The Role of a Nonribosomal Peptide Synthetase in l‐Lysine Lactamization During Capuramycin Biosynthesis |
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Authors: | Dr Xiaodong Liu Yuanyuan Jin Zheng Cui Dr Koichi Nonaka Satoshi Baba Dr Masanori Funabashi Dr Zhaoyong Yang Dr Steven G Van?Lanen |
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Affiliation: | 1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA;2. Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medicinal Sciences & Peking Union Medical College, Beijing, China;3. Biologics Technology Research Laboratories, Daiichi Sankyo, Co. Ltd., Gunma, Japan;4. Natural Product Research Group, Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co. Ltd., Tokyo, Japan |
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Abstract: | Capuramycins are one of several known classes of natural products that contain an l ‐Lys‐derived l ‐α‐amino‐?‐caprolactam (l ‐ACL) unit. The α‐amino group of l ‐ACL in a capuramycin is linked to an unsaturated hexuronic acid component through an amide bond that was previously shown to originate by an ATP‐independent 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‐dependent amide‐bond‐forming catalyst responsible for the biosynthesis of the remaining amide bond present in l ‐ACL. The results are consistent with the adenylation domain of CapU as the essential catalytic component for l ‐Lys 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‐mediated mechanism is employed in the biosynthesis of other l ‐ACL‐containing natural products and, just as intriguingly, how spontaneous lactamization is avoided in the numerous NRPS‐derived peptides that contain an unmodified l ‐Lys residue. |
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Keywords: | antibiotics biosynthesis natural products nonribosomal peptides nucleosides |
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