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The structural biology of biosynthetic megaenzymes

Abstract

The modular polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs) are among the largest and most complicated enzymes in nature. In these biosynthetic systems, independently folding protein domains, which are organized into units called 'modules', operate in assembly-line fashion to construct polymeric chains and tailor their functionalities. Products of PKSs and NRPSs include a number of blockbuster medicines, and this has motivated researchers to understand how they operate so that they can be modified by genetic engineering. Beginning in the 1990s, structural biology has provided a number of key insights. The emerging picture is one of remarkable dynamics and conformational programming in which the chemical states of individual catalytic domains are communicated to the others, configuring the modules for the next stage in the biosynthesis. This unexpected level of complexity most likely accounts for the low success rate of empirical genetic engineering experiments and suggests ways forward for productive megaenzyme synthetic biology.

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Figure 1: Biosynthetic cycles within PKS and NRPS modules.
Figure 2: Non-collinear PKS and NRPS systems.
Figure 3: Models of cis-AT PKS architecture.
Figure 4: Model for stereocontrol in cis-AT PKSs derived from structural and biochemical studies.
Figure 5: Alternation mechanism proposed for NRPS adenylation domains.
Figure 6: Structural characterization of intact modules from cis-AT and trans-AT PKSs.
Figure 7: Crystal structure of an intact NRPS termination module.
Figure 8: Models for carrier protein-centered interactions in assembly line multienzymes.

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Acknowledgements

Work in the author's laboratory is supported by the Agence Nationale de la Recherche (ANR JCJC 2011 PKS-PPIs, K.J.W.), the Centre National de la Recherche Scientifique (CNRS), and the University of Lorraine and the Lorraine Region (BQR grants to K.J.W. and B. Chagot). P.F. Leadlay is gratefully acknowledged for helpful comments and critical reading of the manuscript. T. Annaval and A. Gruez are thanked for help with figure preparation.

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Weissman, K. The structural biology of biosynthetic megaenzymes. Nat Chem Biol 11, 660–670 (2015). https://doi.org/10.1038/nchembio.1883

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