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A building-block model reveals new insights into the biogenesis of yeast mitochondrial ribosomes
(2020)
Most of the mitochondrial proteins in yeast are encoded in the nuclear genome, get synthesized by cytosolic ribosomes and are imported via TOM and TIM23 into the matrix or other subcompartments of mitochondria. The mitochondrial DNA in yeast however also encodes a small set of 8 proteins from which most are hydrophobic membrane proteins and build core components of the OXPHOS complexes. They get synthesized by mitochondrial ribosomes which are descendants of bacterial ribosomes and still have some similarities to them. On the other hand, mitochondrial ribosomes experienced various structural and functional changes during evolution that specialized them for the synthesis of the mitochondrial encoded membrane proteins. The mitoribosome contains mitochondria-specific ribosomal proteins and replaced the bacterial 5S rRNA by mitochondria-specific proteins and rRNA extensions. Furthermore, the mitoribosome is tethered to the inner mitochondrial membrane to facilitate a co-translational insertion of newly synthesized proteins. Thus, also the assembly process of mitoribosomes differs from that of bacteria and is to date not well understood.
Therefore, the biogenesis of mitochondrial ribosomes in yeast should be investigated. To this end, a strain was generated in which the gene of the mitochondrial RNA-polymerase RPO41 is under control of an inducible GAL10-promoter. Since the scaffold of ribosomes is built by ribosomal RNAs, the depletion of the RNA-polymerase subsequently leads to a loss of mitochondrial ribosomes. Reinduction of Rpo41 initiates the assembly of new mitoribosomes, which makes this strain an attractive model to study mitoribosome biogenesis.
Initially, the effects of Rpo41 depletion on cellular and mitochondrial physiology was investigated. Upon Rpo41 depletion, growth on respiratory glycerol medium was inhibited. Furthermore, mitochondrial ribosomal 21S and 15S rRNA was diminished and mitochondrial translation was almost completely absent. Also, mitochondrial DNA was strongly reduced due to the fact that mtDNA replication requires RNA primers that get synthesized by Rpo41.
Next, the effect of reinduction of Rpo41 on mitochondria was tested. Time course experiments showed that mitochondrial translation can partially recover from 48h Rpo41 depletion within a timeframe of 4.5h. Sucrose gradient sedimentation experiments further showed that the mitoribosomal constitution was comparable to wildtype control samples during the time course of 4.5h of reinduction, suggesting that the ribosome assembly is not fundamentally altered in Gal-Rpo41 mitochondria. In addition, the depletion time was found to be critical for recovery of mitochondrial translation and mitochondrial RNA levels. It was observed that after 36h of Rpo41 depletion, the rRNA levels and mitochondrial translation recovered to almost 100%, but only within a time course of 10h.
Finally, mitochondria from Gal-Rpo41 cells isolated after different timepoints of reinduction were used to perform complexome profiling and the assembly of mitochondrial protein complexes was investigated. First, the steady state conditions and the assembly process of mitochondrial respiratory chain complexes were monitored. The individual respiratory chain complexes and the super-complexes of complex III, complex IV and complex V were observed. Furthermore, it was seen that they recovered from Rpo41 depletion within 4.5h of reinduction. Complexome profiles of the mitoribosomal small and large subunit discovered subcomplexes of mitoribosomal proteins that were assumed to form prior to their incorporation into assembly intermediates. The complexome profiles after reinduction indeed showed the formation of these subcomplexes before formation of the fully assembled subunit. In the mitochondrial LSU one subcomplex builds the membrane facing protuberance and a second subcomplex forms the central protuberance. In contrast to the preassembled subcomplexes, proteins that were involved in early assembly steps were exclusively found in the fully assembled subunit. Proteins that assemble at the periphery of the mitoribosome during intermediate and late assembly steps where found in soluble form suggesting a pool of unassembled proteins that supply assembly intermediates with proteins.
Taken together, the findings of this thesis suggest a so far unknow building-block model for mitoribosome assembly in which characteristic structures of the yeast mitochondrial ribosome form preassembled subcomplexes prior to their incorporation into the mitoribosome.
