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Nat Commun. 2019 Aug 16;10(1):3698. doi: 10.1038/s41467-019-11627-6.

The predominance of nucleotidyl activation in bacterial phosphonate biosynthesis.

Author information

1
Department of Chemistry & Biochemistry, Wilfrid Laurier University, Waterloo, ON, N2L 3C5, Canada.
2
Department of Biology, Wilfrid Laurier University, Waterloo, ON, N2L 3C5, Canada.
3
School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK.
4
Department of Chemistry & Biochemistry, Wilfrid Laurier University, Waterloo, ON, N2L 3C5, Canada. ghorsman@wlu.ca.

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.

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