Protein–Protein Interactions in Multienzyme Megasynthetases

The multienzyme polyketide synthases (PKSs), nonribosomal polypeptide synthetases (NRPSs), and their hybrids are responsible for the construction in bacteria of numerous natural products of clinical value. These systems generate high structural complexity by using a simple biosynthetic logic—that of the assembly line. Each of the individual steps in building the metabolites is designated to an independently folded domain within gigantic polypeptides. The domains are clustered into functional modules, and the modules are strung out along the proteins in the order in which they act. Every metabolite results, therefore, from the successive action of up to 100 individual catalysts. Despite the conceptual simplicity of this division‐of‐labor organization, we are only beginning to decipher the molecular details of the numerous protein–protein interactions that support assembly‐line biosynthesis, and which are critical to attempts to re‐engineer these systems as a tool in drug discovery. This review aims to summarize the state of knowledge about several aspects of protein–protein interactions, including current architectural models for PKS and NRPS systems, the central role of carrier proteins, and the structural basis for intersubunit recognition.

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