are linked by membrane-spanning segments [28]. Most response regulator
proteins contain an N-terminal aspartic residue as a site for phosphorylation
and a C-terminal output domain involved in mediating an adaptive response
[28]. Response regulators bind as dimers to a specific site (mostly direct or
inverted repeats) present near the promoter, thereby stimulating or inhibiting
binding of the RNA polymerase to the promoter region [173–177]. Interestingly, direct repeats referred to as potential binding sites for response
regulator dimers have been reported upstream from the promoters of the
different operons involved in the production of several inducible bacteriocin
promoters, suggesting a common positive mechanism of regulation for
bacteriocin production [49].
Such a regulatory operon, encoding an inducer peptide (plantaricin A), a
histidine protein kinase with six transmembrane domains (PlnB) and two
regulatory proteins (PlnC and PlnD) has been reported for plantaricin A [49,
134]. Genes for a histidine protein kinase (nisK, sakK) and a response regulator
(nisR, sakR) were also found in the locus encoding sakacin A, sakacin P, carnobacteriocin A and nisin production [28, 92, 101, 103, 107, 133].
PlnB/SakK, PlnC/SakR and PlnD show highest homology with their counterparts in the agr (accessory gene regulatory) system of Staphylococcus aureus
[134, 149, 150]. The biosynthesis of extracellular proteins which are subject to
growth phase-dependent control and play an important role in staphylococcal
infection are regulated by the agr locus, which consists of two divergent
operons [134, 148, 178–180]. The first transcription unit encoded AgrA (RR),
AgrC (HPK) and AgrD. An octapeptide processed from AgrD, is involved in
activation of the agr locus [49, 181]. Activation of the agr operon also results
in a higher transcription level of hld, which in turn is responsible for the agrdependent regulation of the above mentioned extracellular toxins and enzymes
[134, 180]. Although initially purified, and characterized as a bacteriocin
depending on the complementation of two almost identical peptides, it is now
believed that plantaricin A is not a bacteriocin but acts as an agr-dependent
inducer molecule [47, 49, 134, 145]. Extracellular addition of plantaricin A to a
Bac
– mutant restored transcription of the different units invo1ved in bacteriocin production as well as antagonistic activity, indicating a role as induction
factor for plantaricin A [49]. In general, these induction factors (IF) involved in
bacteriocin production are (i) bacteriocin-like peptides with a double-glycine
leader peptide, (ii) their mature form is shorter than a regular bacteriocin and,
(iii) the genes encoding IF are located upstream from the histidine kinase gene
of the two component system [28]. Small peptides preceding the histidine
proteinase kinase, response regulator tandem have also been reported for
sakacin A (orf4), sakacin P (orf Y) and carnobacteriocins A, B 1 and BM2 (orf6)
[28, 49] (Fig. 5). The role of orf4 in induction of the sakacin P production has
already been established [49].
Analogously, it has been shown that NisK and NisP constitute the histidine
proteinase kinase and response regulator components of the nisin signal
transduction system [92, 101, 107]. NisK is a 447-residue, membrane-integrated
protein with two potential N-terminal membrane anchors and a cytoplasmic
carboxy-terminus [107]. The carboxy-terminus contains a His-238 residue for
Antimicrobial Peptides of Lactic Acid Bacteria: Mode of Action, Genetics and Biosynthesis
39
proteins contain an N-terminal aspartic residue as a site for phosphorylation
and a C-terminal output domain involved in mediating an adaptive response
[28]. Response regulators bind as dimers to a specific site (mostly direct or
inverted repeats) present near the promoter, thereby stimulating or inhibiting
binding of the RNA polymerase to the promoter region [173–177]. Interestingly, direct repeats referred to as potential binding sites for response
regulator dimers have been reported upstream from the promoters of the
different operons involved in the production of several inducible bacteriocin
promoters, suggesting a common positive mechanism of regulation for
bacteriocin production [49].
Such a regulatory operon, encoding an inducer peptide (plantaricin A), a
histidine protein kinase with six transmembrane domains (PlnB) and two
regulatory proteins (PlnC and PlnD) has been reported for plantaricin A [49,
134]. Genes for a histidine protein kinase (nisK, sakK) and a response regulator
(nisR, sakR) were also found in the locus encoding sakacin A, sakacin P, carnobacteriocin A and nisin production [28, 92, 101, 103, 107, 133].
PlnB/SakK, PlnC/SakR and PlnD show highest homology with their counterparts in the agr (accessory gene regulatory) system of Staphylococcus aureus
[134, 149, 150]. The biosynthesis of extracellular proteins which are subject to
growth phase-dependent control and play an important role in staphylococcal
infection are regulated by the agr locus, which consists of two divergent
operons [134, 148, 178–180]. The first transcription unit encoded AgrA (RR),
AgrC (HPK) and AgrD. An octapeptide processed from AgrD, is involved in
activation of the agr locus [49, 181]. Activation of the agr operon also results
in a higher transcription level of hld, which in turn is responsible for the agrdependent regulation of the above mentioned extracellular toxins and enzymes
[134, 180]. Although initially purified, and characterized as a bacteriocin
depending on the complementation of two almost identical peptides, it is now
believed that plantaricin A is not a bacteriocin but acts as an agr-dependent
inducer molecule [47, 49, 134, 145]. Extracellular addition of plantaricin A to a
Bac
– mutant restored transcription of the different units invo1ved in bacteriocin production as well as antagonistic activity, indicating a role as induction
factor for plantaricin A [49]. In general, these induction factors (IF) involved in
bacteriocin production are (i) bacteriocin-like peptides with a double-glycine
leader peptide, (ii) their mature form is shorter than a regular bacteriocin and,
(iii) the genes encoding IF are located upstream from the histidine kinase gene
of the two component system [28]. Small peptides preceding the histidine
proteinase kinase, response regulator tandem have also been reported for
sakacin A (orf4), sakacin P (orf Y) and carnobacteriocins A, B 1 and BM2 (orf6)
[28, 49] (Fig. 5). The role of orf4 in induction of the sakacin P production has
already been established [49].
Analogously, it has been shown that NisK and NisP constitute the histidine
proteinase kinase and response regulator components of the nisin signal
transduction system [92, 101, 107]. NisK is a 447-residue, membrane-integrated
protein with two potential N-terminal membrane anchors and a cytoplasmic
carboxy-terminus [107]. The carboxy-terminus contains a His-238 residue for
Antimicrobial Peptides of Lactic Acid Bacteria: Mode of Action, Genetics and Biosynthesis
39