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1 Department of Microbiology and Immunology, University of Otago, PO Box 56, Dunedin, New Zealand
2 BLIS Technologies Ltd, Centre for Innovation, PO Box 56, Dunedin, New Zealand
Correspondence
Philip A. Wescombe
philip.wescombe{at}blis.co.nz
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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The GenBank/EMBL/DDBJ accession number for the sequence of the partial mutacin K8 locus from S. mutans strain K8 is EF060238.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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). Partially purified SA-FF22 inhibited a variety of Gram-positive bacteria (Jack & Tagg, 1991; Tagg et al., 1973a) and when tested against nine standard indicator bacteria in a streptococcal bacteriocin fingerprinting scheme the producer strain Streptococcus pyogenes FF22 (serotype M52) produced a pattern of inhibition referred to as bacteriocin production (P)-type 436 (Tagg & Bannister, 1979). SA-FF22 was subsequently shown to be a 2794.98 Da, nisin-like lantibiotic (Tagg & Wannamaker, 1978; Jack & Tagg, 1991). Following the cloning of the SA-FF22 structural gene (scnA) in strain FF22, closely homologous genes were shown to be present relatively frequently in serotype M49 S. pyogenes, although these strains typically contained two copies (scnA and scnA1) of the SA-FF22 structural gene (Hynes et al., 1994). Subsequent sequencing of the entire SA-FF22 locus in strain FF22 demonstrated that scnA', a markedly variant form of scnA, lies 203 bp downstream of scnA (McLaughlin et al., 1999). Although scnA' was shown to be transcribed, no evidence for expression of a biologically active product has been reported and thus no function has yet been assigned (McLaughlin et al., 1999).
Strain EB1 is a derivative of strain FF22 that no longer produces SA-FF22 and that also has specifically enhanced sensitivity (i.e. loss of putative immunity) to SA-FF22 (Tagg & Wannamaker, 1976). Our recent observation that several strains of streptococcal species other than S. pyogenes also exhibit relatively stronger inhibitory activity against strain EB1 than strain FF22 raised the prospect that bacteriocins produced by these strains may at least functionally resemble SA-FF22. The first lantibiotic shown to have homologues produced by strains of more than one streptococcal species was salivaricin A (Simpson et al., 1995; Upton et al., 2001; Wescombe et al., 2006). Subsequently, the Streptococcus uberis lantibiotic nisin U has also been found to be produced by a variety of streptococcal species (Wirawan et al., 2006). Here we report that Streptococcus mutans strain K8 produces mutacin K8, a lantibiotic strongly homologous to SA-FF22.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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. Bacterial strains used as indicators are listed in Table 2. The indicators I1 to I9 are a set routinely used in this laboratory to detect bacteriocin activity (Tagg & Bannister, 1979). Culture growth was on either Columbia agar base (Difco) supplemented with 0.1 % CaCO3 and 5 % human blood (BaCa) or Bacto tryptic soy broth (Becton Dickinson) supplemented with 2 % (w/v) Bacto yeast extract, 1.5 % (w/v) bacteriological agar (Scientific Supplies) and 0.25 % (w/v) CaCO3 (TsyCa) for 18 h at 37 °C in 5 % CO2 in air. S. mutans transformants were selected on brain heart infusion agar supplemented with 0.5 % yeast extract and 2 µg erythromycin ml–1. The medium used for production of mutacin K8 was THB agar, which comprised Todd–Hewitt broth (Difco) supplemented with 1 % (w/v) bacteriological agar, aliquoted as 20 ml volumes in Petri dishes.
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was used, either to determine the producer-type (P-type) of bacteriocin-like inhibitory substance (BLIS) activity of the test strains or to compare the relative susceptibilities of different bacterial strains to the BLIS activities produced in agar media. Briefly, the test strain was inoculated on the surface of the agar medium as a 1 cm wide streak across the full diameter of the plate. Following incubation, the visible growth of the test strain was removed using a glass slide, and the surface of the agar was sterilized by exposure to chloroform vapour for 30 min. The plate was then aired for 15 min prior to inoculating 18 h THB cultures of the indicator strains across the line of the original producer growth. The plates were then reincubated for 24 h and examined for zones of interference with the indicator growth. For the purposes of P typing, the inhibitory activity against the nine standard indicators was recorded in code form (the P type) by considering the indicators to be three triplets (i.e. I1, I2, I3; I4, I5, I6; and I7, I8, I9). Inhibition of the first member of an indicator triplet was given a score of 4, that for the second a score of 2, and that for the third a score of 1. No inhibition of an indicator was scored as 0. The complete P-type code was recorded as a sequence of three numbers representing the sum of each triplet. All tests were performed in duplicate, and further testing was undertaken if significant discrepancies were detected in the inhibition patterns obtained.
