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Structural insight into antibiotic fosfomycin biosynthesis by a mononuclear iron enzyme

Author

Listed:
  • Luke J. Higgins

    (Massachusetts Institute of Technology)

  • Feng Yan

    (University of Texas at Austin)

  • Pinghua Liu

    (Massachusetts Institute of Technology
    University of Texas at Austin)

  • Hung-wen Liu

    (University of Texas at Austin)

  • Catherine L. Drennan

    (Massachusetts Institute of Technology)

Abstract

The biosynthetic pathway of the clinically important antibiotic fosfomycin uses enzymes that catalyse reactions without precedent in biology. Among these is hydroxypropylphosphonic acid epoxidase, which represents a new subfamily of non-haem mononuclear iron enzymes. Here we present six X-ray structures of this enzyme: the apoenzyme at 2.0 Å resolution; a native Fe(ii)-bound form at 2.4 Å resolution; a tris(hydroxymethyl)aminomethane–Co(ii)-enzyme complex structure at 1.8 Å resolution; a substrate–Co(ii)-enzyme complex structure at 2.5 Å resolution; and two substrate–Fe(ii)-enzyme complexes at 2.1 and 2.3 Å resolution. These structural data lead us to suggest how this enzyme is able to recognize and respond to its substrate with a conformational change that protects the radical-based intermediates formed during catalysis. Comparisons with other family members suggest why substrate binding is able to prime iron for dioxygen binding in the absence of α-ketoglutarate (a co-substrate required by many mononuclear iron enzymes), and how the unique epoxidation reaction of hydroxypropylphosphonic acid epoxidase may occur.

Suggested Citation

  • Luke J. Higgins & Feng Yan & Pinghua Liu & Hung-wen Liu & Catherine L. Drennan, 2005. "Structural insight into antibiotic fosfomycin biosynthesis by a mononuclear iron enzyme," Nature, Nature, vol. 437(7060), pages 838-844, October.
    • Handle: RePEc:nat:nature:v:437:y:2005:i:7060:d:10.1038_nature03924
    DOI: 10.1038/nature03924
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