Studies on the biosynthesis of clavulanic acid. I. Incorporation of 13C-labelled precursors.

Abstract

The biosynthesis of clavulanic acid was investigated by feeding 13C-labeled precursors to Streptomyces clavuligerus fermentations. The resulting samples of clavulanic acid were isolated as the benzyl ester and were examined by 13C NMR spectroscopy for 13C-enrichment. The results showed that the C skeleton of 1,3-13C2-glycerol was incorporated intact into the 3 .beta.-lactam C of clavulanic acid. Studies with 1-13C-acetate, 2-13C-acetate and 1,2-13C2-acetate indicated that the remaining 5 C of clavulanic acid were probably derived from .alpha.-ketoglutarate. 1-13C-Propionate and 3-13C-propionate were not metabolized via the same route as glycerol, but were probably converted to succinate, via methylmalonyl CoA, and hence via the tricarboxylic acid cycle to the clavulanic acid precursors.