Characterization and mutational analysis of two UDP-galactose 4-epimerases in Streptococcus pneumoniae TIGR4

Chen, L L; Han, Donglei; Zhai, Yijie; Wang, J H; Wang, Y F; Chen, M

doi:10.1134/s0006297918010054

Cited by 7 publications

(4 citation statements)

References 28 publications

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“…This in turn will limit the availability of glucose for the biosynthesis of UDP-GlcNAc, an important substrate for epimerases that catalyze the biosynthesis of the sugars in the repeat unit of CPS. UDP-GlcNAc is converted to UDP-ManNAc and UDP-GalNAc by UDP- N -acetylglucosamine-2-epimerase and UDP-Glu 4-epimerase, respectively (Kay et al, 2016; Chen et al, 2018). UDP-GlcNAc can also be converted to UDP-FucNAc in a multi-step reaction involving SP_0358-60 protein (Kay et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

Polyamine Synthesis Effects Capsule Expression by Reduction of Precursors in Streptococcus pneumoniae

et al. 2019

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Streptococcus pneumoniae (pneumococcus, Spn) colonizes the human nasopharynx asymptomatically but can cause infections such as otitis media, and invasive pneumococcal disease such as community-acquired pneumonia, meningitis, and sepsis. Although the success of Spn as a pathogen can be attributed to its ability to synthesize and regulate capsular polysaccharide (CPS) for survival in the host, the mechanisms of CPS regulation are not well-described. Recent studies from our lab demonstrate that deletion of a putative polyamine biosynthesis gene (Δ cadA ) in Spn TIGR4 results in the loss of the capsule. In this study, we characterized the transcriptome and metabolome of Δ cadA and identified specific mechanisms that could explain the regulatory role of polyamines in pneumococcal CPS biosynthesis. Our data indicate that impaired polyamine synthesis impacts galactose to glucose interconversion via the Leloir pathway which limits the availability of UDP-galactose, a precursor of serotype 4 CPS, and UDP- N -acetylglucosamine (UDP-GlcNAc), a nucleotide sugar precursor that is at the intersection of CPS and peptidoglycan repeat unit biosynthesis. Reduced carbon flux through glycolysis, coupled with altered fate of glycolytic intermediates further supports impaired synthesis of UDP-GlcNAc. A significant increase in the expression of transketolases indicates a potential shift in carbon flow toward the pentose phosphate pathway (PPP). Higher PPP activity could constitute oxidative stress responses in Δ cad A which warrants further investigation. The results from this study clearly demonstrate the potential of polyamine synthesis, targeted for cancer therapy in human medicine, for the development of novel prophylactic and therapeutic strategies for treating bacterial infections.

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Section: Resultsmentioning

confidence: 99%

Polyamine Synthesis Effects Capsule Expression by Reduction of Precursors in Streptococcus pneumoniae

et al. 2019

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“…Upregulation of the Leloir and the tagatose pathways that produce PPP intermediates and transketolase, a key enzyme in PPP, further suggest decreased carbon flow through glycolysis, supported by decreased pyruvate levels in ∆potABCD. Decreased glycolysis could result in reduced acetyl-CoA, a precursor for UDP-GlcNAc, and a donor for the three N-acetylated sugars at the intersection of CPS and PG repeat unit biosynthesis [48,49]. Upregulation of genes involved in the Leloir pathway in ∆potABCD is possibly due to the regulation of this pathway by arginine decarboxylase (speA).…”

Section: Discussionmentioning

confidence: 99%

The Effect of Impaired Polyamine Transport on Pneumococcal Transcriptome

et al. 2021

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Infections due to Streptococcus pneumoniae, a commensal in the nasopharynx, still claim a significant number of lives worldwide. Genome plasticity, antibiotic resistance, and limited serotype coverage of the available polysaccharide-based conjugate vaccines confounds therapeutic interventions to limit the spread of this pathogen. Pathogenic mechanisms that allow successful adaption and persistence in the host could be potential innovative therapeutic targets. Polyamines are ubiquitous polycationic molecules that regulate many cellular processes. We previously reported that deletion of polyamine transport operon potABCD, which encodes a putrescine/spermidine transporter (∆potABCD), resulted in an unencapsulated attenuated phenotype. Here, we characterize the transcriptome, metabolome, and stress responses of polyamine transport-deficient S. pneumoniae. Compared with the wild-type strain, the expression of genes involved in oxidative stress responses and the nucleotide sugar metabolism was reduced, while expression of genes involved in the Leloir, tagatose, and pentose phosphate pathways was higher in ΔpotABCD. A metabolic shift towards the pentose phosphate pathway will limit the synthesis of precursors of capsule polysaccharides. Metabolomics results show reduced levels of glutathione and pyruvate in the mutant. Our results also show that the potABCD operon protects pneumococci against hydrogen peroxide and nitrosative stress. Our findings demonstrate the importance of polyamine transport in pneumococcal physiology that could impact in vivo fitness. Thus, polyamine transport in pneumococci represents a novel target for therapeutic interventions.

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“…Furthermore, upregulation of the Leloir and the tagatose pathways that produce PPP intermediates, and transketolase, a key enzyme in PPP, further suggest decreased carbon ow through glycolysis, supported by decreased pyruvate levels in ΔpotABCD. Decreased glycolysis could result in reduced acetyl-CoA, a precursor for UDP-GlcNAc, and a donor for the three N-acetylated sugars at the intersection of CPS and PG repeat unit biosynthesis [38,39]. However, upregulation of genes involved in the Leloir pathway in ΔpotABCD is contrary to what was observed in ΔspeA [15].…”

Section: Discussionmentioning

confidence: 99%

Polyamine Transport Is Required for Stress Responses and Capsule Production in Streptococcus Pneumoniae

Nakamya

Ayoola

Shack

et al. 2021

Preprint

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Infections due to Streptococcus pneumoniae, a commensal in the nasopharynx, still claim a significant number of lives worldwide. Genetic plasticity, antibiotic resistance, limited serotype coverage of the available polysaccharide-based conjugate vaccines confounds therapeutic interventions. Pathogenic systems that allow successful adaption and persistence in the host could be potential innovative targets for mediations. Polyamines are ubiquitous polycationic molecules and regulate many cellular processes. We previously reported that deletion of potABCD, an operon that encodes a putrescine/spermidine transporter (∆potABCD), resulted in an un-encapsulated attenuated phenotype. Here we characterize the transcriptome, metabolome, and stress responses of S. pneumoniae that is dependent on the polyamine transporter. Expression of genes involved in oxidative stress responses and the central metabolism was reduced while that of genes involved in the Leloir, tagatose, and pentose phosphate pathways was increased in ΔpotABCD. Downregulation of genes of the central metabolism will reduce production of precursors of capsule polysaccharides. Metabolomics results show reduced glutathione and pyruvate levels in the mutant. We also show that the potABCD operon protects pneumococci against hydrogen peroxide and nitrosative stress. These results show the importance of the potABCD operon and polyamine transport in pneumococcal physiology and fitness that represents a novel target for therapeutic interventions.

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Characterization and mutational analysis of two UDP-galactose 4-epimerases in Streptococcus pneumoniae TIGR4

Cited by 7 publications

References 28 publications

Polyamine Synthesis Effects Capsule Expression by Reduction of Precursors in Streptococcus pneumoniae

Polyamine Synthesis Effects Capsule Expression by Reduction of Precursors in Streptococcus pneumoniae

The Effect of Impaired Polyamine Transport on Pneumococcal Transcriptome

Polyamine Transport Is Required for Stress Responses and Capsule Production in Streptococcus Pneumoniae

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