Inter-Modular Linkers play a crucial role in governing the biosynthesis of non-ribosomal peptides

Bioinformatics
Sherif FaragAlexander Tropsha

Abstract

Non-ribosomal peptide synthetases (NRPSs) are modular enzymatic machines that catalyze the ribosome-independent production of structurally complex small peptides, many of which have important clinical applications as antibiotics, antifungals and anti-cancer agents. Several groups have tried to expand natural product diversity by intermixing different NRPS modules to create synthetic peptides. This approach has not been as successful as anticipated, suggesting that these modules are not fully interchangeable. We explored whether Inter-Modular Linkers (IMLs) impact the ability of NRPS modules to communicate during the synthesis of NRPs. We developed a parser to extract 39 804 IMLs from both well annotated and putative NRPS biosynthetic gene clusters from 39 232 bacterial genomes and established the first IMLs database. We analyzed these IMLs and identified a striking relationship between IMLs and the amino acid substrates of their adjacent modules. More than 92% of the identified IMLs connect modules that activate a particular pair of substrates, suggesting that significant specificity is embedded within these sequences. We therefore propose that incorporating the correct IML is critical when attempting combinatorial biosynthesis...Continue Reading

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Citations

Jul 2, 2019·Natural Product Reports·Mohammad AlanjaryMarnix H Medema
Jan 14, 2021·Biochemical Society Transactions·Fleur Ruijne, Oscar P Kuipers
Sep 14, 2019·Biotechnology Advances·Antoine VassauxValérie Leclère

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