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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

Surface plasmon resonance analysis of the interaction between HSP70 or DnaK and GGA.A sensorgram for the binding of DnaK (A) or HSP70 (B) to GGA is shown. Different concentrations of GGA were injected as described under “Materials and Methods”. RU, resonance units.
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f2: Surface plasmon resonance analysis of the interaction between HSP70 or DnaK and GGA.A sensorgram for the binding of DnaK (A) or HSP70 (B) to GGA is shown. Different concentrations of GGA were injected as described under “Materials and Methods”. RU, resonance units.

Mentions: A sensorgram from surface plasmon resonance of the binding of GGA to HSP70 and DnaK is shown in Fig. 2. The kinetic parameters Ka, Kd, and KD were estimated using BIAcore evaluation software, fitting the binding curves to a simple bimolecular binding algorithm. Based on these results with immobilized HSP70 and soluble GGA, the apparent equilibrium dissociation constant (KD) was 2.00 × 10−6 M. In contrast, the KD value of DnaK and GGA was calculated as 7.55 × 10−8 M. Thus, the affinity of GGA to the bacterial DnaK is about 26 times higher than that to mammalian HSP70.


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)

Surface plasmon resonance analysis of the interaction between HSP70 or DnaK and GGA.A sensorgram for the binding of DnaK (A) or HSP70 (B) to GGA is shown. Different concentrations of GGA were injected as described under “Materials and Methods”. RU, resonance units.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Surface plasmon resonance analysis of the interaction between HSP70 or DnaK and GGA.A sensorgram for the binding of DnaK (A) or HSP70 (B) to GGA is shown. Different concentrations of GGA were injected as described under “Materials and Methods”. RU, resonance units.
Mentions: A sensorgram from surface plasmon resonance of the binding of GGA to HSP70 and DnaK is shown in Fig. 2. The kinetic parameters Ka, Kd, and KD were estimated using BIAcore evaluation software, fitting the binding curves to a simple bimolecular binding algorithm. Based on these results with immobilized HSP70 and soluble GGA, the apparent equilibrium dissociation constant (KD) was 2.00 × 10−6 M. In contrast, the KD value of DnaK and GGA was calculated as 7.55 × 10−8 M. Thus, the affinity of GGA to the bacterial DnaK is about 26 times higher than that to mammalian HSP70.

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