Biosynthesis of marine polyketide antibiotics

University Of California, San Diego, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): Marine microbes have recently emerged as an important resource of chemically distinct antimicrobial agents with the potential to contribute significantly to the treatment of infectious diseases. An underlying theme associated with many marine microbial antibiotics involves the use of aromatic polyketide frameworks that have undergone extensive oxidative tailoring reactions catalyzed by halogenase and oxygenase biosynthetic enzymes. The marine microbial polyketide antibiotics enterocin, napyradiomycin, merochlorin, and marinopyrrole each boast unique structural features that result from dedicated oxidative tailoring reactions that contribute to their potent biological activities. In this appliction, we propose a multidisciplinary project involving heterologous biosynthesis, in vivo and in vitro biochemical analysis, and atomic resolution protein x-ray crystallography to understand the molecular basis of polyketide diversification in this series of marine microbial natural products. To accomplish the broad goals outlined in this application, we propose four specific aims. First, we plan to functionally and structurally characterize the enterocin EncM flavoprotein and explore its anticipated favorskiiase catalytic activity. Second, we will functionally and structurally characterize the napyradiomycin V-dependent chloroperoxidases and their catalytic properties in halogen-assisted meroterpenoid cyclization. Third, we aim to genetically and biochemically interrogate the biosynthesis of merochlorin C and its macrocyclizing V-dependent chloroperoxidase. And fourth, we will functionally characterize the biosynthesis of the marinopyrrole antibiotics and their novel bipyrrole coupling enzymology.