Biosynthesis and molecular genetics of clavulanic acid

The biosynthesis of clavulanic acid and related clavam metabolites is only now being elucidated. Understanding of this pathway has resulted from a com bination of both biochemical studies of purified biosynthetic enzymes, and molecular genetic studies of the genes encoding these enzymes. Clavulanic a cid biosynthesis has been most thoroughly investigated in Streptomyces clav uligerus where the biosynthetic gene cluster resides immediately adjacent t o the cluster of cephamycin biosynthetic genes. A minimum of eight structur al genes have been implicated in clavulanic acid biosynthesis, although mor e are probably involved. While details of the early and late steps of the p athway remain unclear, synthesis proceeds from arginine and pyruvate, as th e most likely primary metabolic precursors, through the monocyclic beta-lac tam intermediate, proclavaminic acid, to the bicyclic intermediate, clavami nic acid, which is a branch point leading either to clavulanic acid or the other clavams. Conversion of clavaminic acid to clavulanic acid requires si de chain modfication as well as inversion of ring stereochemistry. This ste reochemical change occurs coincident with acquisition of the beta-lactamase inhibitory activity which gives clavulanic acid its therapeutic and commer cial importance. In contrast, the other clavam metabolites all arise from c lavaminic acid with retention of configuration and lack beta-lactamase inhi bitory activity.