Anisotropy of tracer-coupled networks is a hallmark in many brain regions. In the past, the topography of these networks was analyzed using various approaches, which focused on different aspects, e.g., position, tracer signal, or direction of coupled cells. Here, we developed a vector-based method to analyze the extent and preferential direction of tracer spreading. As a model region, we chose the lateral superior olive—a nucleus that exhibits specialized network topography. In acute slices, sulforhodamine 101-positive astrocytes were patch-clamped and dialyzed with the GJ-permeable tracer neurobiotin, which was subsequently labeled with avidin alexa fluor 488. A predetermined threshold was used to differentiate between tracer-coupled and tracer-uncoupled cells. Tracer extent was calculated from the vector means of tracer-coupled cells in four 90° sectors. We then computed the preferential direction using a rotating coordinate system and post hoc fitting of these results with a sinusoidal function. The new method allows for an objective analysis of tracer spreading that provides information about shape and orientation of GJ networks. We expect this approach to become a vital tool for the analysis of coupling anisotropy in many brain regions
For modeling approaches in systems biology, knowledge of the absolute abundances of cellular proteins is essential. One way to gain this knowledge is the use of quantification concatamers (QconCATs), which are synthetic proteins consisting of proteotypic peptides derived from the target proteins to be quantified. The QconCAT protein is labeled with a heavy isotope upon expression in E. coli and known amounts of the purified protein are spiked into a whole cell protein extract. Upon tryptic digestion, labeled and unlabeled peptides are released from the QconCAT and the native proteins, respectively, and both are quantified by LC-MS/MS. The labeled Q-peptides then serve as standards for determining the absolute quantity of the native peptides/proteins. Here we have applied the QconCAT approach to Chlamydomonas reinhardtii for the absolute quantification of the major proteins and protein complexes driving photosynthetic light reactions in the thylakoid membranes and carbon fixation in the pyrenoid. We found that with 25.2 attomol/cell the Rubisco large subunit makes up 6.6% of all proteins in a Chlamydomonas cell and with this exceeds the amount of the small subunit by a factor of 1.56. EPYC1, which links Rubisco to form the pyrenoid, is eight times less abundant than RBCS, and Rubisco activase is 32-times less abundant than RBCS. With 5.2 attomol/cell, photosystem II is the most abundant complex involved in the photosynthetic light reactions, followed by plastocyanin, photosystem I and the cytochrome b6/f complex, which range between 2.9 and 3.5 attomol/cell. The least abundant complex is the ATP synthase with 2 attomol/cell. While applying the QconCAT approach, we have been able to identify many potential pitfalls associated with this technique. We analyze and discuss these pitfalls in detail and provide an optimized workflow for future applications of this technique.
The cytosolic Fe65 adaptor protein family, consisting of Fe65, Fe65L1 and Fe65L2 is involved in many intracellular signaling pathways linking via its three interaction domains a continuously growing list of proteins by facilitating functional interactions. One of the most important binding partners of Fe65 family proteins is the amyloid precursor protein (APP), which plays an important role in Alzheimer Disease.
To gain deeper insights in the function of the ubiquitously expressed Fe65 and the brain enriched Fe65L1, the goal of my study was I) to analyze their putative synaptic function in vivo, II) to examine structural analysis focusing on a putative dimeric complex of Fe65, III) to consider the involvement of Fe65 in mediating LRP1 and APP intracellular trafficking in murine hippocampal neurons. By utilizing several behavioral analyses of Fe65 KO, Fe65L1 KO and Fe65/Fe65L1 DKO mice I could demonstrate that the Fe65 protein family is essential for learning and memory as well as grip strength and locomotor activity. Furthermore, immunohistological as well as protein biochemical analysis revealed that the Fe65 protein family is important for neuromuscular junction formation in the peripheral nervous system, which involves binding of APP and acting downstream of the APP signaling pathway. Via Co-immunoprecipitation analysis I could verify that Fe65 is capable to form dimers ex vivo, which exclusively occur in the cytosol and upon APP expression are shifted to membrane compartments forming trimeric complexes. The influence of the loss of Fe65 and/or Fe65L1 on APP and/or LRP1 transport characteristics in axons could not be verified, possibly conditioned by the compensatory effect of Fe65L2. However, I could demonstrate that LRP1 affects the APP transport independently of Fe65 by shifting APP into slower types of vesicles leading to changed processing and endocytosis of APP.
The outcome of my thesis advanced our understanding of the Fe65 protein family, especially its interplay with APP physiological function in synapse formation and synaptic plasticity.
