Metabolic labelling of cholesteryl glucosides in Helicobacter pylori reveals how the uptake of human lipids enhances bacterial virulence

Jan, Hau Ming; Chen, Yi Chi; Shih, Yu-Yin; Huang, Yu Chen; Tu, Zhijay; Ingle, Arun B.; Liu, Sheng Wen; Wu, Ming–Shiang; Gervay‐Hague, Jacquelyn; Mong, Kwok Kong Tony; Chen, Yet Ran; Lin, Chun Hung

doi:10.1039/c6sc00889e

Cited by 28 publications

(47 citation statements)

References 46 publications

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“…Upon uptake of cholesterol, H. pylori employs cholesterol glucosyltransferase (CGT) to convert cholesterol to CG, followed by the reaction of CGAT to catalyze the acyltransfer to produce CAG. We previously demonstrated that CAG, rather than CG or cholesteryl 6′-O-phosphatidyl-α-D-glucopyranoside, was able to promote lipid rafts clustering in the host cell membranes, as well as CagA translocation and phosphorylation 14 . Wang et al 13 reported that the loss of cholesteryl-α-glucoside derivatives abolished the adhesion of H. pylori to AGS cells 13 .…”

Section: Resultsmentioning

confidence: 99%

“…Identification and characterization of H. pylori CGAT. Previously phospholipids were shown to serve as the precursors for the biosynthesis of CAG and cholesteryl 6′-O-phosphatidyl-α-Dglucopyranoside 14 . In an attempt of identifying the enzyme to catalyze the formation of CAGs, we performed several geneknockout strains related to phospholipase, esterase, or acyltransferase (see Methods section for the list of candidates) by inserting a kanamycin-resistance cassette into desirable genes of H. pylori 26695.…”

Section: Resultsmentioning

confidence: 99%

“…There is a subsequent modification occurring at O6′ of glucose in CG, i.e., cholesteryl 6′-O-acyl-α-D-glucopyranoside (CAG) or cholesteryl 6′-O-phosphatidyl-α-D-glucopyranoside are made by attaching an acyl or phosphatidyl group, respectively. We previously developed a metabolite-tagging method for characterizing these derivatives with a femto-molar detection limit 14 . The subsequent analysis led to the findings that these bacteria acquire phospholipids from the membrane of epithelial cells for CAG biosynthesis.…”

mentioning

confidence: 99%

“…The subsequent analysis led to the findings that these bacteria acquire phospholipids from the membrane of epithelial cells for CAG biosynthesis. The increase in longer CAG acyl chains helped to promote lipid raft clustering in the host cell membranes and thus the delivery of virulence factor CagA into the host cell 14 .…”

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Cholesteryl α-D-glucoside 6-acyltransferase enhances the adhesion of Helicobacter pylori to gastric epithelium

et al. 2020

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Helicobacter pylori, the most common etiologic agent of gastric diseases including gastric cancer, is auxotrophic for cholesterol and has to hijack it from gastric epithelia. Upon uptake, the bacteria convert cholesterol to cholesteryl 6′-O-acyl-α-D-glucopyranoside (CAG) to promote lipid raft clustering in the host cell membranes. However, how CAG appears in the host to exert the pathogenesis still remains ambiguous. Herein we identified hp0499 to be the gene of cholesteryl α-D-glucopyranoside acyltransferase (CGAT). Together with cholesteryl glucosyltransferase (catalyzing the prior step), CGAT is secreted via outer membrane vesicles to the host cells for direct synthesis of CAG. This significantly enhances lipid rafts clustering, gathers adhesion molecules (including Lewis antigens and integrins α5, β1), and promotes more bacterial adhesion. Furthermore, the clinically used drug amiodarone was shown as a potent inhibitor of CGAT to effectively reduce the bacterial adhesion, indicating that CGAT is a potential target of therapeutic intervention.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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Cholesteryl α-D-glucoside 6-acyltransferase enhances the adhesion of Helicobacter pylori to gastric epithelium

et al. 2020

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“…Although the enzyme proteins involved in the synthesis of either CAG or CPG remain to be clarified, a recent study by other group has demonstrated that the enzymatic activities for the synthesis of CAG and CPG are detected in H. pylori's o u t e r membrane and inner membrane, respectively [16]. In addition, both enzymatic activities for the synthesis of CAG and CPG turned out to use phosphatidylethanolamine (PE) as the substrate [16]. In sum, the CGL acyltransferase (CGLAT) transfers a fatty acid derived from PE to the CGL and thereby synthesizes CAG.…”

Section: Introductionmentioning

confidence: 99%

Development of a Novel Antibacterial Medicine that Targets a Characteristic Lipid of the Cell Membranes ofHelicobacter pylori

Wanibuchi¹,

Masui²,

Takahashi³

et al. 2019

Gastritis - New Approaches and Treatments

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Helicobacter pylori is one of the most prevalent causes of gastritis. This pathogen colonizes for many years human stomach and asymptomatically leads the persons to chronic gastritis. The eradication of H. pylori from human stomach is, therefore, important in order to prevent the digestive diseases including peptic ulcers and gastric cancer that develop via chronic atrophic gastritis. Wide-spectrum antibiotics such as amoxicillin and metronidazole are used for the treatment for H. pylori infectious diseases. However, the H. pylori strains resistant to these antibiotics are increasing year by year around the world. On this basis, we need urgently to develop the antibacterial medicines that act on H. pylori with a novel mechanism. Recent studies by our group have demonstrated that H. pylori shows susceptibility to the bactericidal action of indene compounds derived from decomposition of vitamin D. The bactericidal action of indene compounds is selective not against commonplace bacteria but against H. pylori. The indene compounds turned out to target the H. pylori's phosphatidylethanolamine that retains a myristic acid as the saturated fatty acid side chain. These findings will contribute to the development of new antibacterial medicines specialized to the treatment for H. pylori infectious diseases.

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A β‐Glucosyl Sterol Probe for in situ Fluorescent Labelling in Neuronal Cells to Investigate Neurodegenerative Diseases

Borsato,

Carnio,

Lunardon

et al. 2024

Chemistry A European J

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A b‐glucosyl sterol probe bearing a terminal alkyne moiety for fluorescent tagging enables the investigation of the neuronal and intracellular localization of this class of compounds involved in neurodegenerative diseases. The compound showed localization in the neuronal cells, with marked differences in the uptake and metabolism leading to enhanced persistence with respect to the un‐glycosylated sterol analogue. In addition, a different impact was observed towards lysosomes, with the simple sterol probe showing the enlargement of the lysosome structures, while the b‐glucosyl sterol was less capable to alter the morphology of this specific organel

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Metabolic labelling of cholesteryl glucosides in Helicobacter pylori reveals how the uptake of human lipids enhances bacterial virulence

Abstract: Helicobacter pylori infects approximately half of the human population and is the main cause of various gastric diseases.

Cited by 28 publications

References 46 publications

Cholesteryl α-D-glucoside 6-acyltransferase enhances the adhesion of Helicobacter pylori to gastric epithelium

Cholesteryl α-D-glucoside 6-acyltransferase enhances the adhesion of Helicobacter pylori to gastric epithelium

Development of a Novel Antibacterial Medicine that Targets a Characteristic Lipid of the Cell Membranes ofHelicobacter pylori

A β‐Glucosyl Sterol Probe for in situ Fluorescent Labelling in Neuronal Cells to Investigate Neurodegenerative Diseases

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