achievements in determining crystal structures of various biosynthetic enzymes in recent years. Currently, we are not only interested in biosynthetic enzymes for natural products from our bacteria library, but also those for natural products from gut bacteria, medicinal plants and animals.

3. Biosynthetic enzyme engineering and new product creation. Based on the enzyme structure and catalytic mechanism, we engineer biosynthetic enzymes by means of key residue mutation and sequence replacement to rationally change the substrate selectivity and product profile, thereby creating new molecules with expanded structural diversity and improved druggability. This can provide enzymatic tools for preparing complex pharmaceutical molecules that cannot be feasibly generated by chemical synthesis.

4. Synthetic biology production of pharmaceutical molecules. Towards highly valuable natural pharmaceutical molecules and their derivatives, we construct non-natural biosynthetic pathways by rational combination of biosynthetic enzymes, to achieve highly efficient productions based on suitable heterologous host cell chassis.

By carrying out researches mentioned above, we reveal novel phenomenons and mechanisms underneath natural product biosynthesis, and provide solutions for drug-lead discovery and scale-production during innovative drug development.