Baeyer–Villiger C–C Bond Cleavage Reaction in Gilvocarcin and Jadomycin Biosynthesis

GilOII has been unambiguously identified as the key enzyme performing the crucial C–C bond cleavage reaction responsible for the unique rearrangement of a benz­[<i>a</i>]­anthracene skeleton to the benzo­[<i>d</i>]­naphthopyranone backbone typical of the gilvocarcin-type natural anticancer antibiotics. Further investigations of this enzyme led to the isolation of a hydroxyoxepinone intermediate, leading to important conclusions regarding the cleavage mechanism

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 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 <i>threo</i> diastereomer (5′<i>S</i>,6′<i>S</i>)-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