[beta]-Lactam formation by a non-ribosomal peptide synthetase during antibiotic biosynthesis.

• Autores: Nicole M. Gaudelli, Darcie H Long, Craig A. Townsend
• Localización: Nature: International weekly journal of science, ISSN 0028-0836, Vol. 520, Nº 7547, 2015, págs. 383-387
• Idioma: inglés
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• Resumen

  • Non-ribosomal peptide synthetases are giant enzymes composed of modules that house repeated sets of functional domains, which select, activate and couple amino acids drawn from a pool of nearly 500 potential building blocks 1. The structurally and stereochemically diverse peptides generated in this manner underlie the biosynthesis of a large sector of natural products. Many of their derived metabolites are bioactive such as the antibiotics vancomycin, bacitracin, daptomycin and the [beta]-lactam-containing penicillins, cephalosporins and nocardicins. Penicillins and cephalosporins are synthesized from a classically derived non-ribosomal peptide synthetase tripeptide (from [delta]-(L-[alpha]-aminoadipyl)-L-cysteinyl-D-valine synthetase) 2. Here we report an unprecedented non-ribosomal peptide synthetase activity that both assembles a serine-containing peptide and mediates its cyclization to the critical [beta]-lactam ring of the nocardicin family of antibiotics. A histidine-rich condensation domain, which typically performs peptide bond formation during product assembly, also synthesizes the embedded four-membered ring. We propose a mechanism, and describe supporting experiments, that is distinct from the pathways that have evolved to the three other [beta]-lactam antibiotic families: penicillin/cephalosporins, clavams and carbapenems. These findings raise the possibility that [beta]-lactam rings can be regio- and stereospecifically integrated into engineered peptides for application as, for example, targeted protease inactivators 3,4.