lantibiotics produced by non-lactic acid bacteria, such as Pep5, lactocin S and
epilancin K7, the N-terminal threonine and serine residues are modified into
2-oxy-butyryl, 2-oxy-propionyl and 2-hydroxy-pyruvyl residues, respectively
[82, 186, 187]. The N-terminal deaminations of dehydroamino acids are considered to occur spontaneously [82]. In the case of epilancin, the 2-oxy-pyruvyl
group may be enzymatically reduced to a 2-hydroxy-pyruvyl residue which
then would be the very last biosynthetic reaction [82]. In addition, the Cterminal cysteine residues of epidermin and the related gallidermin are
modified into S-[(Z)-2-aminovinyl]-d-cysteine [90, 188, 189]. In contrast to
earlier reports where C-terminal modifications were claimed to occur after
lanthionine bridge formation [90], it has recently been shown that the Cterminal modification reaction, catalyzed by EpiD, may take place intracellularly as the first step in the post-translational modification of epidermin [184,
189]. This modification reaction and its corresponding enzyme are unique for
epidermin and have not been found in any other lantibiotic. Detection of sixfold, fivefold, fourfold, etc. dehydrated pre-Pep5 molecules in the cytoplasmic
fraction of the PepS producer showed that (i) dehydration and ring formation
are separate steps and (ii) ring formation happens after dehydration [82].
The presence of two genes, nisB and nisC, encoding 993- and 414-residue
proteins without significant homology to other known proteins, but conserved
in several lantibiotic operons, has made them strong candidates for post-translational modifications in the maturation pathway of lantibiotics [40]. Limited
similarity between NisB and E. coli IlvA, a threonine dehydratase, was reported
and hence a dehydratase function for NisB was suggested [40]. Mutation studies
of NisB, NisC, EpiB, EpiC, and SpaB indicated that these proteins were essential
for nisin, epidermin and subtilin biosynthesis, respectively [40, 86, 87, 190]. As
no precursors have been identified and characterized in these mutants, conclusions about the reaction that is catalyzed by these proteins remain speculative [40]. Secondary-structure predictions and experimental evidence confirmed that NisB and SpaB are both membrane-bound [100].
Some lantibiotic operons, such as lactocin S, lactococcin DR (lacticin 481) or
cytolysin contain no homologues of the nisB and nisC genes [82, 118, 122]. In
these operons, the homologous genes lasM, lctM, and cylM were found [82, 118,
122]. Since CylM and LctM contain a C-terminal domain with striking homology to NisC, it could be hypothesized that they combine the function of a
dehydratase and the enzymatic reaction leading to lanthionin ring formation
[40, 122, 123]. There is a striking correlation between this grouping and the classification of lantibiotics based on their leader sequences [22, 40]. It is therefore
tempting to assume that NisB/NisC and its homologues interact with class IA I
leader peptides, whereas an interaction between the larger proteins of the CylM
family and the class IA II leader peptides occurs [40]. The post-translational
modification reactions of a pre-lantibiotic leads to the formation of an inactive
precursor molecule, consisting of the completely matured lantibiotic, still
attached to its leader peptide [101, 102]. The N-terminal modification of the
lantibiotics Pep5, lactocin S and epilancin K7, occurs after proteolytic cleavage
of the precursor and is therefore an exception to this rule [82].
Antimicrobial Peptides of Lactic Acid Bacteria: Mode of Action, Genetics and Biosynthesis
41
epilancin K7, the N-terminal threonine and serine residues are modified into
2-oxy-butyryl, 2-oxy-propionyl and 2-hydroxy-pyruvyl residues, respectively
[82, 186, 187]. The N-terminal deaminations of dehydroamino acids are considered to occur spontaneously [82]. In the case of epilancin, the 2-oxy-pyruvyl
group may be enzymatically reduced to a 2-hydroxy-pyruvyl residue which
then would be the very last biosynthetic reaction [82]. In addition, the Cterminal cysteine residues of epidermin and the related gallidermin are
modified into S-[(Z)-2-aminovinyl]-d-cysteine [90, 188, 189]. In contrast to
earlier reports where C-terminal modifications were claimed to occur after
lanthionine bridge formation [90], it has recently been shown that the Cterminal modification reaction, catalyzed by EpiD, may take place intracellularly as the first step in the post-translational modification of epidermin [184,
189]. This modification reaction and its corresponding enzyme are unique for
epidermin and have not been found in any other lantibiotic. Detection of sixfold, fivefold, fourfold, etc. dehydrated pre-Pep5 molecules in the cytoplasmic
fraction of the PepS producer showed that (i) dehydration and ring formation
are separate steps and (ii) ring formation happens after dehydration [82].
The presence of two genes, nisB and nisC, encoding 993- and 414-residue
proteins without significant homology to other known proteins, but conserved
in several lantibiotic operons, has made them strong candidates for post-translational modifications in the maturation pathway of lantibiotics [40]. Limited
similarity between NisB and E. coli IlvA, a threonine dehydratase, was reported
and hence a dehydratase function for NisB was suggested [40]. Mutation studies
of NisB, NisC, EpiB, EpiC, and SpaB indicated that these proteins were essential
for nisin, epidermin and subtilin biosynthesis, respectively [40, 86, 87, 190]. As
no precursors have been identified and characterized in these mutants, conclusions about the reaction that is catalyzed by these proteins remain speculative [40]. Secondary-structure predictions and experimental evidence confirmed that NisB and SpaB are both membrane-bound [100].
Some lantibiotic operons, such as lactocin S, lactococcin DR (lacticin 481) or
cytolysin contain no homologues of the nisB and nisC genes [82, 118, 122]. In
these operons, the homologous genes lasM, lctM, and cylM were found [82, 118,
122]. Since CylM and LctM contain a C-terminal domain with striking homology to NisC, it could be hypothesized that they combine the function of a
dehydratase and the enzymatic reaction leading to lanthionin ring formation
[40, 122, 123]. There is a striking correlation between this grouping and the classification of lantibiotics based on their leader sequences [22, 40]. It is therefore
tempting to assume that NisB/NisC and its homologues interact with class IA I
leader peptides, whereas an interaction between the larger proteins of the CylM
family and the class IA II leader peptides occurs [40]. The post-translational
modification reactions of a pre-lantibiotic leads to the formation of an inactive
precursor molecule, consisting of the completely matured lantibiotic, still
attached to its leader peptide [101, 102]. The N-terminal modification of the
lantibiotics Pep5, lactocin S and epilancin K7, occurs after proteolytic cleavage
of the precursor and is therefore an exception to this rule [82].
Antimicrobial Peptides of Lactic Acid Bacteria: Mode of Action, Genetics and Biosynthesis
41