Evolution-inspired engineering of nonribosomal peptide synthetases

Evolution-inspired engineering of nonribosomal peptide synthetases

Many clinically used drugs are derived from or inspired by bacterial natural products that often are produced through nonribosomal peptide synthetases (NRPSs), megasynthetases that activate and join individual amino acids in an assembly line fashion. In this work, we describe a detailed phylogenetic...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) Vol. 383; no. 6689; p. eadg4320
Main Authors: Bozhüyük, Kenan A J, Präve, Leonard, Kegler, Carsten, Schenk, Leonie, Kaiser, Sebastian, Schelhas, Christian, Shi, Yan-Ni, Kuttenlochner, Wolfgang, Schreiber, Max, Kandler, Joshua, Alanjary, Mohammad, Mohiuddin, T M, Groll, Michael, Hochberg, Georg K A, Bode, Helge B
Format: Journal Article
Language:English
Published: United States The American Association for the Advancement of Science 22-03-2024
Subjects:
Amino Acids
Assembly lines
Biological evolution
Biology
Breakpoints
Complexity
Condensates
Drug discovery
Drugs
Engineering
Enzymes
Evolution
Exchanging
Gene transfer
Genetic engineering
Genetics
Horizontal transfer
Machine learning
Markov chains
Microorganisms
Narcotics
Natural products
Peptide Synthases - chemistry
Peptide Synthases - genetics
Peptides
Phylogeny
Principal components analysis
Proteasome inhibitors
Proteasomes
Recombination
Redesign
Speciation
Synthetic biology
Taxonomy
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Summary:Many clinically used drugs are derived from or inspired by bacterial natural products that often are produced through nonribosomal peptide synthetases (NRPSs), megasynthetases that activate and join individual amino acids in an assembly line fashion. In this work, we describe a detailed phylogenetic analysis of several bacterial NRPSs that led to the identification of yet undescribed recombination sites within the thiolation (T) domain that can be used for NRPS engineering. We then developed an evolution-inspired "eXchange Unit between T domains" (XUT) approach, which allows the assembly of NRPS fragments over a broad range of GC contents, protein similarities, and extender unit specificities, as demonstrated for the specific production of a proteasome inhibitor designed and assembled from five different NRPS fragments.
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ISSN:0036-8075
1095-9203
DOI:10.1126/science.adg4320