| 1.C.21 The Lacticin 481 (Lacticin 481) Family
Many organisms synthesize proteins (or peptides) which are degraded to relatively small hydrophobic or amphipathic, bioactive peptides. These peptides exhibit antibiotic, fungicidal, virucidal, hemolytic and/or tumoricidal activities by interacting with membranes and forming transmembrane channels that allow the free flow of electrolytes, metabolites and water across the phospholipid bilayers. Most of these peptides appear to function in biological warfare. There are many designations given to these bioactive peptides. They include the magainins, cecropins, melittins, defensins, bacteriocidins, etc. The proteins in each family within this functional superfamily are homologous, but they exhibit little or no significant sequence similarity with members of the other families. Thus, each family may have evolved independently. However, certain common structural features observed between members of distinct families suggest that at least some of these families share a common ancestry.
The generalized transport reaction catalyzed by channel-forming amphipathic peptides is: small solutes, electrolytes and water (in)  small solutes, electrolytes and water (out). A list of these peptides in classes I - IV (below) was derived from [S. Upatissa & RJ Mitchell (PMID: 36753040)].
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Bacteriocin classification
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Examples for each class
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Class
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Subclass
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Class I
Post-translationally modified
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a. Lantibiotics
b. Circular peptides
c. sec dependent circular peptides
d. Linear azol(in)e-containing peptides
e. Glycocins
f. Lasso peptides
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Cinnamycin (Machaidze & Seelig, 2003; Vestergaard et al., 2019)
Duramycin (Huo et al., 2017)
Mersacidin (Altena et al., 2000; Guder et al., 2002), Salivaricin (Birri et al., 2012; Wayah & Philip, 2018), Epidermin (Nakazono et al., 2022; Schnell et al., 1988), Gallidermin (Bengtsson et al., 2018; Saising et al., 2012), Mutacin (Krull et al., 2000; Novak et al., 1994), Mersacidin (Brötz et al., 1998; Kruszewska et al., 2004)
Streptin 1, Streptin 2 (Wescombe & Tagg, 2003)
Plantaricin LR14 (Tiwari & Srivastava, 2008)
Variacin (O’mahony et al., 2001)
Nukacin (Wilaipun et al., 2008)
Lacticin 3147 (Wiedemann et al., 2006)
Nisin (Cheigh & Pyun, 2005; Chen et al., 2020)
Gassericin A (Pandey et al., 2013), Garvicin ML (Borrero et al., 2011)
Microcin C7 (Guijarro et al., 1995)
Microcin J25 (Bayro et al., 2003)
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Class II
Unmodified peptides
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a. Pediocin-like
b. Consists of two different peptides
c. Circular
d. Miscellaneous
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Pediocin PA-1 (Rodríguez et al., 2002)
Microcin L (Gaillard-Gendron et al., 2000)
Leucocin (Hastings et al., 1991; Sawa et al., 2010; Wan et al., 2013), Enterocin (Balla et al., 2000; Mareková et al., 2007)
Enterocin T (Chen et al., 2013)
Bovicin 255 (Whitford et al., 2001)
Lacticin Q (Fujita et al., 2007)
Coagulin (Fu et al., 2018; Le Marrec et al., 2000), Ubericin (Heng et al., 2007; Oftedal et al., 2021), Divergicin (Hoick et al., 1996; Naghmouchi et al., 2007a, 2007b; Tahiri et al., 2004)
Microcin N (Corsini et al., 2010)
Microcin S (Zschüttig et al., 2012)
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Class III
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a. Bacteriolytic
b. Non-lytic
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Helveticin V-1829 (Choi et al., 2022; Vaughan et al., 1992), Caseicin 80 (Choi et al., 2022; Rammelsberg et al., 1990)
Colicin U (Smajs et al., 1997), Colicin B (Hilsenbeck et al., 2004)
Klebicin (Denkovskienė et al., 2019; Riley et al., 2001)
Salmocins (Łojewska et al., 2022; Schneider et al., 2018)
Stenocins (Paškevičius et al., 2022)
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Class IV
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Contains a lipid or carbohydrate moiety
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Bacteriocins are bacterially produced peptide antibiotics with the ability to kill a limited range of bacteria, usually but not always those that are closely related to the producer bacterium. Many of them exhibit structural features typical of members of the eukaryotic channel-forming amphipathic peptides. That is, they are usually synthesized as small precursor proteins or peptides which are processed with proteolytic elimination of their N-terminal leader sequences, and the resultant mature peptides form one, two or more putative amphipathic transmembrane α-helical spanners (TMSs). For those with two TMSs, a characteristic hinge region that separates the two putative transmembrane segments is usually observed. A similar structural arrangement occurs in the two-TMS Cecropin A proteins (TC #1.C.17).
