Natural products, organic compounds produced by microorganisms, plants, and animals, exhibit a wide range of biological activities and have been an attractive and rich source of compounds for drug discovery, providing many important pharmaceuticals. However, since a high number of compounds have been already isolated and characterized, it has become more and more difficult to discover novel natural products with conventional approaches. Thus, completely new strategies are now urgently needed to obtain new and useful molecules. We aim to expand the diversity of natural products and seek to design metabolic pathways to afford useful compounds using several different approaches.
1. Elucidation of the biosynthesis of complex/bioactive natural products
Elucidating the biosynthetic pathway of natural products is important for expanding the natural products diversity because of two aspects; biosynthetic studies often lead to 1) isolation of biosynthetic intermediates that are previously undescribed and 2) discovery of enzymes responsible for intriguing chemical transformations, which could further be used as a biocatalyst to perform difficult reactions in terms of organic synthesis. Given the structural complexity and diversity of natural products, it is suggested that many fascinating biosynthetic enzymes and reactions have yet to be discovered. Thus, we could further expand our repertoire of biosynthetic transformations from biosynthetic studies. We especially focus on compounds with highly complex molecular skeleton with expectation that unexploited reactions could be unveiled. To this end, a multidisciplinary approach are undertaken, including expressing biosynthetic genes in a heterologous host, genome-editing technology-guided engineering of microorganism, and biochemical characterization of biosynthetic enzymes.
Representative examples
2. Genomics-driven discovery and derivatization of natural products
Recent advances in genome sequencing technologies have allowed us to access the whole genome data of many microorganisms, which not only enables the rapid discovery of genes responsible for natural products biosynthesis (“biosynthetic gene clusters”) but also have indicated that microorganisms have many more biosynthetic genes than previously expected. We seek to obtain new compounds by activating or heterologously reconstituting gene clusters that are less similar to well-characterized ones.
Furthermore, as many genome sequence data have been available, similar but somewhat different gene clusters from that for a known compound can now be found in many other organisms. We are trying to establish a new approach to construct artificial pathways by utilizing a series of enzymes working on the same scaffold to afford new analogues with better activity than the original natural product.
Representative examples
3. Generation and evolution of “unnatural” natural product pathways
In addition to above-mentioned two approaches, we are trying to ab initio generate a metabolic pathway or to drastically engineer an existing pathway for new compounds discovery.
