Primary metabolism supports essential chemical processes of living organisms, and is highly conserved among all life forms. In contrast, specialized metabolism contributes to the fitness of its host in specific abiotic and biotic environments, and distributes taxonomically along the evolving tree of life. We seek to understand how complex specialized metabolites are biosynthesized through an assembly line of specialized enzymes, why these specialized metabolic traits are relevant to their hosts under ecological niches, and how these complex pathways could have evolved in a Darwinian fashion.
Operons, defined as genomic DNA units containing a cluster of genes (often functioning in the same pathway) under the control of the same promoter, are widespread in prokaryotic genomes. Conveniently for biochemists, this feature has facilitated de novo metabolic pathway discoveries in prokaryotic systems in the past decades. However, in eukaryotes, metabolic genes of a particular pathway are often randomly scattered across the genome. As a result, it remains a major barrier for scientists to efficiently decode specialized metabolic pathways in a given eukaryotic host of interest with limited genetic tools. To overcome this difficulty, we have developed a gene-discovery workflow geared towards eukaryotic specialized metabolic systems, taking advantage of the fact that most of the specialized metabolites accumulate spatially and temporally under developmental control, and/or are elicited under unique conditions. Combining state-of-the-art metabolomics and genomics technologies, as well as bioinformatics, we can now quickly identify candidate enzyme-encoding genes underlying specific metabolites of interest. These candidate genes will then be functionally examined using more traditional experimental approaches both in vitro and in vivo (see the figure below).
Exploration of the largely untapped eukaryotic specialized metabolic systems not only will advance our understanding of the chemistry of life processes, but also will empower synthetic biologists to engineer microbial production of those high-value natural products of eukaryotic origin in the near future.