S141: Chemical discovery in the microbial world: identifying enzymes that construct unusual molecular architecture

Microbes have amazing chemical capabilities, performing chemical reactions unprecedented in organic synthesis and producing complex, biologically active molecules not easily accessed via total synthesis. The enzymatic transformations encoded in microbial genomes have the potential to completely change the way chemists make molecules. My lab is uncovering new microbial chemistry by developing methods for quickly identifying new enzymatic reactions from genome sequencing data. Starting from secondary metabolites with atypical structures or chemical functionality, we have used chemical knowledge to discover gene clusters encoding pathways that utilize new enzymatic transformations. Preliminary work on cylindrocyclophane F has revealed that a key macrocyclization step likely proceeds via an unusual direct oxidative C–C bond formation. Likewise, identification of the biosynthetic gene clusters responsible for producing several diazo-containing metabolites has revealed likely candidate enzymes for installation of this highly reactive group, resolving a longstanding mystery in biosynthesis. Functional and mechanistic characterization of biosynthetic enzymes from these pathways is revealing fundamentally new chemical reactivity with potential applications in biocatalysis and metabolic engineering.