Chemical Synthesis of <scp>d</scp>-<i>glycero</i>-<scp>d</scp>-<i>manno</i>-Heptose 1,7-Bisphosphate and Evaluation of Its Ability to Modulate NF-κB Activation

Inuki, Shinsuke; Aiba, Toshihiko; Kawakami, Shota; Akiyama, Taishin; Inoue, Jun; Fujimoto, Yukari

doi:10.1021/acs.orglett.7b01158

Cited by 27 publications

(21 citation statements)

References 35 publications

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“…In line with IL-8 data, bHBP induced the formation of large TIFA-GFP oligomers in a dose-dependent manner ( Fig 2C and D). This result was in agreement with previous reports showing that synthetic bHBP induces NF-jB activation after several hours of treatment [15,16]. Given that TIFA oligomerization is observed within minutes of S. flexneri, S. typhimurium, or H. pylori infections [3,11], we also monitored TIFA oligomerization after 30 min of treatment.…”

Section: Resultssupporting

confidence: 92%

“…bHBP was also chemically synthesized [14][15][16][17]. Its pro-inflammatory activity was validated on the basis that it induced NF-jB activation after several hours of treatment [15,16]. In this report, we compare the ability of chemically synthesized bHBP and S. flexneri lysate to induce TIFA oligomerization and IL-8 production in human epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

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ADP‐heptose is a newly identified pathogen‐associated molecular pattern of Shigella flexneri

et al. 2018

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During an infection, the detection of pathogens is mediated through the interactions between pathogen‐associated molecular patterns (PAMPs) and pathogen recognition receptors. β‐Heptose 1,7‐bisphosphate (βHBP), an intermediate of the lipopolysaccharide (LPS) biosynthesis pathway, was recently identified as a bacterial PAMP. It was reported that βHBP sensing leads to oligomerization of TIFA proteins, a mechanism controlling NF‐κB activation and pro‐inflammatory gene expression. Here, we compare the ability of chemically synthesized βHBP and Shigella flexneri lysate to induce TIFA oligomerization in epithelial cells. We find that, unlike bacterial lysate, βHBP fails to initiate rapid TIFA oligomerization. It only induces delayed signaling, suggesting that βHBP must be processed intracellularly to trigger inflammation. Gene deletion and complementation analysis of the LPS biosynthesis pathway revealed that ADP‐heptose is the bacterial metabolite responsible for rapid TIFA oligomerization. ADP‐heptose sensing occurs down to 10−10 M. During S. flexneri infection, it results in cytokine production, a process dependent on the kinase ALPK1. Altogether, our results rule out a major role of βHBP in S. flexneri infection and identify ADP‐heptose as a new bacterial PAMP.

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Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

ADP‐heptose is a newly identified pathogen‐associated molecular pattern of Shigella flexneri

et al. 2018

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“…In line with IL-8 data, βHBP induced the formation of large TIFA-GFP oligomers in a dose-dependent manner ( Figure 2C and 2D). This result was in agreement with previous reports showing that synthetic βHBP induces NF-κB activation after several hours of treatment [14,15]. Given that TIFA oligomerization is observed within minutes of S. flexneri, S. typhimurium or H. pylori infections [3,10], we also monitored TIFA oligomerization after 30 minutes of treatment.…”

Section: Resultssupporting

confidence: 91%

“…It was first synthesized in vitro from the sedoheptulose 7-phosphate precursor by the sequential activities of purified GmhA and HldE [1]. More recently,βHBP was also chemically synthesized [13][14][15][16]. Its pro-inflammatory activity was validated on the basis that it induced NF-κB activation after several hours of treatment [14,15].…”

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confidence: 99%

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ADP-heptose is a pathogen-associated molecular pattern of Shigella flexneri infection

