Structural insights into nonribosomal peptide enzymatic assembly lines

Abstract

Nonribosomal peptides have a variety of medicinal activities including activity as antibiotics, antitumor drugs, immunosuppressives, and toxins. Their biosynthesis on multimodular assembly lines as a series of covalently tethered thioesters, in turn covalently attached on pantetheinyl arms on carrier protein way stations, reflects similar chemical logic and protein machinery to fatty acid and polyketide biosynthesis. While structural information on excised or isolated catalytic adenylation (A), condensation (C), peptidyl carrier protein (PCP) and thioesterase (TE) domains had been gathered over the past decade, little was known about how the NRPS catalytic and carrier domains interact with each other both within and across elongation or termination modules. This highlight reviews recent breakthrough achievements in both X-ray and NMR spectroscopic studies that illuminate the architecture of NRPS PCP domains, PCP-containing didomain-fragments and of a full termination module (C-A-PCP-TE).

Evolution of cyclic peptide protease inhibitors

“…Considerable effort has focused on reprogramming this natural biosynthetic machinery to generate diverse libraries of structurally complex peptides that can be subsequently selected for a desired biological activity. Although various synthetic and in vitro methods have also been developed to generate large peptide libraries from natural and unnatural amino acids and enrich them using affinity-based methods (e.g., phage and ribosomal display, DNA directed synthesis, and encoded synthetic peptide libraries) (8)(9)(10)(11)(12)(13), to date the synthesis and bacterial selection of cyclic peptides containing unnatural amino acid (UAA) building blocks has remained elusive.…”

Vibrio Iron Transport: Evolutionary Adaptation to Life in Multiple Environments

“…There are two cyclization domains, followed by an adenylation domain, a condensation domain, a peptidyl carrier protein (PCP) domain, and a second condensation domain (46). This assembly process on a NRPS with distinct, modular domains is characteristic of bacterial catechol siderophores and other secondary metabolites, including antibiotics, and has been described in detail for E. coli and other species (52)(53)(54). The domain structure of the NRPSs has facilitated the evolution of a large family of distinct siderophores with variations in the peptide backbones, chelating moieties, or other modifications.…”

Polymerization of Peptide Polymers for Biomaterial Applications

“…[58,59] The activated amino acids are transferred to the PCP-domain where they are covalently tethered to the 4′-phosphopantetheinyl cofactor. [60] Propagation takes place at the C-domain, where the amino acids are linked via a condensation reaction. Termination occurs at the TE domain through either a hydrolysis or a cyclization reaction, resulting in a linear or cyclic polypeptide, respectively.…”