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

Tim Schuhmann, Daniel Vollmar, Stephanie Grond

Received: October 5, 2006 / Accepted: December 21, 2006
© Japan Antibiotics Research Association

Abstract The microbial macrolides bafilomycin A1, B1 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.

Keywords biosynthesis, stereospecific isotopic labeling, macrolides, natural products, polyketides

S. Grond (Corresponding author), T. Schuhmann, D. Vollmar: Institut für Organische und Biomolekulare Chemie, Georg-August Universität Göttingen, Tammannstr. 2, 37077 Göttingen, Germany, E-mail: sgrond@gwdg.de