Using branch point inventories to identify new biosynthetic pathways Geoff Horsman Wilfrid Laurier University, Canada Microbially-produced phosphonates are an underexplored class of natural products but include medically and agriculturally important molecules like fosfomycin and phosphinothricin, respectively. Because a single enzyme called phosphoenolpyruvate mutase (Ppm) initiates almost all phosphonate production, the composition of the ppm gene neighborhood can inform hypotheses regarding its chemical output. After the initial Ppm-catalyzed reaction there are only a limited set of subsequently acting enzymes, or ‘branch points’, to direct these early- stage phosphonates to alternate chemical fates. However, the relative abundance of different branch points – or the existence of new ones – has not been evaluated. Here we describe a ‘branch point inventory’ to determine relative proportions of known branch points and assess the diversity within each branch point. Significantly, this study suggests that a significant proportion (~13%) of gene neighborhoods do not fit into known branch points and therefore may be fertile hunting grounds for new phosphonate biochemistry. Sequence similarity network analysis revealed families of unusual gene neighborhoods including possible production of phosphonoacrylate and phosphonofructose, the apparent biosynthetic use of the C-P lyase operon, and a virus-encoded phosphonate. Overall, these results highlight the utility of branch point inventories to identify novel gene neighborhoods and guide future phosphonate discovery efforts. References 1. Li S, Horsman GP (2022)An inventory of early branch points in microbial phosphonate biosynthesis Microbial Genomics , 8:000781
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