{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T13:10:24Z","timestamp":1760015424781,"version":"3.37.3"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"19","license":[{"start":{"date-parts":[[2019,2,20]],"date-time":"2019-02-20T00:00:00Z","timestamp":1550620800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100009744","name":"Eshelman Institute for Innovation","doi-asserted-by":"crossref","award":["R1010 RX03620204"],"award-info":[{"award-number":["R1010 RX03620204"]}],"id":[{"id":"10.13039\/100009744","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["GM112981"],"award-info":[{"award-number":["GM112981"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>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\u00a0804 IMLs from both well annotated and putative NRPS biosynthetic gene clusters from 39\u00a0232 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 of novel NRPS.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>The IMLs database as well as the NRPS-Parser have been made available on the web at https:\/\/nrps-linker.unc.edu. The entire source code of the project is hosted in GitHub repository (https:\/\/github.com\/SWFarag\/nrps-linker).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Supplementary information<\/jats:title>\n                  <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btz127","type":"journal-article","created":{"date-parts":[[2019,2,18]],"date-time":"2019-02-18T04:25:53Z","timestamp":1550463953000},"page":"3584-3591","source":"Crossref","is-referenced-by-count":8,"title":["Inter-Modular Linkers play a crucial role in governing the biosynthesis of non-ribosomal peptides"],"prefix":"10.1093","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0324-5738","authenticated-orcid":false,"given":"Sherif","family":"Farag","sequence":"first","affiliation":[{"name":"Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill , Chapel Hill, NC, USA"},{"name":"Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, NC, USA"}]},{"given":"Rachel M","family":"Bleich","sequence":"additional","affiliation":[{"name":"Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, NC, USA"}]},{"given":"Elizabeth A","family":"Shank","sequence":"additional","affiliation":[{"name":"Department of Biology, University of North Carolina at Chapel Hill , Chapel Hill, NC, USA"},{"name":"Department of Microbiology and Immunology, University of North Carolina at Chapel Hill , Chapel Hill, NC, USA"}]},{"given":"Olexandr","family":"Isayev","sequence":"additional","affiliation":[{"name":"Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, NC, USA"}]},{"given":"Albert A","family":"Bowers","sequence":"additional","affiliation":[{"name":"Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, NC, USA"}]},{"given":"Alexander","family":"Tropsha","sequence":"additional","affiliation":[{"name":"Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, NC, USA"}]}],"member":"286","published-online":{"date-parts":[[2019,2,20]]},"reference":[{"key":"2023013108153564400_btz127-B1","doi-asserted-by":"crossref","first-page":"2264","DOI":"10.1093\/bioinformatics\/bti363","article-title":"Prediction of protein interdomain linker regions by a hidden Markov model","volume":"21","author":"Bae","year":"2005","journal-title":"Bioinformatics"},{"key":"2023013108153564400_btz127-B2","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1038\/nbt1265","article-title":"Molecular engineering approaches to peptide, polyketide and other antibiotics","volume":"24","author":"Baltz","year":"2006","journal-title":"Nat. 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