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Applied and Environmental Microbiology, December 2006, p. 7626-7633, Vol. 72, No. 12
0099-2240/06/$08.00+0     doi:10.1128/AEM.01802-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Sec-Mediated Transport of Posttranslationally Dehydrated Peptides in Lactococcus lactis ^,

BiOMaDe Technology Foundation, Nijenborgh 4, 9747 AG Groningen, The Netherlands,¹ Department of Microbiology,² Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Kerklaan 30, 9751 NN Haren, The Netherlands³

Received 30 July 2006/ Accepted 2 October 2006

Nisin is a lanthionine-containing antimicrobial peptide produced by Lactococcus lactis. Its (methyl)lanthionines are introduced by two posttranslational enzymatic steps involving the dehydratase NisB, which dehydrates serine and threonine residues, and the cyclase NisC, which couples these dehydrated residues to cysteines, yielding thioether-bridged amino acids called lanthionines. The prenisin is subsequently exported by the ABC transporter NisT and extracellularly processed by the peptidase NisP. L. lactis expressing the nisBTC genes can modify and secrete a wide range of nonlantibiotic peptides. Here we demonstrate that in the absence of NisT and NisC, the Sec pathway of L. lactis can be exploited for the secretion of dehydrated variants of therapeutic peptides. Furthermore, posttranslational modifications by NisB and NisC still occur even when the nisin leader is preceded by a Sec signal peptide or a Tat signal peptide 27 or 44 amino acids long, respectively. However, transport of fully modified prenisin via the Sec pathway is impaired. The extent of NisB-mediated dehydration could be improved by raising the intracellular concentration NisB or by modulating the export efficiency through altering the signal sequence. These data demonstrate that besides the traditional lantibiotic transporter NisT, the Sec pathway with an established broad substrate range can be utilized for the improved export of lantibiotic enzyme-modified (poly)peptides.

Published ahead of print on 13 October 2006.

Supplemental material for this article may be found at http://aem.asm.org/.

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