Biosynthesis of 2-hydroxyethylphosphonate, an unexpected intermediate common to multiple phosphonate biosynthetic pathways.
Phosphonic acids encompass a common yet chemically diverse class of natural products that often possess potent biological activities. Here we report that, despite the significant structural differences among many of these compounds, their biosynthetic routes contain an unexpected common intermediate, 2-hydroxyethyl-phosphonate, which is synthesized from phosphonoacetaldehyde by a distinct family of metal-dependent alcohol dehydrogenases (ADHs). Although the sequence identity of the ADH family members is relatively low (34-37%), in vitro biochemical characterization of the homologs involved in biosynthesis of the antibiotics fosfomycin, phosphinothricin tripeptide, and dehydrophos (formerly A53868) unequivocally confirms their enzymatic activities. These unique ADHs have exquisite substrate specificity, unusual metal requirements, and an unprecedented monomeric quaternary structure. Further, sequence analysis shows that these ADHs form a monophyletic group along with additional family members encoded by putative phosphonate biosynthetic gene clusters. Thus, the reduction of phosphonoacetaldehyde to hydroxyethyl-phosphonate may represent a common step in the biosynthesis of many phosphonate natural products, a finding that lends insight into the evolution of phosphonate biosynthetic pathways and the chemical structures of new C-P containing secondary metabolites.
Shao
Zengyi
Z
Department of Chemical and Biomolecular Engineering and Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Blodgett
Joshua A V
JA
Circello
Benjamin T
BT
Eliot
Andrew C
AC
Woodyer
Ryan
R
Li
Gongyong
G
van der Donk
Wilfred A
WA
Metcalf
William W
WW
Zhao
Huimin
H
D000595:Amino Acid Sequence; D000613:Aminobutyrates / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001419:Bacteria / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D005578:Fosfomycin / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008670:Metals / Q000737:chemistry; D008969:Molecular Sequence Data; D063065:Organophosphonates / Q000737:chemistry* / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D010802:Phylogeny; D020836:Protein Structure, Quaternary; D013379:Substrate Specificity
C519566:2-hydroxyethyl phosphonate; D000613:Aminobutyrates; D000900:Anti-Bacterial Agents; D004151:Dipeptides; D008670:Metals; D063065:Organophosphonates; D010455:Peptides; C056804:A 53868A; D005578:Fosfomycin; C003121:phosphinothricin