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

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 gamma-glutamylation of an ACP-derived gamma-aminobutyrate intermediate, possibly a rare example of protective group chemistry in biosynthesis.

• Publication year

  2005

• Venue

  Chemistry and Biology

• Publication date

  2005-06-01

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1016/J.CHEMBIOL.2005.04.010PMID 15975512
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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• Holo-(Acyl Carrier Protein) Synthase and Phosphopantetheinyl Transfer in Escherichia coli *

  2000cited by this paper
• Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics

  2000cited by this paper
• Butirosin-biosynthetic gene cluster from Bacillus circulans.

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  2000cited by this paper
• Modulation of RNA function by aminoglycoside antibiotics

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• Aminoglycoside-modifying enzymes.

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• Characterization of a Two-component Alkanesulfonate Monooxygenase from Escherichia coli*

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  1998cited by this paper
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  1997cited by this paper
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• Antibacterial Chemotherapeutic Agents

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  1995cited by this paper
• A 4-amino-2-hydroxybutyrate activating enzyme from butirosin-producing Bacillus circulans.

  1993cited by this paper
• The Crisis in Antibiotic Resistance

  1992cited by this paper
• Kinetic evidence for the formation of D-alanyl phosphate in the mechanism of D-alanyl-D-alanine ligase.

  1990cited by this paper
• Mechanism and regulation of the glutamine-dependent carbamyl phosphate synthetase of Escherichia coli.

  1989cited by this paper
• ATPase activity of biotin carboxylase provides evidence for initial activation of HCO3- by ATP in the carboxylation of biotin.

  1986cited by this paper
• Biochemistry and physiology of bioluminescent bacteria.

  1985cited by this paper
• Purification and characterization of glutathione synthetase from Escherichia coli B.

  1983cited by this paper
• Aminoglycoside-modifying enzymes.

  1979cited by this paper
• Isolation and properties of Escherichia coli K-12 mutants impaired in the utilization of gamma-aminobutyrate

  1979cited by this paper
• Mistranslation in E. coli.

  1977cited by this paper
• Butirosin, a New Aminoglycosidic Antibiotic Complex: Antibacterial Activity In Vitro and in Mice

  1972cited by this paper
• Butirosin, a New Aminoglycosidic Antibiotic Complex: Bacterial Origin and Some Microbiological Studies

  1972cited by this paper
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  1972cited by this paper
• Partial reactions catalyzed by -glutamylcysteine synthetase and evidence for an activated glutamate intermediate.

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