Biological soil crusts (biocrusts) are a common element of the Queensland (Australia) dry savannah ecosystem and are composed of cyanobacteria, algae, lichens, bryophytes, fungi and heterotrophic bacteria. Here we report how the CO2 gas exchange of the cyanobacteria-dominated biocrust type from Boodjamulla National Park in the north Queensland Gulf Savannah responds to the pronounced climatic seasonality and on their quality as a carbon sink using a semi-automatic cuvette system. The dominant cyanobacteria are the filamentous species Symplocastrum purpurascens together with Scytonema sp. Metabolic activity was recorded between 1 July 2010 and 30 June 2011, during which CO2 exchange was only evident from November 2010 until mid-April 2011, representative of 23.6 % of the 1-year recording period. In November at the onset of the wet season, the first month (November) and the last month (April) of activity had pronounced respiratory loss of CO2. The metabolic active period accounted for 25 % of the wet season and of that period 48.6 % was net photosynthesis (NP) and 51.4 % dark respiration (DR). During the time of NP, net photosynthetic uptake of CO2 during daylight hours was reduced by 32.6 % due to water supersaturation. In total, the biocrust fixed 229.09 mmol CO2 m−2 yr−1, corresponding to an annual carbon gain of 2.75 g m−2 yr−1. Due to malfunction of the automatic cuvette system, data from September and October 2010 together with some days in November and December 2010 could not be analysed for NP and DR. Based on climatic and gas exchange data from November 2010, an estimated loss of 88 mmol CO2 m−2 was found for the 2 months, resulting in corrected annual rates of 143.1 mmol CO2 m−2 yr−1, equivalent to a carbon gain of 1.7 g m−2 yr−1. The bulk of the net photosynthetic activity occurred above a relative humidity of 42 %, indicating a suitable climatic combination of temperature, water availability and light intensity well above 200 µmol photons m−2 s−1 photosynthetic active radiation. The Boodjamulla biocrust exhibited high seasonal variability in CO2 gas exchange pattern, clearly divided into metabolically inactive winter months and active summer months. The metabolic active period commences with a period (of up to 3 months) of carbon loss, likely due to reestablishment of the crust structure and restoration of NP prior to about a 4-month period of net carbon gain. In the Gulf Savannah biocrust system, seasonality over the year investigated showed that only a minority of the year is actually suitable for biocrust growth and thus has a small window for potential contribution to soil organic matter.
Esterases and lipases are widely used as industrial enzymes and for the synthesis of chiral drugs. Because of their rich secondary metabolism, Streptomyces species offer a relatively untapped source of interesting esterases and lipases. S. coelicolor and S. avermitilis contain 51 genes annotated as esterases and/or lipases. In this study I have cloned 14 different genes encoding for lipolytic enzymes from S. coelicolor (11 genes) and S. avermitilis (four genes). Some of these genes were over-expressed in E. coli. Three of the produced enzymes, which were produced by the genes SCO 7131, SCO6966 and SCO3644, were characterized biochemically and one of them was subjected for directed evolution. The gene estA (locus SCO 7131) was annotated as a putative lipase/esterase in the genome sequence of S. coelicolor A3(2), but does not have a homologue in the genome sequence of S. avermitilis or in other known Streptomyces sequences. estA was cloned and expressed in E. coli as a His-tagged protein. The protein was purified and could be recovered in its non-tagged form after digestion with factor Xa. The relative molecular weight was estimated to be 35.5kDa. The enzyme was only active towards acetate esters and not on larger substrates. It had a stereospecificity towards α-naphathylacetate. It was thermostable, with a half-life at 50C of 4.5 hours. Est A showed stability over pH range 5.5-10, and had optimum pH of 7.5. Its activity was drastically decreased when it was pre-incubated in 10mM PMSF, Cu+2 and Hg+2. It was not very stable in most organic solvents and had only slight enantioselectivity. Est A belongs to the HSL family whose founder member is the human hormone-sensitive lipase. I have developed a protein profile for the HSL family modifying the conserved motifs found by Arpigny and Jaeger (1999). Due to the presence of several HSL members with known 3D structure and good homology to Est A, I was able to make a homology model of Est A. Five different mutants of Est A were produced through site directed mutagenesis: W87F, V158A, W87F/V158A, M162L and S163A. The mutants M162L and S163A did not produce a significant change either in substrate specificity or enzyme kinetics. The mutants V158A and W87F/V158A could act on the larger substrates p-nitrophenylbutyrate and caproate and tributyrin. The mutant V158A had improved thermostability and its t1/2 at 50ºC increased to 24h. The affinity of V158A towards p-nitrophenyacetate increased 6-fold when compared with the wild type, whereas the affinity of W87F decreased 4-fold. Directed evolution of Est A was done