Review
Protein–Protein Interactions in Multienzyme Megasynthetases
Kira J. Weissman Dr.,
Rolf Müller Prof.,
Kira J. Weissman Dr.
Pharmaceutical Biotechnology, Saarland University, P. O. Box 151150, 66041 Saarbrücken, Germany, Fax: (+49) 681-302-5473
Search for more papers by this authorRolf Müller Prof.
Pharmaceutical Biotechnology, Saarland University, P. O. Box 151150, 66041 Saarbrücken, Germany, Fax: (+49) 681-302-5473
Search for more papers by this author
Kira J. Weissman Dr.,
Rolf Müller Prof.,
Kira J. Weissman Dr.
Pharmaceutical Biotechnology, Saarland University, P. O. Box 151150, 66041 Saarbrücken, Germany, Fax: (+49) 681-302-5473
Search for more papers by this authorRolf Müller Prof.
Pharmaceutical Biotechnology, Saarland University, P. O. Box 151150, 66041 Saarbrücken, Germany, Fax: (+49) 681-302-5473
Search for more papers by this authorGraphical Abstract
Enzymatic teamwork in action: Assembly-line biosynthesis of natural products by multienzyme megasynthetases requires numerous protein–protein interactions. This review summarizes the current state of knowledge about several aspects of these interactions, including architectural models for these systems, carrier protein centered communication (see figure), and intersubunit docking.
Abstract
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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