Mechanisms of polyketide, amino acid and Polypeptide biosynthesis

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The major objectives of the proposed research in bioorganic chemistry and natural products chemistry include: a) development of new approaches to study secondary metabolism (especially polyketide and polypeptide biosynthesis); and b) study of the mechanism and inhibition of enzymes involved in amino acid and peptide metabolism. The program involves a combination of methods used in organic chemistry (e.g. synthesis, spectroscopic analysis) and biochemistry (e.g. molecular biology, protein characterization, enzyme inhibition, NMR solution structures and, in collaboration, x-ray crystallography of proteins). One part of the program focuses on the way fungi assemble polyketides, a class of secondary metabolites typically built from acetate, that often have important biological activity. In particular, the details of assembly of lovastatin, a cholesterol-lowering agent and precursor to the drug simvastatin (Zocor) will be examined. Construction of this molecule requires the polyketide synthase (PKS) enzyme LovB and the enoyl reductase enzyme LovC, which together produce most of the skeleton of lovastatin in 35 highly programmed steps. We will study the step by step transformations of this remarkable molecular machine with the goal of elucidating its mechanism and generating new analogs of the drug. Similar approaches will be used to study biosynthesis of three other biologically active fungal polyketide compounds. A second part of the program targets bacteriocins, which are antimicrobial peptides produced by bacteria that occur naturally in food. They are many orders of magnitude more potent than conventional antibiotics and are effective against pathogens resistant to current therapy. In particular, chemical synthesis of lantibiotics, a class of bacteriocins that contain monosulfide lanthionine rings, will be investigated with the goal of understanding structure-activity relationships and making more stable derivatives. Targets include lacticin 3147 and gallidermin. Another aspect involves determination of the details of biosynthesis of thuricins, which are active against the dangerous pathogen, Clostridium difficile ribotype 027. Their the 3D structures will also be examined by new approaches