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Geranylgeranylacetone selectively binds to the HSP70 of Helicobacter pylori and alters its coccoid morphology.

Grave E, Yokota S, Yamamoto S, Tamura A, Ohtaki-Mizoguchi T, Yokota K, Oguma K, Fujiwara K, Ogawa N, Okamoto T, Otaka M, Itoh H - Sci Rep (2015)

Bottom Line: GGA-treated cells elicited enhanced interleukin-8 production by gastric cancer cell lines and potentiated susceptibility to complement as compared to untreated cells.This morphological conversion by GGA resulted in accelerated growth of H. pylori.These results suggest a model in which GGA sensitizes H. pylori to antibiotic treatment by converting the cells to an actively growing state.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Science, Graduate School and Faculty of Engineering Science, Akita University, Akita 010-8502, Japan.

ABSTRACT
Geranylgeranylacetone (GGA) is used to treat patients suffering from peptic ulcers and gastritis. We examined the effect of GGA on Helicobacter pylori, which is a causative factor of gastrointestinal diseases. Previously, we have reported that GGA binds specifically to the molecular chaperone HSP70. In this paper, we report that GGA bounds to H. pylori HSP70 (product of the DnaK gene) with 26-times higher affinity than to human HSP70, and induced large conformational changes as observed from surface plasmon resonance and circular dichroism. Binding of GGA suppressed the activity of the H. pylori chaperone. GGA also altered several characteristics of H. pylori cells. GGA-treated cells elicited enhanced interleukin-8 production by gastric cancer cell lines and potentiated susceptibility to complement as compared to untreated cells. GGA also caused morphological alterations in H. pylori as reflected in fewer coccoid-like cells, suggesting that GGA converts H. pylori to an actively dividing, spiral state (vegetative form) from a non-growing, coccoid state. This morphological conversion by GGA resulted in accelerated growth of H. pylori. These results suggest a model in which GGA sensitizes H. pylori to antibiotic treatment by converting the cells to an actively growing state.

No MeSH data available.


Related in: MedlinePlus

Effect of GGA on the conformational changes of DnaK and HSP70.(A) the CD spectrum of DnaK was measured in the absence (closed red diamond) or presence (closed blue square) of GGA as described under “Materials and Methods” denotes the mean residue ellipticity. (B) the CD spectrum of HSP70 was measured in the absence (closed red diamond) or presence (closed blue square) of GGA as described under “Materials and Methods” the mean residue ellipticity.
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f3: Effect of GGA on the conformational changes of DnaK and HSP70.(A) the CD spectrum of DnaK was measured in the absence (closed red diamond) or presence (closed blue square) of GGA as described under “Materials and Methods” denotes the mean residue ellipticity. (B) the CD spectrum of HSP70 was measured in the absence (closed red diamond) or presence (closed blue square) of GGA as described under “Materials and Methods” the mean residue ellipticity.

Mentions: We investigated whether GGA may give rise to conformational change in HSP70 and DnaK using far UV Circular Dichroism (CD) spectra. GGA induced changes in DnaK spectrum (Fig. 3A) that were consistent with decreased β-sheet and increased α-helix, β-turn, and random structure [α-helix (22.0 ± 1.4 to 24.0 ± 1.0), β-sheet (16.2 ± 2.3 to 9.4 ± 3.0* (*p < 0.05), β-turn (25.2 ± 1.4 to 28.3 ± 1.6), and random structure (36.5 ± 0.9 to 38.3 ± 0.8)]. In contrast, GGA caused only slight conformational changes in HSP70 (Fig. 3B) [α-helix (26.4 ± 3.9 to 27.0 ± 6.4), β-sheet (27.0 ± 0.7 to 24.4 ± 2.9), β-turn (26.1 ± 2.5 to 26.1 ± 5.2), and random structure (20.4 ± 1.7 to 22.4 ± 4.6)]. The conformational changes in HSP70 and DnaK in the presence or absence of GGA are summarized in Table 1.


