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The \u03b1\u2010amino group of <jats:sc>l<\/jats:sc>\u2010ACL in a capuramycin is linked to an unsaturated hexuronic acid component through an amide bond that was previously shown to originate by an ATP\u2010independent enzymatic route. With the aid of a combined in vivo and in vitro approach, a predicted tridomain nonribosomal peptide synthetase CapU is functionally characterized here as the ATP\u2010dependent amide\u2010bond\u2010forming catalyst responsible for the biosynthesis of the remaining amide bond present in <jats:sc>l<\/jats:sc>\u2010ACL. The results are consistent with the adenylation domain of CapU as the essential catalytic component for <jats:sc>l<\/jats:sc>\u2010Lys activation and thioesterification of the adjacent thiolation domain. However, in contrast to expectations, lactamization does not require any additional domains or proteins and is likely a nonenzymatic event. The results set the stage for examining whether a similar NRPS\u2010mediated mechanism is employed in the biosynthesis of other <jats:sc>l<\/jats:sc>\u2010ACL\u2010containing natural products and, just as intriguingly, how spontaneous lactamization is avoided in the numerous NRPS\u2010derived peptides that contain an unmodified <jats:sc>l<\/jats:sc>\u2010Lys residue.<\/jats:p>","DOI":"10.1002\/cbic.201500701","type":"journal-article","created":{"date-parts":[[2016,2,3]],"date-time":"2016-02-03T11:35:58Z","timestamp":1454499358000},"page":"804-810","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The Role of a Nonribosomal Peptide Synthetase in <scp>l<\/scp>\u2010Lysine Lactamization During Capuramycin Biosynthesis"],"prefix":"10.1002","volume":"17","author":[{"given":"Xiaodong","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences College of Pharmacy University of Kentucky  Lexington KY 40536 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanyuan","family":"Jin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Biotechnology of Antibiotics Institute of Medicinal Biotechnology Chinese Academy of Medicinal Sciences &amp; Peking Union Medical College  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zheng","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences College of Pharmacy University of Kentucky  Lexington KY 40536 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koichi","family":"Nonaka","sequence":"additional","affiliation":[{"name":"Biologics Technology Research Laboratories Daiichi Sankyo, Co. 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