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- W3144300192 abstract "Abstract Microbial phosphonate biosynthetic machinery has been identified in ~5% of bacterial genomes and encodes natural products like fosfomycin as well as cell surface decorations. Almost all biological phosphonates originate from the rearrangement of phosphoenolpyruvate (PEP) to phosphonopyruvate (PnPy) catalyzed by PEP mutase (Ppm), and PnPy is often converted to phosphonoacetaldehyde (PnAA) by PnPy decarboxylase (Ppd). Seven enzymes are known or likely to act on either PnPy or PnAA as early branch points en route to diverse biosynthetic outcomes, and these enzymes may be broadly classified into three reaction types: hydride transfer, aminotransfer, and carbon-carbon bond formation. However, the relative abundance of these branch points in microbial phosphonate biosynthesis is unknown. Also unknown is the proportion of ppm -containing gene neighborhoods encoding new branch point enzymes and potentially novel phosphonates. In this study we computationally sorted 434 ppm -containing gene neighborhoods based on these seven branch point enzymes. Unsurprisingly, the majority (56%) of these pathways encode for production of the common naturally occurring compound 2-aminoethylphosphonate (AEP) or a hydroxylated derivative. The next most abundant genetically encoded intermediates were phosphonoalanine (PnAla, 9.2%), 2-hydroxyethylphosphonate (HEP, 8.5%), and phosphonoacetate (PnAc, 6%). Significantly, about 13% of the gene neighborhoods could not be assigned to any of the seven branch points and may encode novel phosphonates. 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. IMPACT STATEMENT Microbially-produced phosphonates are relatively rare and underexplored but include medically and agriculturally important molecules like fosfomycin and phosphinothricin, respectively. Because a single enzyme called phosphoenolpyruvate mutase (Ppm) inititates almost all phosphonate production, the composition of the ‘gene neighborhood’ surrounding a Ppm-encoding gene can inform hypotheses regarding the chemical output of this chromosomal region. 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. This study provides just such 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. Data Summary Supporting information is available at Scholars Portal Dataverse ( https://dataverse.scholarsportal.info/ ) with DOI 10.5683/SP2/T33ZP6. This includes scripts and the network data for visualizing in BiG-SCAPE and Cytoscape." @default.
- W3144300192 created "2021-04-13" @default.
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- W3144300192 date "2021-04-09" @default.
- W3144300192 modified "2023-10-14" @default.
- W3144300192 title "An inventory of early branch points in microbial phosphonate biosynthesis" @default.
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- W3144300192 doi "https://doi.org/10.1101/2021.04.07.438883" @default.
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