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.
|Number of pages||7|
|State||Published - May 3 2016|
Bibliographical noteFunding 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.).
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
- natural products
- nonribosomal peptides
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Organic Chemistry