AI Article Synopsis
- Many drugs used in medicine come from bacterial natural products created by complex enzymes called nonribosomal peptide synthetases (NRPSs) that link amino acids together.
- This research identifies new recombination sites within a specific part of NRPSs, the thiolation (T) domain, paving the way for innovative engineering of these enzymes.
- The study introduces a method called "eXchange Unit between T domains" (XUT), which enables scientists to combine NRPS fragments with different characteristics to create specific drugs, such as a proteasome inhibitor constructed from five distinct NRPS pieces.
Article Abstract
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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| http://dx.doi.org/10.1126/science.adg4320 | DOI Listing |
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