DNA extraction and PCR amplification.
DNA was prepared using a lithium chloride extraction method (Wirawan et al., 2006). All PCR reactions used an Eppendorf Mastercycler thermal cycling apparatus. Elongation times were 1 min at 65 °C for every kb of DNA to be amplified, annealing temperatures as shown in Table 3. Reagents used were HotMaster Taq DNA polymerase (5 U µl–1) and 10x PCR reaction buffer (Eppendorf). Each reaction mix contained 2 µl DNA, 1.5 µl (15 pmol) of each primer, 5 µl 10x buffer, 1 µl nucleotide mix (Eppendorf), 0.5 µl Taq polymerase and sterile deionized water (to a final volume of 50 µl). A set of 26 S. mutans strains were screened for known mutacin genes using the following primer pairs (Table 3): mukA upper and mukA lower (mutacin K8); mutI F and mutI R (mutacin I); mutII upper and mutII lower (mutacin II); mutIIIintF and mutIIIintR (mutacin III); mutIVKoF and mutIVKoA (mutacin IV); BHTA DS and BHTA US (Smb); mutN F and mutN R (mutacin N).
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Inactivation of the mutacin K8 locus and the mutacin IV ABC transporter nlmT.
The mutacin K8 locus was disrupted using a PCR ligation strategy to replace a portion of the mukM (5' end) and mukT (3' end) genes with the erythromycin resistance determinant ermAM (Brehm et al., 1987). Mutacin IV production was eliminated by insertion of ermAM into nlmT, which encodes the ABC transporter that effects export of non-lantibiotic mutacins (Hale et al., 2005a). PCR ligation mutagenesis was based on the Hale et al. (2005b) modification of the original Lau et al. (2002) procedure. In essence, two sets of primers are utilized to generate each mutant. Primers mutK8P1 and mutK8P2-EcoRI amplified the 5' portion of mukM, while primers mutK8P3-PstI and mutK8P4 were used to amplify the 3' end of mukT. The mutK8P2-EcoRI and mutK8P3-PstI primers incorporate a restriction site to facilitate cloning of the antibiotic marker. PCR amplification utilized HotMaster Taq DNA polymerase, as described above.
The PCR products and plasmid pSLER1 [pSL1190 (Pharmacia) containing ermAM (Lau et al., 2002)] were digested (18 h at 37 °C) with PstI and EcoRI (Roche), following which the products were combined, cleaned using the V-gene PCR clean up kit (V-Gene Biotechnology) and then ligated (16 °C, for 18 h) using T4 DNA ligase (Roche). Using the outer primers mutK8P1 and mutK8P4 the ligated sequence was amplified to increase the yield of the mutagenic construct.
For the inactivation of mutacin IV expression the mutagenic construct was amplified using primers ComADwR and ComAUpF from S. mutans UA
NlmT, an nlmT mutant of S. mutans strain UA159 (Hale et al., 2005a). Each mutagenic construct was subsequently used to transform S. mutans strain K8 using a protocol described previously by Hale et al. (2005a). The ermAM determinant was always inserted in the same transcriptional orientation as the gene to be mutated, and as ermAM lacks a transcription terminator, any downstream polar effects are minimized (Hale et al., 2005a).
Purification of mutacin K8.
Lawn cultures were inoculated onto 36 THB agar plates using swabs charged with growth from 18 h THB agar cultures of S. mutans strain K8NlmT. Following incubation, the cells were harvested using sterile swabs and resuspended in 30 ml 95 % methanol (pH 2). After 18 h at 4 °C the cells were removed by centrifugation (15 300 g, 10 min) and the supernatant assayed for inhibitory activity by spot assay (Wirawan et al., 2006) using Micrococcus luteus I1 as the indicator strain. The methanol was removed by Speedvac (Eppendorf) and 400 µl of concentrated extract was applied to an HPLC system fitted with a Phenomenex Jupiter C18 column (5 U, 3000 nm, 250x4.6 mm). The flow rate was 1 ml min–1 with an acetonitrile gradient of 0–100 % in 55 min.
Mass spectrometry and N-terminal sequencing.