Many bacteriocins are encoded in operons that also encode an immunity protein and an ABC transport system (TC #3.A.1) with a protease domain at the N-terminus. The ABC systems export the bacteriocins while the protease domains cleave the N-terminal leader sequence. A few bacteriocins are exported by the type II general secretory pathway rather than by ABC-type export systems. In some cases, expression of the bacteriocin-encoding operon is induced by a bacteriocin-like peptide which acts in conjunction with a two component sensor kinase-response regulator to effect induction.
Class I lantibiotic bacteriocins are small membrane-active channel-forming peptides of less than 5 kDa. They contain the unusual amino acids lanthionine and β-methyl lanthionine, as well as dehydrated residues. One member of family 1.C.22 (TC #1.C.22.1.2) is the thiol-activated peptide, Lactococcin B, included in Class IIc by Klaenhammer (1993).
Many bacteriocins have been identified in addition to those tabulated in the TC system, but those listed are among the best characterized, with respect to evidence for channel formation in target bacterial membranes. Class III and IV bacteriocins (Klaenhammer, 1993) are large heat-labile proteins that function by mechanisms unrelated to those of the bacteriocins listed here.
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This family belongs to the Lantibiotic Bacteriocin (La-Ba) Superfamily.
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| References: |
Allison, G.E., C. Fremaux and T.R. Klaenhammer (1994). Expansion of bacteriocin activity and host range upon complementation of two peptides encoded within the lactacin F operon. J. Bacteriol. 176: 2235-2241.
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Anjana, and S.K. Tiwari. (2022). Bacteriocin-Producing Probiotic Lactic Acid Bacteria in Controlling Dysbiosis of the Gut Microbiota. Front Cell Infect Microbiol 12: 851140.
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Aso, Y., J. Nagao, H. Koga, K. Okuda, Y. Kanemasa, T. Sashihara, J. Nakayama, and K. Sonomoto. (2004). Heterologous expression and functional analysis of the gene cluster for the biosynthesis of and immunity to the lantibiotic, nukacin ISK-1. J Biosci Bioeng 98: 429-436.
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Biswas, S. and I. Biswas. (2014). A conserved streptococcal membrane protein, LsrS, exhibits a receptor-like function for lantibiotics. J. Bacteriol. 196: 1578-1587.
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Chikindas, M.L., J. Novák, A.J. Driessen, W.N. Konings, K.M. Schilling, and P.W. Caufield. (1995). Mutacin II, a bactericidal antibiotic from Streptococcus mutans. Antimicrob. Agents Chemother. 39: 2656-2660.
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Diep, D.B., L.S. Håvarstein and I.F. Nes (1995). A bacteriocin-like peptide induces bacteriocin synthesis in Lactobacillus plantarum C11. Mol. Microbiol. 18: 631-639.
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Klaenhammer, T.R. (1993). Genetics of bacteriocins produced by lactic acid bacteria. FEMS Microbiol. Rev. 12: 39-85.
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Nes, I.F., D.B. Diep, L.S. Håvarstein, M.B. Brurberg, V. Eijsink and H. Holo (1996). Biosynthesis of bacteriocins in lactic acid bacteria. Antonie van Leeuwenhoek 70: 113-128.
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Okuda, K., Y. Aso, J. Nakayama, and K. Sonomoto. (2008). Cooperative transport between NukFEG and NukH in immunity against the lantibiotic nukacin ISK-1 produced by Staphylococcus warneri ISK-1. J. Bacteriol. 190: 356-62.
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Sahl, H.-G. and G. Bierbaum (1998). Lantibiotics: biosynthesis and biological activities of uniquely modified peptides from Gram-positive bacteria. Annu. Rev. Microbiol. 52: 41-79.
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van Heel, A.J., A. de Jong, M. Montalbán-López, J. Kok, and O.P. Kuipers. (2013). BAGEL3: Automated identification of genes encoding bacteriocins and (non-)bactericidal posttranslationally modified peptides. Nucleic Acids Res 41: W448-453.
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Venema, K., G. Venema and J. Kok (1995). Lactococcal bacteriocins: mode of action and immunity. Trends Microbiol. 3: 299-304.
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Wescombe, P.A., M. Upton, P. Renault, R.E. Wirawan, D. Power, J.P. Burton, C.N. Chilcott, and J.R. Tagg. (2011). Salivaricin 9, a new lantibiotic produced by Streptococcus salivarius. Microbiology 157: 1290-1299.
