The structural biology of biosynthetic megaenzymes.
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.
UMR 7365, Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), CNRS-Université de Lorraine, Biopôle de l'Université de Lorraine, Campus Biologie Santé, Vandœuvre-lès-Nancy, France.
Kira J
0000000230122960
KJ
Weissman
D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020134:Catalytic Domain; D015870:Gene Expression; D005818:Genetic Engineering / Q000379:methods*; D007700:Kinetics; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010453:Peptide Synthases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D048630:Polyketide Synthases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis; D017510:Protein Folding; D017433:Protein Structure, Secondary; D013302:Streptomyces / Q000201:enzymology / Q000235:genetics; D013379:Substrate Specificity; D058615:Synthetic Biology / Q000379:methods*
D001426:Bacterial Proteins; D009097:Multienzyme Complexes; D048630:Polyketide Synthases; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase