Structure of β-lactam synthetase reveals how to synthesize antibiotics instead of asparagine

Matthew T. Miller, Brian O. Bachmann, Craig A. Townsend, Amy C. Rosenzweig*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

The enzyme β-lactam synthetase (β-LS) catalyzes the formation of the β-lactam ring in clavulanic acid, a clinically important β-lactamase inhibitor. Whereas the penicillin β-lactam ring is generated by isopenicillin N synthase (IPNS) in the presence of ferrous ion and dioxygen, β-LS uses ATP and Mg2+ as cofactors. According to sequence alignments, β-LS is homologous to class B asparagine synthetases (AS-Bs), ATP/Mg2+-dependent enzymes that convert aspartic acid to asparagine. Here we report the first crystal structure of a β-LS. The 1.95 Å resolution structure of Streptomyces clavuligerus β-LS provides a fully resolved view of the active site in which substrate, closely related ATP analog α,β-methyleneadenosine 5′-triphosphate (AMP-CPP) and a single Mg2+ ion are present. A high degree of substrate preorganization is observed. Comparison to Escherichia coli AS-B reveals the evolutionary changes that have taken place in β-LS that impede interdomain reaction, which is essential in AS-B, and that accommodate β-lactam formation. The structural data provide the opportunity to alter the synthetic potential of β-LS, perhaps leading to the creation of new β-lactamase inhibitors and β-lactam antibiotics.

Original languageEnglish (US)
Pages (from-to)684-689
Number of pages6
JournalNature Structural Biology
Volume8
Issue number8
DOIs
StatePublished - Aug 29 2001

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Genetics

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