Abstract
Modular nonribosomal peptide synthetases (NRPSs) are large, multidomain engines of bioactive natural product biosynthesis that function as molecular "assembly lines" in which monomer units are selectively bound, modified, and linked in a specific order and number dictated by their mega-enzyme templates. Recently, a condensation domain in an NRPS was discovered to carry out the synthesis of an integrated β-lactam ring from a substrate seryl residue during antibiotic biosynthesis. We report here a series of experiments supporting a mechanism that involves C-N bond formation by stepwise elimination/addition reactions followed by canonical NRPS-catalyzed amide bond synthesis to achieve β-lactam formation. Partitioning of reactive intermediates formed during the multistep catalytic cycle provided insight into the ability of the NRPS to overcome the reversibility of corresponding reactions in solution and enforce directionality during synthesis.
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