Antibiotic Glycosyltransferases: Antibiotic Maturation and Prospects for Reprogramming

摘要

Many varieties of natural products elaborated by microorganisms are regio- and stereospecifically glycosylated. These include polyketides, both in the aromatic tetracyclic family as exemplified by daunomycin 1 (Figure 1) and in the macrocyclic lactones such as the 14-membered macrocycle erythromycin 2 and the 16-membered macrocycle tylosin 3. The polyketide macrolides and the nonribosomal peptide NRPS natural products are biosynthesized by analogous assembly line enzymatic logic, and glycosylation is a common postassembly line tailoring step. The antibiotics vancomycin (4) and ramoplanin (5) and the antitumor drug bleomycin (6) all have disaccharide chains added late in the biosynthetic pathways. While ramoplanin has a dimannosyl chain, the remaining polyketide and nonribosomal peptide natural products are more typically decorated with specialized deoxyhexose and aminode-oxyhexose units generated via pathways dedicated to antibiotic modifications. The aminocoumarin antibiotics novobiocin (7, Figure 1), clorobiocin (8), and coumermycin A1 (9) target the B subunit of the type II topo-isomerase DNA gyrase and have an L-noviosyl sugar that presents 4'-O-carbamoyl or 4'-O-methylpyrrolyl substituents as competitive ligands for the ATP binding site in GyrB. Many other natural product scaffolds including enediyne antitumor agents and polyene antifungal agents contain specialized hexosyl moieties.