期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2019863118
关键词
fosfomycin; phosphonate; nonheme iron; decarboxylase; metallohydrolase
资金
- NIH [P01 GM077596, S10-RR028833]
- HHMI
- Roy J. Carver Charitable Trust (Muscatine, Iowa) [15-4521]
Fosfomycin, a broad-spectrum antibiotic used in the treatment of cystitis, is produced by both the plant pathogen Pseudomonas syringae and soil-dwelling streptomycetes. Research has identified PsfC as the central enzyme responsible for completing the biosynthetic pathway in pseudomonads, with crystallographic studies revealing that PsfC belongs to a new class of diiron metalloenzymes.
The epoxide-containing phosphonate natural product fosfomycin is a broad-spectrum antibiotic used in the treatment of cystitis. Fosfomycin is produced by both the plant pathogen Pseudomonas syringae and soil-dwelling streptomycetes. While the streptomycete pathway has recently been fully elucidated, the pseudomonad pathway is still mostly elusive. Through a systematic evaluation of heterologous expression of putative biosynthetic enzymes, we identified the central enzyme responsible for completing the biosynthetic pathway in pseudomonads. The missing transformation involves the oxidative decarboxylation of the intermediate 2-phosphonomethylmalate to a new intermediate, 3-oxo-4-phosphonobutanoate, by PsfC. Crystallographic studies reveal that PsfC unexpectedly belongs to a new class of diiron metalloenzymes that are part of the polymerase and histidinol phosphatase superfamily.
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