Fractions corresponding to absorbance peaks of purified inhibitory peptides eluting from the C18 column were submitted to the Protein Microchemistry Facility (Department of Biochemistry, University of Otago) for mass spectrometry and N-terminal sequencing. The masses were determined by MALDI-TOF MS as described by Hubbard & McHugh (1996). The molecular mass of the peptide was calculated by taking the mean (±SE) of the masses from three to five aims. Automated micro-sequencing utilized a pulsed-liquid protein sequencer (Procise 492, Perkin Elmer/Applied Biosystems) (Hubbard et al., 2000).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Sequencing of the mutacin K8 locus from S. mutans strain K8
Five ORFs (SMU.1811–1809 and SMU.1815–1814) having close homology to the SA-FF22 immunity genes (scnF, scnE, and scnG) and regulatory genes (scnR and scnK) respectively are present in the genome of S. mutans strain UA159 (Ajdic et al., 2002). PCR using the primer pair scnK and scnF (designed to amplify the region between SMU.1814 and SMU.1811) was used to screen the S. mutans strains K8 and K24 previously mentioned, as well as strain K21, which had relatively less pronounced differential activity against S. pyogenes strains EB1 and SA-FF22. Also included were two S. mutans strains (UA159 and H7) that did not exhibit this differential inhibitory activity. Two markedly different PCR product sizes were obtained: the larger (10 kb) was from those strains (K8, K21, K24) displaying some differential inhibitory activity against strains FF22 and EB1 and the smaller (2.5 kb) was from the non-differentially inhibitory strains UA159 and H7 (Fig. 1a).
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) shows sequence (shaded) obtained directly from strain K8 while that initially derived from the published strain UA159 genome, and then confirmed by PCR also to be present in S. mutans strain K8, is unshaded. The sequence of the 6359 bp partial muk locus from strain K8 was analysed using the BLASTX algorithm (Altschul et al., 1997). The sequences of the prepeptides MukA1, MukA2 and MukA3 (Fig. 2c) have closest homology to the SA-FF22 and SA-M49 precursor peptides. However, the putative propeptide sequence of MukA2 shares greatest homology (58 % identity) with the propeptide components of the lantibiotics Bvi79a (GenBank accession no. AAK32694.1) and RumA (GenBank accession no. AJ276653) produced by Butyrivibrio fibrisolvens and Ruminococcus gnavus respectively. On the other hand, the MukA1 and MukA3 propeptides have 73 % identity to the SA-FF22 propeptide.
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) differs from the predicted ScnA' propeptide of the SA-FF22 locus at 7 of 24 amino acids.
PCR ligation mutagenesis of the mutacin K8 locus and of nlmT, which encodes the ABC transporter of non-lantibiotic bacteriocins such as mutacin IV
The mutacin K8 locus and the non-lantibiotic ABC transporter were separately inactivated in S. mutans strain K8 and the resulting effects on inhibitor production were analysed by deferred antagonism on BaCa and TsyCa (Table 4). The inhibitory activity (P-type 100) of K8MutK8 on BaCa was markedly less than the activity (P-type 776) of the parent K8 strain. The P-type 100 (anti-I3) activity appears to be due to either mutacin IV, mutacin N or some other as yet uncharacterized inhibitory peptide transported by NlmT, since this activity was absent in the transporter mutant strain K8NlmT. On TsyCa medium the production of mutacin K8 by strain K8NlmT appeared relatively less (P-type 410) than that produced on BaCa (P-type 676). By comparison, the production by strain K8MutK8 of mutacin IV, mutacin N and/or other inhibitory peptides transported by NlmT, appeared to be substantially greater on TsyCa (P-type 377) than on BaCa (P-type 100).
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). Indicators that appeared to be inhibited by mutacin K8 (i.e. only inhibited by strain K8 and strain K8NlmT) and not by SA-FF22 were S. pyogenes strain FF22 and Streptococcus dysgalactiae strain 67. By contrast, indicators Streptococcus sanguinis ATCC 10556, Lactococcus lactis strains A5 and C2102, and Streptococcus anginosus strains G39 and K11 appeared sensitive to SA-FF22, but not to mutacin K8. Indicators S. sanguinis ATCC 10556, S. anginosus strains G39, K33 and K11 and S. dysgalactiae strain 67 were sensitive to additional (as yet uncharacterized), but apparently nlmT-dependent inhibitory substance(s) produced by strain K8.
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). Strain K8 was PCR-positive for the mutacin IV, mutacin N and mutacin K8 structural genes. The mutacin structural gene most frequently detected, i.e. in 14 (54 %) of the tested strains, was that encoding mutacin IV. PCR-positive reactions for mutacin K8 were given by 9 (35 %) of 26 strains. Strain JH1140 is of particular interest as it is currently being investigated for its anti-caries potential (Hillman et al., 1998). In the present study strain JH1140 was PCR-positive for mutacin III (also referred to as mutacin 1140), mutacin IV, Smb and mutacin K8.
