The Biosynthetic Enzymology of Beta-Lactone Natural Products
Timothy A. Wencewicz, PhD
Department of Chemistry
Washington University in St. Louis
Beta-lactone rings are found in diverse natural product scaffolds including polyketides, nonribosomal peptides, and terpenoids. The strained beta-lactone ring is an important pharmacophore used clinically as serine hydrolase inhibitors for the treatment of obesity, diabetes, and cancer. Our lab recently discovered the first beta-lactone synthetase enzyme that catalyzes formation of the beta-lactone ring in the antibiotic obafluorin during cleavage of a covalently tethered thioester substrate from a nonribosomal peptide synthetase assembly line. The genetic and molecular basis for the biosynthetic conversion of 2,3-dihydroxybenzoic acid (2,3-DHB), L-threonine (L-Thr), and para-aminophenylpyruvic acid (PAPPA) building blocks to obafluorin beta-lactone in plant-associated Pseudomonas fluorescens will be presented along with a flexible precursor-directed strategy for the chemoenzymatic production of peptide beta-lactones with potential therapeutic value as anticancer, antimicrobial, and anti-obesity agents.