Biosynthetic Origin of the Methoxyl Extender Unit in Bafilomycin and Concanamycin using Stereospecifically Labeled Precursors

• Published in: Journal of antibiotics Vol. 60; no. 1; pp. 52 - 60
• Main Authors: Schuhmann, Tim, Vollmar, Daniel, Grond, Stephanie
• Format: Journal Article
• Language: English
• Published: Japan Nature Publishing Group 01.01.2007
• Subjects: Biosynthesis; Carbon Isotopes - metabolism; Carboxylic Acids; Citric Acid Cycle; Glycerol - metabolism; Glycerol Kinase - metabolism; Glycolates - metabolism; Macrolides - metabolism; Metabolic Networks and Pathways; Molecular Structure; Streptomyces - metabolism
• ISSN: 0021-8820; 1881-1469
• DOI: 10.1038/ja.2007.7

The microbial macrolides bafilomycin A1, B, and concanamycin A from Streptomyces spp. are potent and specific inhibitors of V-ATPases. The question of the biosynthetic origin of the two uncommon "glycolate units" of each of the macrolide structures was addressed by feeding experiments with stereospecifically 13C-labeled precursors. Our studies clearly indicate that glycerol is a source for the methoxylated C2-units and determines the orientation of the incorporation. Products from the carboxylic acid pool or TCA cycle are ruled out as key precursors. The data suggest the action of a glycerol kinase and point to phosphoglycerate as an intermediate in their biosynthesis. However, glycerate itself is not accepted as a precursor. We present the likely biosynthetic pathway and show the value of stereospecifically labeled presursors as an important tool for biosynthetic investigations.