Biosynthesis of the unique amino acid side chain of butirosin: Possible protective-group chemistry in an acyl carrier protein-mediated pathway

Yanyan Li, Nicholas M. Llewellyn, Ramesh Giri, Fanglu Huang, Jonathan B. Spencer

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Butirosins A and B are naturally occurring aminoglycoside antibiotics that have a (2S)-4-amino-2-hydroxybutyrate (AHBA) side chain. Semisynthetic addition of AHBA to clinically valuable aminoglycoside antibiotics has been shown both to improve their pharmacological properties and to prevent their deactivation by a number of aminoglycoside-modifying enzymes involved in bacterial resistance. We report here that the biosynthesis of AHBA from L-glutamate, encoded within a previously identified butirosin biosynthetic gene cluster, proceeds via intermediates tethered to a specific acyl carrier protein (ACP). Five components of the pathway have been purified and characterized, including the ACP (BtrI), an ATP-dependent ligase (BtrJ), a pyridoxal phosphate-dependent decarboxylase (BtrK), and a two-component flavin-dependent monooxygenase system (BtrO and the previously unreported BtrV). The proposed biosynthetic pathway includes a γ-glutamylation of an ACP-derived γ-aminobutyrate intermediate, possibly a rare example of protective group chemistry in biosynthesis.

Original languageEnglish (US)
Pages (from-to)665-675
Number of pages11
JournalChemistry and Biology
Volume12
Issue number6
DOIs
StatePublished - 2005

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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