The predominance of nucleotidyl activation in bacterial phosphonate biosynthesis.
Kyle RiceKissa BatulJacqueline WhitesideJayne KelsoMonica PapinskiEdward SchmidtAlena PratasouskayaDacheng WangRebecca SullivanChristopher K BartlettJoel T WeadgeMarc W Van der KampMoreno-Gabriel HagelsiebMichael D L SuitsGeoff P HorsmanPublished in: Nature communications (2019)
Phosphonates are rare and unusually bioactive natural products. However, most bacterial phosphonate biosynthetic capacity is dedicated to tailoring cell surfaces with molecules like 2-aminoethylphosphonate (AEP). Although phosphoenolpyruvate mutase (Ppm)-catalyzed installation of C-P bonds is known, subsequent phosphonyl tailoring (Pnt) pathway steps remain enigmatic. Here we identify nucleotidyltransferases in over two-thirds of phosphonate biosynthetic gene clusters, including direct fusions to ~60% of Ppm enzymes. We characterize two putative phosphonyl tailoring cytidylyltransferases (PntCs) that prefer AEP over phosphocholine (P-Cho) - a similar substrate used by the related enzyme LicC, which is a virulence factor in Streptococcus pneumoniae. PntC structural analyses reveal steric discrimination against phosphocholine. These findings highlight nucleotidyl activation as a predominant chemical logic in phosphonate biosynthesis and set the stage for probing diverse phosphonyl tailoring pathways.