Studies on the biosynthesis of clavulanic acid. III. Incorporation of DL-(3,4-13C2)glutamic acid.

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Abstract
The role of glutamate in clavulanic acid biosynthesis was investigated by feeding DL-[3,4-13C2]glutamate to a Streptomyces clavuligerus fermentation. The DL-[3,4-13C2]glutamate was synthesized by reacting [2-13C]diethylmalonate with O-tosyl-N-benzoyl-[3-13C]dehydroserine ethyl ester, which in turn was synthesized by condensing [13C]ethylformate with N-benzoylglycine ethyl ester. 13C NMR examination of the benzyl clavulanate derived from the fermentation revealed the predicted labeling of carbons 2 and 8 with accompanying 13C-13C spin-spin coupling. Other enrichments and couplings were observed which could be explained by metabolism of the labeled glutamate via the tricarboxylic acid cyclic to give further clavulanic acid precursors. Glutamate evidently provides the oxazolidine carbon skeleton as predicted by previous experiments.