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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actinobacteria
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Aminoethylphosphonic Acid / metabolism*
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Bacteria / genetics
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Bacteria / metabolism*
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Bacterial Proteins / genetics
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Bacterial Proteins / metabolism*
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Biosynthetic Pathways / physiology*
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Cell Wall / metabolism
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Crystallization
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Crystallography, X-Ray
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Escherichia coli
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N-Acylneuraminate Cytidylyltransferase / genetics
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N-Acylneuraminate Cytidylyltransferase / metabolism*
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Nucleotidyltransferases / genetics
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Nucleotidyltransferases / metabolism
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Organophosphonates / metabolism*
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Phospholipids / metabolism
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Phosphorylcholine / metabolism
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Phosphotransferases (Phosphomutases)
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Polysaccharides / metabolism
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Substrate Specificity
Substances
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Bacterial Proteins
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Organophosphonates
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Phospholipids
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Polysaccharides
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phosphonolipids
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Phosphorylcholine
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Aminoethylphosphonic Acid
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Nucleotidyltransferases
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N-Acylneuraminate Cytidylyltransferase
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Phosphotransferases (Phosphomutases)
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phosphoenolpyruvate mutase
Supplementary concepts
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Atopobium rimae
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Olsenella uli