Abstract
Lantibiotics are lanthionine-containing peptide antibiotics. Nisin, encoded by nisA, is a pentacyclic lantibiotic produced by some Lactococcus lactis strains. Its thioether rings are posttranslationally introduced by a membrane-bound enzyme complex. This complex is composed of three enzymes: NisB, which dehydrates serines and threonines; NisC, which couples these dehydrated residues to cysteines, thus forming thioether rings; and the transporter NisT. We followed the activity of various combinations of the nisin enzymes by measuring export of secreted peptides using antibodies against the leader peptide and mass spectroscopy for detection. L. lactis expressing the nisABTC genes efficiently produced fully posttranslationally modified prenisin. Strikingly, L. lactis expressing the nisBT genes could produce dehydrated prenisin without thioether rings and a dehydrated form of a non-lantibiotic peptide. In the absence of the biosynthetic NisBC enzymes, the NisT transporter was capable of excreting unmodified prenisin and fusions of the leader peptide with non-lantibiotic peptides. Our data show that NisT specifies a broad spectrum (poly)peptide transporter that can function either in conjunction with or independently from the biosynthetic genes. NisT secretes both unmodified and partially or fully posttranslationally modified forms of prenisin and non-lantibiotic peptides. These results open the way for efficient production of a wide range of peptides with increased stability or novel bioactivities.
Highlights
A wide spectrum of biological functions, such as hormone, growth factor, enzyme inhibitor, antigen, antibiotic, and ionophore, can be found among peptides
By controlling the lanthionine-synthesizing enzyme complex, one might envisage the possibility of introducing thioether rings at any peptide position
The leader peptide of nisin may fulfill several functions. Prior to export, it may have a role in the posttranslational modification and recognition events [17, 38]. It is needed for recognition by the transport system, and third, it keeps the lantibiotic in an inactive state until maturation has taken place [4]
Summary
A wide spectrum of biological functions, such as hormone, growth factor, enzyme inhibitor, antigen, antibiotic, and ionophore, can be found among peptides. Lantibiotics are bacterial peptides with intramolecular thioether bridges [5] They owe their name to their antibiotic activities and the presence of lanthionine residues. A variety of activities have been demonstrated for lantibiotics, e.g. the autoinduction of lantibiotic synthesis [6], permeabilization of target membranes [7,8,9,10,11], inhibition of cell wall synthesis [12], lipid II binding [13], inhibition of phospholipase A2 [14], and modulation of autolytic enzymes [15] and of an angiotensin-converting enzyme [16] These activities all depend on the presence of thioether rings. We show that the processing enzyme, NisP, requires lanthionine formation of the propeptide for proper functioning
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