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Recently, a new class of lasso peptides containing a second macrocycle, formed between a lysine sidechain and the C\u2010terminus, was discovered, resulting in an even more compact architecture. Here, we report the first NMR structure of the class V lasso peptide, gelatinamin A. Using heterologous expression of the gelatinamin biosynthetic gene cluster (BGC) in\n                    <jats:italic>Bacillus subtilis<\/jats:italic>\n                    , we delineated the biosynthetic pathway through targeted gene deletions. We expressed and characterized the predicted transpeptidase, GelP, that catalyzes the formation of an isopeptide bond between Lys2 and the C\u2010terminus and mediates the reversible conversion of gelatinamin B to gelatinamin A. In addition, we characterize GelT, an\n                    <jats:italic>N\u2010<\/jats:italic>\n                    acetyltransferase that inactivates lasso peptide antimicrobial activity by acetylating a key lysine residue. Furthermore, we demonstrate that gelatinamin is highly potent against several important pathogens and that the activity is strongly bicarbonate\u2010dependent. Finally, we propose a complete biosynthetic pathway for gelatinamin. The structural insight of gelatinamin A and the functional characterization of GelP provide the foundation for future discovery of class V lasso peptides and for engineering transpeptidases to modify other lasso peptide scaffolds.\n                  <\/jats:p>","DOI":"10.1002\/cbic.70378","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T12:23:19Z","timestamp":1778847799000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Biosynthesis, Structure, and Antibiotic Properties of Gelatinamin A, a Triculamin\u2010Like Lasso Peptide"],"prefix":"10.1002","volume":"27","author":[{"given":"Tiziana","family":"Svenningsen","sequence":"first","affiliation":[{"name":"Department of Biological &amp; Chemical Engineering Aarhus University  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aske","family":"Merrild","sequence":"additional","affiliation":[{"name":"Department of Biological &amp; Chemical Engineering Aarhus University  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biological &amp; Chemical Engineering Aarhus University  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederikke D.","family":"Hansen","sequence":"additional","affiliation":[{"name":"Department of Biological &amp; Chemical Engineering Aarhus University  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toby G.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering Princeton University  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reina","family":"Iwase","sequence":"additional","affiliation":[{"name":"Department of Chemistry Aarhus University  Aarhus Denmark"},{"name":"Interdisciplinary Nanoscience Center (iNANO) Aarhus University  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thibault","family":"Viennet","sequence":"additional","affiliation":[{"name":"Department of Chemistry Aarhus University  Aarhus Denmark"},{"name":"Interdisciplinary Nanoscience Center (iNANO) Aarhus University  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morten K.","family":"Larsen","sequence":"additional","affiliation":[{"name":"Department of Biological &amp; Chemical Engineering Aarhus University  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5066-9691","authenticated-orcid":false,"given":"A. 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