Amalgamation of Nucleosides and Amino Acids in Antibiotic Biosynthesis: Discovery of an l‑Threonine:Uridine-5′-Aldehyde Transaldolase

The lipopeptidyl nucleoside antibiotics represented by A-90289, caprazamycin, and muraymycin are structurally highlighted by a nucleoside core that contains a nonproteinogenic β-hydroxy-α-amino acid named 5′-C-glycyluridine (GlyU). Bioinformatic analysis of the biosynthetic gene clusters revealed a...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2012-11, Vol.134 (45), p.18514-18517
Main Authors: Barnard-Britson, Sandra, Chi, Xiuling, Nonaka, Koichi, Spork, Anatol P, Tibrewal, Nidhi, Goswami, Anwesha, Pahari, Pallab, Ducho, Christian, Rohr, Jurgen, Van Lanen, Steven G
Format: Article
Language:English
Subjects:
Aldehydes - metabolism
Anti-Bacterial Agents - biosynthesis
Anti-Bacterial Agents - chemistry
Biocatalysis
Computational Biology
Molecular Conformation
Nucleosides - chemistry
Nucleosides - metabolism
Threonine - metabolism
Transaldolase - metabolism
Uridine - metabolism
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Summary:The lipopeptidyl nucleoside antibiotics represented by A-90289, caprazamycin, and muraymycin are structurally highlighted by a nucleoside core that contains a nonproteinogenic β-hydroxy-α-amino acid named 5′-C-glycyluridine (GlyU). Bioinformatic analysis of the biosynthetic gene clusters revealed a shared open reading frame encoding a protein with sequence similarity to serine hydroxymethyltransferases, resulting in the proposal that this shared enzyme catalyzes an aldol-type condensation with glycine and uridine-5′-aldehyde to furnish GlyU. Using LipK involved in A-90289 biosynthesis as a model, we now functionally assign and characterize the enzyme responsible for the C–C bond-forming event during GlyU biosynthesis as an l-threonine:uridine-5′-aldehyde transaldolase. Biochemical analysis revealed this transformation is dependent upon pyridoxal-5′-phosphate, the enzyme has no activity with alternative amino acids, such as glycine or serine, as aldol donors, and acetaldehyde is a coproduct. Structural characterization of the enzyme product is consistent with stereochemical assignment as the threo diastereomer (5′S,6′S)-GlyU. Thus this enzyme orchestrates C–C bond breaking and formation with concomitant installation of two stereocenters to make a new l-α-amino acid with a nucleoside side chain.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja308185q