Subsystem: Sex pheromones in Enterococcus faecalis and other Firmicutes

This subsystem's description is:

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Group Alias
Abbrev.Functional RoleReactionsScenario ReactionsGOLiterature

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Taxonomy Pattern 
Variant [?] 
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Variant codes:

-1 = no known pheromones of enterococcal type can be identified in a genome
1 = Putative cAM373-type pheromone precursor lipoprotein is present in an organism
2 = Putative cAD1-type pheromone precursor lipoprotein is present in an organism
3 = both putative lipoprotein precursors are present in an organism

The known enterococcal sex pheromones (cAD1, cPD1, cCF10, cAM373, and cOB1) and related inhibitors are all relatively hydrophobic, linear octa- or heptapeptides that are active at nanomolar concentrations (reviewed in Clewell, 1993; 1999; Wirth, 1994; Dunny and Leonard, 1997). For example, pheromone cAD1 is an octapeptide with the sequence LFSLVLAG.

The observation that Enterococcus faecalis strains containing certain plasmids give rise to bacterial aggregates when mixed with plasmid-free cells led to the discovery of bacterial sex pheromones (Dunny et al., 1978). These small linear peptide molecules act as signals that facilitate the conjugative transfer of a specific category of plasmids referred to as pheromone- responsive plasmids. Pheromones secreted by plasmid-free cells can induce a process in which plasmid-containing cells become activated for both adherence to potential recipients (those that produced and secreted the pheromone) and plasmid transfer. Once a recipient cell acquires a given plasmid, the corresponding pheromone is no longer detected in the culture supernatant of the transconjugant because of ‘shutdown’ or ‘masking’ of the endogenous peptide (although pheromones specific for unrelated plasmids continue to be secreted). The newly resident plasmid encodes and directs the production of a small peptide that is somewhat similar to its cognate pheromone but acts as a competitive inhibitor. Uptake of pheromones is mediated by Pheromone binding protein TraC/PrgZ, which recruits chromosomal oligopeptide Opp transport system (Leonard, et al., 1996).

With the recent availability of enterococcal genome sequence data, it was noted that a pheromone peptide is encoded as a part of the signal sequences of precursors of certain lipoproteins (An & Clewell. 2002.). In most cases, the signal sequences correspond to 21- or 22-amino-acid segments, with the last 7 or 8 residues representing the specific pheromone. Typical lipoprotein signal peptidase target sites are appropriately located such that cleavage results in separation of the signal sequence, which in turn needs only to be processed at a second location seven or eight residues from the other processing site to generate a mature pheromone peptide. The former process is believed to be catalyzed by Signal peptidase II, the later – by metalloprotease Eep (An & Clewell, 2002). It is not known if there is a functional relationship between the activity of the putative lipoproteins and the pheromone component of their precursor structures or whether the lipoprotein connection is simply fortuitous.

Pheromone-responding plasmids are highly transmissible between strains of E. faecalis and are believed to contribute to the horizontal dissemination of antibiotic resistance genes (Clewell, 1990) and virulence factors such as cytolysin (Gilmore etal., 1994) and adhesins (Hirt et al., 2000; Rozdzinski et al., 2001). Biosynthesis of plasmid-encoded hemolysin and aggregation substance, induced by pheromones have been shown to contribute to virulence (e.g., Sussmuth et al., 2000). Aggregation substance Asa1/PrgB has two RGD motifs that may be responsible for the ability of plasmid-carrying cells to attach to porcine renal kidney epithelial cells (Kreft et al., 1992).

Surprisingly, the E. faecalis pheromone-responsive plasmid pAM373 (De Boever et al., 2000), has the unusual ability to respond not only to a specific E. faecalis peptide, cAM373, but also to similar peptides secreted by the non-enterococcal species: Streptococcus gordonii and Staphylococcus aureus (Clewell et al., 1985). The staphylococcal peptide has been identified – AIFILAA (Nakayama et al., 1996) and differs from the enterococcal cAM373 peptide by only one amino acid – an alanine rather than a serine at the carboxyl-terminus. Furthermore, orthologs of the Putative pheromone cAM373 precursor lipoprotein CamS are evident in the genomes of many Bacilli, Listeria, Thermoanaerobacter, Lactobacilli, etc. (Flannagan & Clewell, 2002). Although it is not known whether the peptides produced by different genera actually represent sex pheromones significant to these organisms, it is conceivable that they could play a role in the acquisition of pAM373 and related plasmids from enterococci, contributing to cross-species spread of antibiotic-resistance factors.


1. An F.Y. and Don B. Clewell. 2002. Identification of the cAD1 Sex Pheromone Precursor in Enterococcus faecalis. Journal of Bacteriology, 184(7): 1880-1887
2. An FY, Sulavik MC, Clewell DB. 1999. Identification and characterization of a determinant (Eep) on the Enterococcus faecalis chromosome that is involved in production of the peptide sex pheromone cAD1. J Bacteriol, 181(19):5915-21
3. Don B. Clewell, Linda T. Pontius, Florence Y. An, et al. 1990. Nucleotide sequence of the sex pheromone inhibitor (iAD1) determinant ofEnterococcus faecalis conjugative plasmid pAD1. Volume 24, Issue 2, September 1990, Pages 156-161
4. Flannagan SE, Clewell DB. 2002. Identification and characterization of genes encoding sex pheromone cAM373 activity in Enterococcus faecalis and Staphylococcus aureus. Mol Microbiol, 44(3):803-17
5. Kreft, R Marre, U Schramm and R Wirth. 1992. Aggregation substance of Enterococcus faecalis mediates adhesion to cultured renal tubular cells. Infect Immun, 60(1): 25-30
6. Leonard, B. A. B., A. Podbielski, P. J. Hedberg, and G. M. Dunny. 1996. Enterococcus faecalis pheromone binding protein, PrgZ, recruits a chromosomal oligopeptide permease system to import sex pheromone cCF10 for induction of conjugation. Proc. Natl. Acad. Sci. USA 93:260-264
7. Shuhei Fujimoto, and Don B. Clewell. 1998. Regulation of the pAD1 sex pheromone response of Enterococcus faecalis by direct interaction between the cAD1 peptide mating signal and the negatively regulating, DNA-binding TraA protein. Vol. 95, Issue 11, 6430-6435
8. Sussmuth S., Muscholl-Silberhorn A., Wirth R., Susa M., Marre R., and Eva Rozdzinski. 2000. Aggregation Substance Promotes Adherence, Phagocytosis, and Intracellular Survival of Enterococcus faecalis within Human Macrophages and Suppresses Respiratory Burst. Infection and Immunity, 68(9):4900-4906
9. Tanimoto, K., F. Y. An, and D. B. Clewell. 1993. Characterization of the traC determinant of the Enterococcus faecalis hemolysin-bacteriocin plasmid pAD1: binding of sex pheromone. J. Bacteriol. 175:5260-5264.
10. Wirth R. 1994. The sex pheromone system of Enterococcus faecalis. More than just a plasmid-collection mechanism? Eur. J. Biochem. 222, 235-246###############################