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The central component of the muk locus (i.e. mukK to mukF) in each of the nine strains was amplified using the primer pair scnK and scnF. Eight strains yielded amplicons of approximately 10–11 kb. Only S. mutans strain 4N differed, its PCR product being approximately 1.5 kb larger. Further sequence analysis of the strain 4N muk locus showed that it contained DNA homologous to SMU.1812 of strain UA159, a segment closely resembling a plasmid insertion sequence from S. mutans UA855 (GenBank accession no. AF104380). This sequence appears to account for the extra 1.5 kb of sequence within the strain 4N muk locus.
Extraction, purification and partial characterization of mutacin K8
Methanol extraction of cells of S. mutans strain K8nlmT (i.e. phenotypically negative for mutacin IV and mutacin N) that had been grown on THB agar yielded putative mutacin K8 inhibitory activity of titre 2 AU ml–1 against M. luteus. The mutacin K8 activity was bound to a C18 reversed-phase resin and then eluted at approximately 35 % in a 0–100 % acetonitrile gradient (Fig. 2a). An absorbance peak corresponding to the inhibitor-positive fraction 26 contained a single peptide with a mass of 2734.2±20 Da when analysed using MALDI-TOF MS (Fig. 2b). N-terminal sequencing of the first six amino acids yielded the sequence Met-Gly-Lys-Gly-Ala-Val. This sequence corresponds exactly to that predicted for the putative propeptides MukA1 and MukA3 (Fig. 2c). Although MukA1 and MukA3 are identical in their predicted propeptide sequences and hence would be expected to co-purify, they differ by three amino acids in their leader peptide sequences. The relative expression levels in strain K8 of the MukA1 and MukA3 propeptides have not been determined.
Inhibitory spectra of mutacin K8 and SA-FF22
Some differences were noted in the relative strain targeting activities of purified preparations of mutacin K8 and SA-FF22. For example, strains L. lactis C2102 and S. anginosus G39 appeared sensitive to SA-FF22, but not to mutacin K8. Furthermore, although strain EB1 (the SA-FF22-negative derivative of strain FF22) was more than 32-fold more sensitive than the parent strain FF22 to SA-FF22, it appeared to be only marginally (i.e. twofold) more sensitive than strain FF22 to mutacin K8. By contrast, strain K8mutK8 (the mutacin K8-negative derivative of strain K8) did not seem to differ from the parent strain K8 in its susceptibility to the available test concentrations of either mutacin K8 or SA-FF22.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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), inhibitor production by these three S. mutans strains appeared to be completely abrogated when either 1 % MgCl2 or 2 mg trypan blue ml–1 was added to the test medium (results not shown).
Although five ORFs having close homology to the SA-FF22 regulatory and immunity genes are present in the S. mutans strain UA159 genome, no genes having homology to those required for SA-FF22 biosynthesis are detectable, indicating that the locus is inactive. Similarly, although more than 95 % of S. pyogenes harbour the structural gene salA1 for the lantibiotic salivaricin A1, it seems to date that only serotype M4 strains contain the entire salA1 locus and thus are capable of producing biologically active salivaricin A1 (Upton et al., 2001; Wescombe et al., 2006).
In the present study, primers for the 2.5 kb region between SMU.1815 (scnR-like) and SMU.1811 (scnF-like) in the genome of S. mutans strain UA159 yielded an approximately 10 kb amplification product from strain K8. The additional DNA in strain K8 was sequenced and four ORFs (mukA1, mukA2, mukA3 and mukA') encoding putative type AII lantibiotic prepeptides were identified in addition to ORFs having homology to typical lantibiotic modification (mukM) and transport (mukT) genes. The entire mutacin K8 locus resembles that of the SA-FF22 locus in S. pyogenes strain FF22 (McLaughlin et al., 1999), indicating that the two loci probably share a common ancestry. Interestingly, however, mukK and mukR are in the same transcriptional orientation as the putative mutacin K8 immunity and biosynthetic genes, whereas scnR and scnK are encoded by the complementary strand within the SA-FF22 locus.
