The predominance of nucleotidyl activation in bacterial phosphonate biosynthesis

Kyle Rice, Kissa Batul, Jaqueline Whiteside, Jayne Kelso, Monica Papinski, Edward Schmidt, Alena Pratasouskaya, Dacheng Wang, Rebecca Sullivan, Christopher Bartlett, Joel Weadge, Marc Van der Kamp, Gabriel Moreno-Hagelsieb, Michael Suits, Geoff Horsman

Research output: Contribution to journalArticle (Academic Journal)

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Abstract

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.
Original languageEnglish
Article number3698 (2019)
Number of pages12
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 16 Aug 2019

Keywords

  • Biosynthesis
  • Transferases
  • X-ray crystallography

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