García‐Weber

Dangeard

Cornil

et al. 2018

Preprint

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During an infection, the detection of pathogens is mediated through interactions between pathogen-associated molecular patterns (PAMPs) and pathogen recognition receptors. β-Heptose 1,7-bisphosphate (βHBP), a metabolite of the lipopolysaccharide (LPS) biosynthesis pathway, was recently identified as a PAMP of gram-negative bacteria. It was reported that βHBP sensing leads within minutes to oligomerization of the protein TIFA, a mechanism controlling NF-κB activation and pro-inflammatory gene expression. Here, we compared the ability of chemically synthesized βHBP and Shigella flexneri lysate to induce TIFA oligomerization in epithelial cells. In contrast to lysate, we found that βHBP fails to trigger rapid oligomerization of TIFA. βHBP only induces delayed signaling, suggesting that it has to be processed intracellularly to induce inflammation. By dissecting the LPS biosynthesis pathway with deletion mutants and functional complementation experiments, we show that ADP-D-glycero-β-D-manno-heptose and ADP-L-glycero-β-D-manno-heptose are the bacterial metabolites responsible for rapid TIFA oligomerization, and that they strongly induce interleukin-8 expression during S. flexneri infection. Altogether, our results rule out a major role of βHBP in S. flexneri infection and identify ADP-heptose as a new PAMP. PAMPs include among others lipopolysaccharide (LPS), flagellin, peptidoglycan, lipoteichoic acid and DNA. β-Heptose 1,7-bisphosphate (βHBP) was recently identified as a PAMP of Neisseria meningitidis [1]. βHBP is a soluble metabolite of the LPS biosynthesis pathway. In N. meningitidis, it is produced by the D-β-D-heptose 7phosphate kinase activity of the HldA protein that phosphorylates D-glycero-β-Dmanno-heptose 7-phosphate into βHBP [2]. Gaudet et al. showed that it can be secreted by N. meningitidis and sensed in the cytosol of eukaryotic cells after being internalized by endocytosis [1]. Our laboratory reported that βHBP sensing was involved in the inflammatory response of epithelial cells to Shigella flexneri and Salmonella typhimurium infection [3]. This finding was based on the analysis of the hlde and gmhb deletion mutants of the LPS biosynthesis pathway. In these bacterial species closely related to Escherichia coli, hlde encodes a bifunctional protein that harbors both D-β-D-heptose 7-phosphate kinase and D-β-D-heptose 1-phosphate adenylyltransferase activities, responsible for the production of βHBP and ADP-Dglycero-β-D-manno-heptose (ADP-D-β-D-heptose), respectively [4]. The dephosphorylation of βHBP into D-glycero-β-D-manno heptose 1-phosphate is provided by the phosphatase activity of GmhB [5]. We showed that infection with an hlde deletion (∆hldE) mutant failed to induce the expression of the inflammatory cytokine interleukin-8 (IL-8) whereas this latter was restored after infection with a mutant deleted for gmhb (∆gmhB) [3]. S. flexneri infection leads to oligomerization of the proteins TRAF-interacting protein with FHA domain-containing protein A (TIFA) and TNF receptor-associated factor 6 (TRAF6)...

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Synthesis of Reversed C‐Acyl Glycosides through Ni/Photoredox Dual Catalysis

et al. 2018

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The incorporation of C-glycosides in drug design has become ar outine practice for medicinal chemists.T hese naturally occurring building blocks exhibit attractive pharmaceutical profiles,a nd have become an important target of synthetic efforts in recent decades. [1] Described herein is ap ractical, scalable,a nd versatile route for the synthesis of non-anomeric and unexploited C-acyl glycosides through aNi/ photoredox dual catalytic system. By utilizing an organic photocatalyst, arange of glycosyl-based radicals are generated and efficiently coupled with highly functionalizedc arboxylic acids at room temperature.D istinctive features of this transformation include its mild conditions,impressive compatibility with awide arrayoffunctional groups,and most significantly, preservation of the anomeric carbon:ahandle for further,latestage derivatization.Scheme 1. Recent developments in the synthesis of C-acyl glycosides.

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Chemical Synthesis of d-glycero-d-manno-Heptose 1,7-Bisphosphate and Evaluation of Its Ability to Modulate NF-κB Activation

Cited by 27 publications

References 35 publications

ADP‐heptose is a newly identified pathogen‐associated molecular pattern of Shigella flexneri

ADP‐heptose is a newly identified pathogen‐associated molecular pattern of Shigella flexneri

ADP-heptose is a pathogen-associated molecular pattern of Shigella flexneri infection

Synthesis of Reversed C‐Acyl Glycosides through Ni/Photoredox Dual Catalysis

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