through random mutagenesis and ER-PCR. A library of 6336 mutants was constructed and screened for mutants with a broader spectrum of substrate specificity. The mutant XXVF7 did show alteration in the substrate specificity of Est A. The mutant XXVF7 had 5 amino acids changes L76R, L146P, S196G, W213R and L267R. The gene locus SCO 6966 (estB gene) was cloned and expressed in E. coli as a His-tagged protein. It was not possible to remove the His-tag using factor Xa. The tagged protein had a molecular weight 31.9kDa. Est B was active against short chain fatty acid esters (C2-C6). Its optimum temperature was 30ºC and was stable for 1h at temperatures up to 37ºC. The enzyme had maximum activity at pH 8-8.5 and was stable over pH range 7.5-11 for 24h. It was highly sensitive for PMSF, Cu+2 and Hg+2. The enzymatic activity deceased in presence of organic solvents, however it was fairly stable for 1h in 20% organic solvents solutions. A third esterase was produced from the gene locus SCO 3644. This esterase was a thermosensitive one with optimum temperature of 35ºC. The three characterized enzymes included a thermophilic, mesophilic and psychrophilic ones. This indicates the high variation in the characters of Streptomyces lipolytic enzymes and highlighting Streptomyces as a source for esterases and lipases of interesting catalytic activity. This study was an initial trial to provide a strategy for a comprehensive use of genome data.
Grape powdery mildew, Erysiphe necator, is one of the most significant plant pathogens, which affects grape growing regions world-wide. Because of its short generation time and the production of large amounts of conidia throughout the season, E. necator is classified as a moderate to high risk pathogen with respect to the development of fungicide resistance. The number of fungicidal mode of actions available to control powdery mildew is limited and for some of them resistances are already known. Aryl-phenyl-ketones (APKs), represented by metrafenone and pyriofenone, and succinate-dehydrogenase inhibitors (SDHIs), composed of numerous active ingredients, are two important fungicide classes used for the control of E. necator. Over the period 2014 to 2016, the emergence and development of metrafenone and SDHI resistant E. necator isolates in Europe was followed and evaluated. The distribution of resistant isolates was thereby strongly dependent on the European region. Whereas the north-western part is still predominantly sensitive, samples from east European countries showed higher resistance frequencies.
Classical sensitivity tests with obligate biotrophs can be challenging regarding sampling, transport and especially the maintenance of the living strains. Whenever possible, molecular genetic methods are preferred for a more efficient monitoring. Such methods require the knowledge of the resistance mechanisms. The exact molecular target and the resistance mechanism of metrafenone is still unknown. Whole genome sequencing of metrafenone sensitive and resistant wheat powdery mildew isolates, as well as adapted laboratory mutants of Aspergillus nidulans, where performed with the aim to identify proteins potentially linked to the mode of action or which contribute to metrafenone resistance. Based on comparative SNP analysis, four proteins potentially associated with metrafenone resistance were identified, but validation studies could not confirm their role in metrafenone resistance. In contrast to APKs, the mode of action of SDHIs is well understood. Sequencing of the sdh-genes of less sensitive E. necator isolates identified four different target-site mutations, the B-H242R, B-I244V, C-G169D and C-G169S, in sdhB and sdhC, respectively. Based on this information it was possible to develop molecular genetic monitoring methods for the mutations B-H242R and C-G169D. In 2016, the B-H242R was thereby identified as by far the most frequent mutation. Depending on the analysed SDH compound and the sdh-genotype, different sensitivities were observed and revealed a complex cross-resistance pattern.
Growth competition assays without selection pressure, with mixtures of sensitive and resistant E. necator isolates, were performed to determine potential fitness costs associated with fungicide resistance. With the experimental setups used, a clear fitness disadvantage associated with metrafenone resistance was not identified, although a strong variability of fitness was observed among the tested resistant E. necator isolates. For isolates with a reduced sensitivity towards SDHIs, associated fitness costs were dependent on the sdh-genotype analysed. Competition tests with the B-H242R genotypes gave evidence that there are no fitness costs associated with this mutation. In contrast, the C-G169D genotypes were less competitive, indicating a restricted fitness compared to the tested sensitive partners. Competition assays of field isolates, which exhibited several resistances towards different fungicide classes, indicated that there are no fitness costs associated with a multiple resistant phenotype in E. necator. Overall, these results clearly indicate the importance to analyse a representative number of isolates with sensitive and resistant phenotypes.
