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Volume 154, Issue 9

Non-ribosomal peptide synthetase module fusions to produce derivatives of daptomycin in Free

Abstract

Genetic engineering has been applied to reprogramme non-ribosomal peptide synthetases (NRPSs) to produce novel antibiotics, but little is known about what determines the efficiency of production. We explored module exchanges at nucleotide sequences encoding interpeptide linkers in , a gene encoding a di-modular NRPS subunit that incorporates 3-methylglutamic acid (3mGlu) and kynurenine (Kyn) into daptomycin. Mutations causing amino acid substitutions, deletions or insertions in the inter-module linker had no negative effects on lipopeptide yields. Hybrid DptD subunits were generated by fusing the 3mGlu module to terminal modules from calcium-dependent antibiotic (CDA) or A54145 NRPSs, and recombinants produced daptomycin analogues with Trp or Ile at high efficiencies. A recombinant expressing DptD with a hybrid Kyn module containing a di-domain from a -Asn module caused the production of a new daptomycin analogue containing Asn.

  • Received:
  • Accepted:
  • Revised:
  • Published Online:
Keyword(s): 3mGlu, 3-methylglutamic acid , A, adenylation , C, condensation , CDA, calcium-dependent antibiotic , d-hAsn, d-hydroxyasparagine , d-hPhg, d-hydroxyphenylglycine , E, epimerization , ESI, electrospray ionization , HR-MS, high resolution mass spectrometry , Kyn, kynurenine , LC-MS, liquid chromatography-mass spectrometry , mOAsp, methoxyaspartic acid , NRPS, non-ribosomal peptide synthetase , PCP, peptidyl carrier protein , Sar, sarcosine , T, thiolation and Te, thioesterase
Cubist Pharmaceuticals
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2008-09-01
2024-04-18
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Non-ribosomal peptide synthetase module fusions to produce derivatives of daptomycin in Streptomyces roseosporus
Microbiology 154, 2872 (2008); https://doi.org/10.1099/mic.0.2008/020685-0
/content/journal/micro/10.1099/mic.0.2008/020685-0
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