The presence in strain K8 of three almost identical copies of a lantibiotic structural gene has a precedent in the ruminococcin A locus of Ruminococcus gnavus (Gomez et al., 2002). Interestingly, all three RumA structural genes are transcribed and may also be translated (Gomez et al., 2002). In the case of mutacin K8, the putative mukA2 translation product would have a significantly different structure, being capable of forming just two of the three lanthionine rings predicted to be present in the MukA1 and MukA3 propeptides. It seems that the structural differences imposed upon MukA2 by the absence of one ring structure will necessarily result in some alternative function(s) for that peptide. One possibility is that mutacin K8 may be a two-component lantibiotic, consisting of MukA1 and/or MukA3 in combination with MukA2 or MukA'. However, fractionation of a mutacin K8 preparation identified only a single peak having inhibitory activity, and this fraction contained just one peptide, the sequence of which matched the predicted translation product of mukA1 and/or mukA3. However, it is possible that the MukA2 and MukA' propeptides have no activity on their own, but that they enhance the activity of the MukA1/A3 peptides. Interestingly, the MukA1/MukA3 peptide preparation had only slightly more inhibitory activity against strain EB1 than against strain FF22, a finding consistent with the relatively minor apparent susceptibility differences exhibited by strains EB1 and FF22 when used as indicators in deferred antagonism tests of strain K8NlmT.
Although no function has yet been defined for the putative product of scnA' within the SA-FF22 locus, it is however known that SA-FF22 is not the specific signal peptide for its own upregulation (Wescombe, 2002). Consequently it can be speculated that the scnA' translation product may fulfil this function. The significant homology of mukA' and scnA' supports a possible similar function for the peptide product of mukA'.
Inactivation of the muk locus demonstrated that mutacin K8 accounts for the majority of observed antimicrobial activity of strain K8 in deferred antagonism tests on BaCa against the nine standard indicators. The exception is the activity against indicator I3 (S. anginosus). This latter activity could, however, be eliminated by inactivation of nlmT, which encodes an ABC transporter known to export non-lantibiotic bacteriocins such as mutacin IV (Hale et al., 2005a). Further inhibitory spectrum testing of this nlmT-knockout strain (predicted to produce only mutacin K8 on BaCa) indicated that M. luteus as well as all tested S. pyogenes and some L. lactis, Streptococcus constellatus and S. uberis strains were susceptible. Interestingly, the lantibiotic-producing L. lactis strains A5 (a producer of nisin Z) and C2102 (a producer of lacticin 481) appeared relatively less sensitive than the non-lantibiotic-producing L. lactis strain I6 to the mutacin K8-producer strain K8NlmT. On the other hand both A5 and C2102 appeared quite sensitive to SA-FF22, making them useful indicators for differentiating between mutacin K8 and SA-FF22. This apparent susceptibility difference was confirmed by comparing the activity spectra of purified preparations of SA-FF22 and mutacin K8. In contrast, mutacin K8 (but not SA-FF22) is inhibitory to S. dysgalactiae strain 67 (which harbours the SA-FF22 structural gene). These findings indicate that the SA-FF22 immunity gene products do not provide very effective cross-protection against mutacin K8.
This study clearly indicates that the demonstration of a particular mutacin structural gene does not necessarily facilitate prediction of the host strain's anti-bacterial spectrum, since many S. mutans encode a wide variety of mutacins. The most common bacteriocin structural gene pairing for strains having the muk locus was with the mutacin IV (nlmA and nlmB) locus, with 5 of the 9 muk-positive strains having both loci. The muk locus appears to be relatively widespread within S. mutans, being detected in 9 (35 %) of 26 tested strains. Indeed, on the basis of our study its occurrence in S. mutans appears similar to that of mutacin III, as determined in both the present (38 %) and other (25 %) studies (Bekal-Si Ali et al., 2002). Interestingly, however, we found only one strain (JH1140) that contained the structural genes for both mutacin III and mutacin K8. We speculate that, on the basis of its high prevalence, mutacin K8 probably provides the S. mutans producer strain with a significant ecological advantage within the high-density, heterogeneous Gram-positive bacterial populations present in supra-gingival dental plaque. This benefit could result either from the direct inhibition of competitors or alternatively by providing a measure of protective immunity against various of the closely similar bacteriocins produced by members of the mutans or other streptococcal species that abound within the indigenous oral consortium of humans.
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ACKNOWLEDGEMENTS |
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Edited by: T. Msadek
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Received 26 October 2006;
revised 20 December 2006;
accepted 25 January 2007.
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. Residues predicted to be either dehydrated or involved in lanthionine ring formation are shaded black. Also shown (in grey) is the N-terminal sequence derived from fraction 26 (Fig. 2a