Characterization of neuronal activity in the auditory brainstem of rats: An optical imaging approach
(2004)
In this doctoral thesis, several aspects of neuronal activity in the rat superior olivary complex (SOC), an auditory brainstem structure, were analyzed using optical imaging with voltage-sensitive dyes (VSD). The thesis is divided into 5 Chapters. Chapter 1 is a general introduction, which gives an overview of the auditory brainstem and VSD imaging. In Chapter 2, an optical imaging method for the SOC was standardized, using the VSD RH795. To do so, the following factors were optimized: (1) An extracellular potassium concentration of 5 mM is necessary during the incubation and recording to observe synaptically evoked responses in the SOC. (2) Employing different power supplies reduced the noise. (3) Averaging of 10 subsequent trials yielded a better signal-to-noise ratio. (4) RH795 of 100 µM with 50 min prewash was optimal to image SOC slices for more than one hour. (5) Stimulus-evoked optical signals were TTX sensitive, revealing action potential-driven input. (6) Synaptically evoked optical signals were characterized to be composed of pre- and postsynaptic components. (7) Optical signals were well correlated with anatomical structures. Overall, this method allows the comparative measurement of electrical activity of cell ensembles with high spatio-temporal resolution. In Chapter 3, the nature of functional inputs to the lateral superior olive (LSO), the medial superior olive (MSO), and the superior paraolivary nucleus (SPN) were analyzed using the glycine receptor blocker strychnine and the AMPA/kainate receptor blocker CNQX. In the LSO, the known glutamatergic inputs from the ipsilateral, and the glycinergic inputs from the ipsilateral and contralateral sides, were confirmed. Furthermore, a CNQX-sensitive input from the contralateral was identified. In the MSO, the glutamatergic and glycinergic inputs from the ipsilateral and contralateral sides were corroborated. In the SPN, besides the known glycinergic input from the contralateral, I found a glycinergic input from the ipsilateral and I also identified CNQX-sensitive inputs from the contralateral and ipsilateral sides. Together, my results thus corroborate findings obtained with different preparations and methods, and provide additional information on the pharmacological nature of the inputs. In Chapter 4, the development of glycinergic inhibition for the LSO, the MSO, the SPN, and the medial nucleus of the trapezoid body (MNTB) was studied by characterizing the polarity of strychnine-sensitive responses. In the LSO, the high frequency region displayed a shift in the polarity at P4, whereas the low frequency region displayed at P6. In the MSO, both the regions displayed the shift at P5. The SPN displayed a shift in the polarity at E18-20 without any regional differences. The MNTB lacked a shift between P3-10. Together, these results demonstrate a differential timing in the development of glycinergic inhibition in these nuclei. In Chapter 5, the role of the MSO in processing bilateral time differences (t) was investigated. This was done by stimulating ipsilateral and contralateral inputs to the MSO with different t values. In preliminary experiments, the postsynaptic responses showed a differential pattern in the spread of activity upon different t values. This data demonstrates a possible presence of delay lines as proposed by Jeffress in the interaural time difference model of sound localization. In conclusion, this study demonstrates the usage of VSD imaging to analyze the neuronal activity in auditory brainstem slices. Moreover, this study expands the knowledge of the inputs to the SOC, and has identified one glycinergic and three AMPA/kainate glutamatergic novel inputs to the SOC nuclei.
Cells depend on the continuous renewal of their proteome composition during the cell cycle and in order to replace aberrant proteins or to react to changing environmental conditions. In higher eukaryotes, protein synthesis is achieved by up to five million ribosomes per cell. With the fast kinetics of translation, the large number of newly made proteins generates a substantial burden for protein homeostasis and requires a highly orchestrated cascade of factors promoting folding, sorting and final maturation. Several of the involved factors directly bind to translating ribosomes for the early processing of emerging nascent polypeptides and the translocation of ribosome nascent chain complexes to target membranes. In plant cells, protein synthesis also occurs in chloroplasts serving the expression of a relatively small set of 60–100 protein-coding genes. However, most of these proteins, together with nucleus-derived subunits, form central complexes majorly involved in the essential processes of photosynthetic light reaction, carbon fixation, metabolism and gene expression. Biogenesis of these heterogenic complexes adds an additional level of complexity for protein biogenesis. In this review, we summarize the current knowledge about co-translationally binding factors in chloroplasts and discuss their role in protein folding and ribosome translocation to thylakoid membranes.
