title: Biosynthesis of fosfazinomycin is a convergent process.
abstract: Fosfazinomycin A is a phosphonate natural product in which the C-terminal carboxylate of a Val-Arg dipeptide is connected to methyl 2-hydroxy-2-phosphono-acetate (Me-HPnA) via a unique hydrazide linkage. We report here that Me-HPnA is generated from phosphonoacetaldehyde (PnAA) in three biosynthetic steps through the combined action of anO-methyltransferase (FzmB) and an α-ketoglutarate (α-KG) dependent non-heme iron dioxygenase (FzmG). Unexpectedly, the latter enzyme is involved in two different steps, oxidation of the PnAA to phosphonoacetic acid as well as hydroxylation of methyl 2-phosphonoacetate. TheN-methyltransferase (FzmH) was able to methylate Arg-NHNH2(3) to give Arg-NHNHMe (4), constituting the second segment of the fosfazinomycin molecule. Methylation of other putative intermediates such as desmethyl fosfazinomycin B was not observed. Collectively, our current data support a convergent biosynthetic pathway to fosfazinomycin.
authors.affiliation: Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801. ; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801. ; Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
authors.forename: Zedu
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801. ; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801. ; Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
authors.forename: Kwo-Kwang A
authors.initials: KK
authors.lastname: Wang
authors.affiliation: Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
authors.forename: Jaeheon
authors.initials: J
authors.lastname: Lee
authors.affiliation: Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801. ; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801. ; Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
authors.forename: Wilfred A
authors.initials: WA
authors.lastname: van der Donk