Four out of seven amino acids of the balhimycin peptide-backbone originate from the shikimate pathway which therefore may be a bottleneck in precursor supply. Analysis of the key steps (such as DAHP synthase, prephenate dehydrogenase) revealed a complex interaction of these enzymes including feedback inhibition which limit antibiotic yield.
The four-step biosynthetic route for the provision of phenylglycine, which is one of the amino acids in pristinamycinB, comprises three steps corresponding to those in dihydroxyphenylglycine synthesis in the balhimycin pathway: Dioxygenation, transamination and the release of a biosynthetic intermediate by a hydrolase are performed analogously, whereas the initial step, the formation of phenylacetyl-CoA resembles the acetyl-CoA formation by the pyruvate dehydrogenase complex of the primary metabolism.
An even more striking similarity between an enzyme of the primary metabolism and its counterpart in secondary metabolism was observed in PTT biosynthesis: The phosphinomethylmalic acid isomerase, which converts phosphinomethylmalic acid cannot be distinguished from the TCA cycle aconitase by sequence and structure data.
The knowledge on precursor supply is the basis for experiments on precursor-directed biosynthesis and for manipulating the metabolic flux to increase the antibiotic yield.