The number of sequenced genomes increases rapidly due to the development of faster, better and new technologies. Thus, there is a great interest in automation, and standardization of the subsequent processing and analysis stages of the generated enormous amount of data. In the current work, genomes of clones, strains and species of Streptococcus were compared, which were sequenced, annotated and analysed with several technologies and methods. For sequencing, the 454- and Illumina-technology were used. The assembly of the genomes mainly was performed by the gsAssembler (Newbler) of Roche, the annotation was performed by the annotation pipeline RAST, the transfer tool RATT or manually. Concerning analysis, sets of deduced proteins of several genomes were compared to each other and common components, the so-called core-genome, of the used genomes of one or closely related species determined. Detailed comparative analysis was performed for the genomes of isolates of two clones to gather single nucleotide variants (SNV) within genes.
This work focusses on the pathogenic organism Streptococcus pneumoniae. This species is a paradigm for transformability, virulence and pathogenicity as well as resistance mechanisms against antibiotics. Its close relatives S. mitis, S. pseudopneumoniae and S. oralis have no pathogenicity potential as high as S. pneumoniae available and are thus of high interest to understand the evolution of S. pneumoniae. Strains of two S. pneumoniae clones were chosen. One is the ST10523 clone, which is associated with patients with cystic fibrosis and is characterized by long-term persistence. This clone is lacking an active hyaluronidase, which is one of the main virulence factors. The lack of two phage clusters possibly contributed to the long persistence in the human host. The clone ST226 shows a high penicillin resistance but interestingly one strain is sensitive against penicillin. Here it could be seen that the penicillin resistance mainly arose from the presence of mosaic-PBPs, while special alleles of MurM and CiaH - both genes are associated with penicillin-resistance – were present in resistant and sensitive strains as well. Penicillin resistance of S. pneumoniae is the result of horizontal gene transfer, where DNA of closely related species, mainly S. mitis or S. oralis, served as donor. The transfer of DNA from the high-level penicillin-resistant strain S. oralis Uo5 to the sensitive strain S. pneumoniae R6 was intentioned to reveal the amount of transferred DNA and whether it is possible to reach the high resistance level of S. oralis Uo5. Altogether, about 19kb of S. oralis DNA were transferred after three successive transformation steps, about 10-fold less than during transfer from S. mitis, which is more closely related to S. pneumoniae, as donor. MurE was identified as new resistance determinant. Since the resistance level of the donor strain could not be reached, it is assumed, that further unknown factors are present which contribute to penicillin resistance. The comparison of S. pneumoniae and its close relatives was performed using deduced protein sequences. 1.041 homologous proteins are common to the four complete genomes of S. pneumoniae R6, S. pseudopneumoniae IS7493, S. mitis B6 and S. oralis Uo5. Most of the virulence and pathogenicity factors described for S. pneumoniae could also be found in commensal species. These observations were confirmed by further investigations by Kilian et al. (Kilian, et al., 2019). After adding 26 complete S. pneumoniae genomes to the analysis, only 104 gene products could be identified as specific for this species. Investigations of a larger number of related streptococci, which were isolated from human and several primates, confirmed the presence of most of the virulence factors of human pneumococci in S. oralis and S. mitis strains from primates. While NanBC is common among S. pneumoniae and is missing in all S. oralis, all S. oralis contain a ß-N-acetyl-hexosaminidase which vice versa is missing in S. pneumoniae. The occurrence of S. oralis also in free-living chimpanzees suggests the assumption, that this species is part of the commensal flora of these Old-World monkeys unlike S. pneumoniae which has evolved with its human host. Compared to S. pneumoniae, S. oralis shows an amazing variability in factors important for biosynthesis of peptidoglycan and teichoic acid (PBP, MurMN, lic-cluster). Some streptococci contain a second PGP3 homologue. Additional analyses with further isolates, especially of wild animals, are necessary to determine host-specific components.
