Role of phosphate in the central metabolism of two lactic acid bacteria – a comparative systems biology approach

Levering, Jennifer; Musters, Mark; Bekker, Martijn; Bellomo, Domenico; Fiedler, Tomas; Vos, Willem M. de; Hugenholtz, Jeroen; Kreikemeyer, Bernd; Kummer, Ursula; Teusink, Bas

doi:10.1111/j.1742-4658.2012.08523.x

Cited by 56 publications

(49 citation statements)

References 76 publications

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“…Since the pst mutations are all loss-of-function mutations, they could confer PB resistance either through the inappropriate assembly of the transporter's remaining components or through an effect on phosphate metabolism. For lactic acid bacteria, alterations of phosphate metabolism have been implicated in regulation of central metabolism and stress resistance (69,70).…”

Section: Discussionmentioning

confidence: 99%

Streptococcus pyogenes Polymyxin B-Resistant Mutants Display Enhanced ExPortal Integrity

et al. 2014

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The ExPortal protein secretion organelle in Streptococcus pyogenes is an anionic phospholipid-containing membrane microdomain enriched in Sec translocons and postsecretion protein biogenesis factors. Polymyxin B binds to and disrupts ExPortal integrity, resulting in defective secretion of several toxins. To gain insight into factors that influence ExPortal organization, a genetic screen was conducted to select for spontaneous polymyxin B-resistant mutants displaying enhanced ExPortal integrity. Whole-genome resequencing of 25 resistant mutants revealed from one to four mutations per mutant genome clustered primarily within a core set of 10 gene groups. Construction of mutants with individual deletions or insertions demonstrated that 7 core genes confer resistance and enhanced ExPortal integrity through loss of function, while 3 were likely due to gain of function and/or combinatorial effects. Core resistance genes include a transcriptional regulator of lipid biosynthesis, several genes involved in nutrient acquisition, and a variety of genes involved in stress responses. Two members of the latter class also function as novel regulators of the secreted SpeB cysteine protease. Analysis of the most frequently isolated mutation, a single nucleotide deletion in a track of 9 consecutive adenine residues in pstS, encoding a component of a high-affinity P i transporter, suggests that this sequence functions as a molecular switch to facilitate stress adaptation. Together, these data suggest the existence of a membrane stress response that promotes enhanced ExPortal integrity and resistance to cationic antimicrobial peptides.

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Section: Discussionmentioning

confidence: 99%

Streptococcus pyogenes Polymyxin B-Resistant Mutants Display Enhanced ExPortal Integrity

et al. 2014

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“…Correct insertion of the PCR products was confirmed by plasmid sequencing. The construction of the expression plasmid for the S. pyogenes M49 591 ldh gene has been described previously (18).…”

Section: Methodsmentioning

confidence: 99%

Regulation of the Activity of Lactate Dehydrogenases from Four Lactic Acid Bacteria

Feldman‐Salit

Hering²,

Messiha

et al. 2013

Journal of Biological Chemistry

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Background: Lactate dehydrogenases (LDHs) are key metabolic enzymes in lactic acid bacteria (LAB). Results: The effects of fructose 1,6-bisphosphate, phosphate, pH, and ionic strength on enzyme activity differ for six LDHs from four LAB. Conclusion:The regulation of LDH activity differs among LAB. Significance: These results have implications for understanding enzyme evolutionary adaptation, for quantitative comparative modeling, and for biotechnological application of LAB.

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“…GAS, as one of the major pathogenic lactic acid bacteria, utilizes glucose as a main carbon source (40). GAS glycolysis has recently been studied by a systems biology approach, and the first GAS glycolytic kinetic model has been published (23).…”

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confidence: 99%

Effects of the ERES Pathogenicity Region Regulator Ralp3 on Streptococcus pyogenes Serotype M49 Virulence Factor Expression

et al. 2012

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Streptococcus pyogenes (group A streptococcus [GAS]) is a highly virulent Gram-positive bacterium. For successful infection, GAS expresses many virulence factors, which are clustered together with transcriptional regulators in distinct genomic regions. Ralp3 is a central regulator of the ERES region. In this study, we investigated the role of Ralp3 in GAS M49 pathogenesis. The inactivation of Ralp3 resulted in reduced attachment to and internalization into human keratinocytes. The ⌬ralp3 mutant failed to survive in human blood and serum, and the hyaluronic acid capsule was slightly decreased. In addition, the mutant showed a lower binding capacity to human plasminogen, and the SpeB activity was significantly decreased. Complementation of the ⌬ralp3 mutant restored the wild-type phenotype. The transcriptome and quantitative reverse transcription-PCR analysis of the serotype M49 GAS strain and its isogenic ⌬ralp3 mutant identified 16 genes as upregulated, and 43 genes were found to be downregulated. Among the downregulated genes, there were open reading frames encoding proteins involved in metabolism (e.g., both lac operons and the fru operon), genes encoding lantibiotics (e.g., the putative salivaricin operon), and ORFs encoding virulence factors (such as the whole Mga core regulon and further genes under Mga control). In summary, the ERES region regulator Ralp3 is an important serotype-specific transcriptional regulator for virulence and metabolic control. Group A streptococcus (GAS) is a causative agent of human diseases ranging from commonly mild superficial infections of the skin and mucous membranes of the nasopharynx to severe but rare toxic and invasive diseases (2, 5, 7). GAS strains are equipped with an arsenal of virulence factors which allow this pathogen to infect and survive in the human host. Regulation of virulence factor expression is fine-tuned by two-component systems and stand-alone regulators (11, 18). Many GAS virulence factor-and transcriptional regulator-encoding genes cluster together in discrete genomic regions (11). The longest known and best-characterized virulence regulator is Mga, the central regulator of the virulence factor-encoding Mga region (14). This regulator controls genes encoding proteins involved in adherence, internalization, and host immune evasion. Mga also influences the expression of many genes and operons involved in metabolism and sugar utilization (14).Several studies showed that Mga also interacts with RofA-like protein family (RALP) regulators RofA and Nra, the central regulators of the FCT virulence region (1,5,16,29). Transcriptome analysis of a serotype M49 GAS strain and its isogenic Nra knockout mutant revealed the transcriptional control of another RALP family regulator, Ralp3 (RofA-like protein regulator type 3 [19]). ralp3 homologous genes were exclusively found in serotypes M1, M4, M12, M28, and M49. ralp3 is linked with a gene encoding Epf (extracellular protein factor from Streptococcus suis), a putative plasminogen-binding protein in GAS. Plasminogen a...

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Role of phosphate in the central metabolism of two lactic acid bacteria – a comparative systems biology approach

Cited by 56 publications

References 76 publications

Streptococcus pyogenes Polymyxin B-Resistant Mutants Display Enhanced ExPortal Integrity

Streptococcus pyogenes Polymyxin B-Resistant Mutants Display Enhanced ExPortal Integrity

Regulation of the Activity of Lactate Dehydrogenases from Four Lactic Acid Bacteria

Effects of the ERES Pathogenicity Region Regulator Ralp3 on Streptococcus pyogenes Serotype M49 Virulence Factor Expression

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