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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

Purified DnaK and HSP70.DnaK and HSP70 were purified as described under “Materials and Methods” and the purity was analyzed by SDS-PAGE (9% gels).
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f1: Purified DnaK and HSP70.DnaK and HSP70 were purified as described under “Materials and Methods” and the purity was analyzed by SDS-PAGE (9% gels).

Mentions: We investigated the sequence homology between human HSP70 and H. pylori DnaK. It has been shown that HSP70 is composed of two domains, ATPase and peptide-binding domain. The ATPase and peptide-binding domains are located in the N-terminal and C-terminal halves of the protein, respectively. There was 47% sequence identity between those two proteins, which was evenly distributed across the two halves. There are some differences in the peptide-binding domains (Supplementary Figure S1). After expression and purification, the human and H. pylori proteins were compared by SDS-PAGE (Fig. 1). The apparent molecular weight of the H. pylori protein (referred to henceforth as DnaK) was slightly larger. These purified proteins were used in the present study.


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)

Purified DnaK and HSP70.DnaK and HSP70 were purified as described under “Materials and Methods” and the purity was analyzed by SDS-PAGE (9% gels).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Purified DnaK and HSP70.DnaK and HSP70 were purified as described under “Materials and Methods” and the purity was analyzed by SDS-PAGE (9% gels).
Mentions: We investigated the sequence homology between human HSP70 and H. pylori DnaK. It has been shown that HSP70 is composed of two domains, ATPase and peptide-binding domain. The ATPase and peptide-binding domains are located in the N-terminal and C-terminal halves of the protein, respectively. There was 47% sequence identity between those two proteins, which was evenly distributed across the two halves. There are some differences in the peptide-binding domains (Supplementary Figure S1). After expression and purification, the human and H. pylori proteins were compared by SDS-PAGE (Fig. 1). The apparent molecular weight of the H. pylori protein (referred to henceforth as DnaK) was slightly larger. These purified proteins were used in the present study.

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