Research

 
 Discovering Untapped Natural Chemical Diversity with Genomics and Synthetic Biology 
 

Fungi are an important part of the nutrient cycle in the Earth ecosystem and they play important roles in many aspects of human life. In agriculture, they are a major cause for yield loss in crop due to diseases. Some fungi are also known to cause devastating diseases in human especially in immunocompromised individuals. At the same time, fungi have been used for thousands of years in the production of food and beverage. More recently in the human history, fungi are used as a source of industrial enzymes for pulp processing, detergent making, and biofuel production.
    
    Fungi produce bioactive small molecules known as secondary metabolites. These fungal secondary metabolites have been the source of medicines, including important clinical drugs, such as the antibiotic penicillin and the cholesterol-lowering statins. Some of these secondary metabolites are harmful to humans and they are known as mycotoxins. Occurrence of mycotoxins in pre- and post-harvest food crops poses significant health risk and economic loss. Fungal secondary metabolites have also been implicated as virulence mediators of plant and animal fungal diseases. However, their level of involvement and the mechanism are still poorly understood in most fungal pathogens of plants and animal. 

    The surge of microbial genomic information in recent years revealed that fungi encode for secondary metabolite biosynthetic potential that far surpasses the chemical diversity that we have previously appreciated. This not only presents immense opportunities for genome-based discovery of novel chemical entities but at the same time highlight our lack of understanding of the roles of secondary metabolites in fungal biology and ecology.

Extended Central Dogma for Microbial Secondary Metabolite Biosynthesis

    

To be able to efficiently tap into the biosynthetic capabilities of fungal genomes we have to answer these questions:

1. How do fungi do chemical synthesis?
2. What is the relationship between SM structure and DNA sequences?
3. How do fungi control when and where to produce SMs?
4. How can we efficiently translate genomic information to molecules?

    Thus, a core part of the research in our lab is focusing on establishing the link between genes and secondary metabolites and understanding the biosynthetic mechanism using various molecular genetic, biochemistry and synthetic biology tools. Besides fueling bioactive molecule discovery, many unique biosynthetic enzymes have been discovered in various fungal secondary metabolite pathways. Some of these have the potential to be developed into useful biocatalysts for chemical synthesis.

    Our work also deals with the biological aspects of secondary metabolism in fungi, in particular through establishing the genotype-to-chemotype link, we seek to uncover the role of secondary metabolites in host-pathogen interactions by integrating functional genomics (transcriptomics and metabolomics) and chemical ecology. This emerging integrated approach is termed "chemical ecogenomics".


Given that many of the secondary metabolites in animal and plant pathogens have been evolving to interact with their host, some of these bioactive molecules may be re-purposed as medicine or herbicides.