Abstract
Non-ribosomal peptide synthetases (NRPSs) are multienzymes that produce complex natural metabolites with many applications in medicine and agriculture. They are composed of numerous catalytic domains that elongate and chemically modify amino acid substrates or derivatives and of non-catalytic carrier protein domains that can tether and shuttle the growing products to the different catalytic domains. The intrinsic flexibility of NRPSs permits conformational rearrangements that are required to allow interactions between catalytic and carrier protein domains. Their large size coupled to this flexibility renders these multi-domain proteins very challenging for structural characterization. Here, we summarize recent studies that offer structural views of multi-domain NRPSs in various catalytically relevant conformations, thus providing an increased comprehension of their catalytic cycle. A better structural understanding of these multienzymes provides novel perspectives for their re-engineering to synthesize new bioactive metabolites.
Highlights
Non-ribosomal peptide synthetases (NRPSs) are classified into two categories, type I and type II
This flexibility is a drawback to structural characterizations of large NRPS fragments and, successful structural studies have often required the employment of chemical tools to reduce conformational heterogeneity [19,20,21,22]
We focus on recent aspects of NRPS flexibility that allow peptidyl carrier protein (PCP) movements during a catalytic cycle, by describing both the successive conformations adopted by these enzymes during a cycle as well as movements that engender passage from one conformation to the
Summary
Natural products are secondary metabolites synthesized by microorganisms in order to adapt to their environment [1]. The type I NRPS megaenzymes use an assembly line strategy (figure 1) with modules that act sequentially, each being responsible for the incorporation of an amino acid into the final metabolite. Polyketide synthases (PKSs) that are modular megaenzymes, adopt the same assembly line logic as NRPSs but they use small carbon chain substrates instead of amino acid substrates [10] This similar strategy explains the existence of numerous hybrid NRPS/PKS assembly lines that produce hybrid peptide-polyketide metabolites [11]. Each assembly line ends with a domain, such as a thioesterase (TE) or a reductase (Re) (module 7 in figure 1a), that releases the final product This final stage can introduce further diversity in the peptide as the release can occur either by hydrolysis or cyclization. We focus on recent aspects of NRPS flexibility that allow PCP movements during a catalytic cycle, by describing both the successive conformations adopted by these enzymes during a cycle as well as movements that engender passage from one conformation to the
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