Structural highlights
Publication Abstract from PubMedPhosphonate 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 cocrystal 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. Discovery of the Phosphonate Flavophos Produced by Burkholderia.,Simon MA, Ramos-Figueroa JS, Reyes Lopez V, Ongpipattanakul C, Zhu L, Giurgiu C, Hoffpauir ZA, Lamb AL, Nair SK, van der Donk WA J Am Chem Soc. 2026 May 6;148(17):18030-18043. doi: 10.1021/jacs.6c01748. Epub , 2026 Apr 26. PMID:42036871[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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