Studying the assembly of natural products reveals a growing number of cases of evolutionary divergence from known protein catalytic activities to new biosynthetic tasks. Impressive synthetic efficiency is often captured in these changes as will be illustrated in this lecture taking examples from the four distinct ways beta-lactam antibiotics are constructed in Nature. The gene cluster for the nocardicins will be presented, the first example of a monocyclic member of this antibiotic family. Inter alia, an unusual pair of non-ribosomal peptide synthetases is present. Total syntheses of all seven of the known nocardicins will be described as well as their biochemical applications to understanding this pathway. Microbial resistance to the beta-lactams and other widely prescribed antibiotics is now recognized to be inescapable. Understanding their biosynthetic pathways opens a practical and powerful way to manipulation and protein engineering to produce structural variants capable of overcoming resistance mechanisms. Early results from a series of X-ray “snapshots” of a beta-lactam synthetase catalytic cycle will exemplify how these enzymes could be used in the semi-synthesis of new antibiotics. Related to this theme will be a brief introduction to fatty acid synthase inhibition and the treatment of cancer, tuberculosis and obesity. Syntheses of FAS inhibitors will be described together with biochemical characterization of combinatorially modified structures in a joint effort with scientists at the Johns Hopkins School of Medicine.
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