Geranylgeranylacetone selectively binds to the HSP70 of Helicobacter pylori and alters its coccoid morphology.

Grave E, Yokota S, Yamamoto S, Tamura A, Ohtaki-Mizoguchi T, Yokota K, Oguma K, Fujiwara K, Ogawa N, Okamoto T, Otaka M, Itoh H - Sci Rep (2015)

Effect of GGA on the conformational changes of DnaK and HSP70.(A) the CD spectrum of DnaK was measured in the absence (closed red diamond) or presence (closed blue square) of GGA as described under “Materials and Methods” denotes the mean residue ellipticity. (B) the CD spectrum of HSP70 was measured in the absence (closed red diamond) or presence (closed blue square) of GGA as described under “Materials and Methods” the mean residue ellipticity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4561889&req=5

f3: Effect of GGA on the conformational changes of DnaK and HSP70.(A) the CD spectrum of DnaK was measured in the absence (closed red diamond) or presence (closed blue square) of GGA as described under “Materials and Methods” denotes the mean residue ellipticity. (B) the CD spectrum of HSP70 was measured in the absence (closed red diamond) or presence (closed blue square) of GGA as described under “Materials and Methods” the mean residue ellipticity.
Mentions: We investigated whether GGA may give rise to conformational change in HSP70 and DnaK using far UV Circular Dichroism (CD) spectra. GGA induced changes in DnaK spectrum (Fig. 3A) that were consistent with decreased β-sheet and increased α-helix, β-turn, and random structure [α-helix (22.0 ± 1.4 to 24.0 ± 1.0), β-sheet (16.2 ± 2.3 to 9.4 ± 3.0* (*p < 0.05), β-turn (25.2 ± 1.4 to 28.3 ± 1.6), and random structure (36.5 ± 0.9 to 38.3 ± 0.8)]. In contrast, GGA caused only slight conformational changes in HSP70 (Fig. 3B) [α-helix (26.4 ± 3.9 to 27.0 ± 6.4), β-sheet (27.0 ± 0.7 to 24.4 ± 2.9), β-turn (26.1 ± 2.5 to 26.1 ± 5.2), and random structure (20.4 ± 1.7 to 22.4 ± 4.6)]. The conformational changes in HSP70 and DnaK in the presence or absence of GGA are summarized in Table 1.

Bottom Line: GGA-treated cells elicited enhanced interleukin-8 production by gastric cancer cell lines and potentiated susceptibility to complement as compared to untreated cells.This morphological conversion by GGA resulted in accelerated growth of H. pylori.These results suggest a model in which GGA sensitizes H. pylori to antibiotic treatment by converting the cells to an actively growing state.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Science, Graduate School and Faculty of Engineering Science, Akita University, Akita 010-8502, Japan.

ABSTRACT
Geranylgeranylacetone (GGA) is used to treat patients suffering from peptic ulcers and gastritis. We examined the effect of GGA on Helicobacter pylori, which is a causative factor of gastrointestinal diseases. Previously, we have reported that GGA binds specifically to the molecular chaperone HSP70. In this paper, we report that GGA bounds to H. pylori HSP70 (product of the DnaK gene) with 26-times higher affinity than to human HSP70, and induced large conformational changes as observed from surface plasmon resonance and circular dichroism. Binding of GGA suppressed the activity of the H. pylori chaperone. GGA also altered several characteristics of H. pylori cells. GGA-treated cells elicited enhanced interleukin-8 production by gastric cancer cell lines and potentiated susceptibility to complement as compared to untreated cells. GGA also caused morphological alterations in H. pylori as reflected in fewer coccoid-like cells, suggesting that GGA converts H. pylori to an actively dividing, spiral state (vegetative form) from a non-growing, coccoid state. This morphological conversion by GGA resulted in accelerated growth of H. pylori. These results suggest a model in which GGA sensitizes H. pylori to antibiotic treatment by converting the cells to an actively growing state.

No MeSH data available.


Related in: MedlinePlus