The enzyme clavulanic acid synthase /CAS/ catalyzes the formation of the first bicyclic intermediate in the biosynthetic pathway to the potent beta-lactamase inhibitor clavulanic acid, Townsend has proposed that the cyclization/desaturation of the substrate proclavaminic acid /PCA/ proceeds in two oxidative steps involving radical intermediates. The process is very similar to the second ring closure in penicillin biosynthesis and the subsequent ring expansion to deacetoxycephalosporin C in cephalosporin C biosynthesis. The homolytic character of these latter transformations were successfully tested in the laboratory of Prof. Jack E.Baldwin /in which I actively took part/ by cyclopropylcarbinyl test experiments using cyclopropane substituted penicillin and cephalosporin derivatives. Analogous radical clock experiments are planned with cyclopropane-substituted PCA derivatives and their deuterated analogues. Substrate specificity and active site topology of CAS will also be examined by unsaturated and other modified substrates.
The aims of these studies are to obtain clavulanic acid in higher yield by fermentation. By using modified precursors, biologically more active clavulanic acid derivatives can also be prepared.
| Pitlik, J (1995) Cycloaddition and related reactions of cephalosporin antibiotics. Bioorg Med Chem 3:1157-81 |