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| Examples: |
| TC# | Name | Organismal Type | Example |
| 1.C.21.1.1 | Class I lantibiotic bacteriocin Lacticin 481 | Gram-positive bacteria | Lacticin 481 of Lactococcus lactis |
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| 1.C.21.1.10 | Mutacin II (Mutacin-2) of 53 aas. It dissipates the pmf and the H+ gradient and interfers with energy metabolism (Chikindas et al. 1995). | | Mutacin-2 of Streptococcus mutans |
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| 1.C.21.1.2 | Class I lantibiotic bacteriocin Variacin precursor | Gram-positive bacteria | Variacin of Micrococcus varians |
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| 1.C.21.1.3 | Class I lantibiotic bacteriocin Streptococcin A-M29 precursor | Gram-positive bacteria | Streptococcin A of Streptococcus pyogenes |
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| 1.C.21.1.4 | Class I lantibiotic bacteriocin Salivaricin A precursor | Gram-positive bacteria | Salivaricin A precursor of Streptococcus salivarius |
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| 1.C.21.1.5 | Nukacin ISK-1 of 57 aas (Okuda et al., 2008). It is active on Gram-positive bacteria, including Lactobacillus sakei, Leuconostoc mesenteroides and Pediococcus
pentosaceus. The bactericidal activity is based on
depolarization of energized bacterial cytoplasmic membranes, initiated
by the formation of aqueous transmembrane pores (Aso et al. 2004). It is processed and secreted by NukT (TC# 3.A.1.111.7) (Zheng et al. 2017).
| Gram-positive bacteria | Nukacin ISK-1 of Staphylococcus warneri (Q9KWM4) |
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| 1.C.21.1.6 | Cyclic bacteriocin, Group II, Butyrivibriocin ARIO (BviA; 80 aas) | Firmicutes | BviA of Butyrivibrio fibrisolvens (Q99Q15) |
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| 1.C.21.1.7 | Salivaricin 9 (SivA; 56 aas; 1 or 2 TMSs) (Wescombe et al., 2011) | Firmicutes | SivA of Strepococcus salivarius (Q09I51) |
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| 1.C.21.1.8 | Lantibiotic nukacin (Nukacin KQ-1) (Nukacin KQU-131) | | nukA of Staphylococcus hominis |
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| 1.C.21.1.9 | Macedocin, McdA1, a pore-forming lantibiotic of 53 aas | | Macedocin of Streptococcus macedonicus |
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| Examples: |
| TC# | Name | Organismal Type | Example |
| 1.C.21.2.1 | Putative lantibiotic bacteriocin precursor of 71 aas (van Heel et al. 2013). | Firmicutes | Bacteriocin of Streptococcus pneumoniae |
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| 1.C.21.2.2 | Lichenicidin prepeptide, LanA of 68 aas | Firmicutes | Lichenicidin of Bacillus licheniformis |
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| 1.C.21.2.3 | Lantibiotic, mersacidin, of 69 aas | Firmicutes | Mersacidin of Bacillus halodurans |
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| 1.C.21.2.4 | Two component Lacticin 3147 (Ltnα of 59 aas and Ltnβ of 65 aas (Draper et al. 2015). Lacticin 3147 and other lantibiotics target Lipid II to
inhibit cell wall synthesis, and then form pores in the membrane (Biswas and Biswas 2014). They target a large number of bacteria, and several mechanisms of pore-formation have been proposed (Draper et al. 2015). | Firmicutes | Lactincin 3147 of Streptococcus mutans |
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| 1.C.21.2.5 | Uncharacterized protein of 55 aas | Firmicutes | UP of Clostridium saccharobutylicum |
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| 1.C.21.2.6 | Lantibiotic, mersacadin, MrsA, of 58 aa | Firmicutes | MrsA of Bacillus subtilis |
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| 1.C.21.2.7 | Uncharacterized protein of 72 aas and 1 TMS. Shows sequence similarity with members of both lantibiotic families, 1.C.21 and 1.C.60. | | UP of Lentibacillus amyloliquefaciens |
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| 1.C.21.2.8 | Vagococcin T bacteriocin (a two-Peptide Lantibiotic) of 75 aas and 1 C-terminal TMS. It kills many Gram-positive firmicutes. | | Vagococcin T of Vagococcus fluvialis |
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| Examples: |
| TC# | Name | Organismal Type | Example |
| 1.C.21.3.1 | Bactofencin A family cationic bacteriocin of 53 aas and 0 TMSs (Anjana and Tiwari 2022). | | Bacteriocin of Ligilactobacillus salivarius |
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| 1.C.21.3.2 | Bactofencin A family cationic bacteriocin of 51 aas. | | Bactofencin A of Lactobacillus sp. AN1001 |
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