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The Role of a Nonribosomal Peptide Synthetase in l ‐Lysine Lactamization During Capuramycin Biosynthesis
Author(s) -
Liu Xiaodong,
Jin Yuanyuan,
Cui Zheng,
aka Koichi,
Baba Satoshi,
Funabashi Masanori,
Yang Zhaoyong,
Van Lanen Steven G.
Publication year - 2016
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201500701
Subject(s) - nonribosomal peptide , adenylylation , biosynthesis , chemistry , amide , residue (chemistry) , stereochemistry , peptide bond , peptide , amino acid , enzyme , biochemistry
Capuramycins are one of several known classes of natural products that contain an l ‐Lys‐derived l ‐α‐amino‐ɛ‐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.