The Role of a Nonribosomal Peptide Synthetase in l -Lysine Lactamization during Capuramycin Biosynthesis

Xiaodong Liu, Yuanyuan Jin, Zheng Cui, Koichi Nonaka, Satoshi Baba, Masanori Funabashi, Zhaoyong Yang, Steven G. Van Lanen

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish
Pages (from-to)804-810
Number of pages7
JournalChemBioChem
Volume17
Issue number9
DOIs
StatePublished - May 3 2016

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health grants AI087849 and UL1TR000117 (S.V.L.) and National Natural Science Foundation of China grants 81261120417, 81321004, and 81273414 (Z.Y.).

Publisher Copyright:
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Keywords

  • antibiotics
  • biosynthesis
  • natural products
  • nonribosomal peptides
  • nucleosides

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

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