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 a beta-lactone synthase enzyme that catalyzes formation of the beta-lactone ring in the antibiotic obafluorin during product release from a rare thioesterase domain that is part of 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 <i>Pseudomonas fluorescens</i> will be presented along with chemoenzymatic synthesis of novel analogs.

Biosynthesis of beta-lactones

255th National Meeting (2018)

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