Discovery of the Phosphonate Flavophos Produced by Burkholderia

Simon, M. A.; Ramos-Figueroa, J. S.; Reyes Lopez, V.; Ongpipattanakul, C.; Zhu, L.; Giurgiu, C.; Hoffpauir, Z. A.; Lamb, A. L.; Nair, S. K.; van der Donk, W. A.

doi:10.64898/2026.01.15.699783

bioRxiv · 10.64898/2026.01.15.699783

Discovery of the Phosphonate Flavophos Produced by Burkholderia

Simon, M. A.·Ramos-Figueroa, J. S.·Reyes Lopez, V.·Ongpipattanakul, C.·Zhu, L.·Giurgiu, C.·Hoffpauir, Z. A.·Lamb, A. L.·Nair, S. K.·van der Donk, W. A.

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Abstract

Phosphonate natural products have proven value to society as antibiotics and herbicides. They inhibit a range of enzyme targets usually by mimicking the enzyme substrates. In this study, we investigate a family of phosphonate biosynthetic gene clusters (BGCs) found in Burkholderia. Heterologous expression in Escherichia coli resulted in production of an antimicrobial compound. Spectroscopic characterization and chemical synthesis assigned its structure as 2,4-dioxopentylphosphonic acid. One of the biosynthetic enzymes is a member of the domain of unknown function (DUF) 849 family with homology to {beta}-keto acid cleavage enzymes (BKACEs). In vitro characterization shows that this enzyme catalyzes chemistry that is divergent from previously characterized BKACEs. The observed catalytic activity is explained by a series of co-crystal structures with substrates and intermediates. The BGC also contains a gene encoding lumazine synthase (LS), an essential enzyme in flavin biosynthesis. Biochemical experiments revealed that 2,4-dioxopentylphosphonic acid inhibits LS. In addition, expression of the LS encoded in the BGC, or LS orthologs from a range of organisms, in E. coli conferred resistance to the new phosphonate, which we therefore name flavophos.

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Simon, M. A., Ramos-Figueroa, J. S., Reyes Lopez, V., Ongpipattanakul, C., Zhu, L., Giurgiu, C., Hoffpauir, Z. A., Lamb, A. L., Nair, S. K., van der Donk, W. A.. 2026-01-16. Discovery of the Phosphonate Flavophos Produced by Burkholderia. https://doi.org/10.64898/2026.01.15.699783

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