Genetic microheterogeneity and phenotypic variation of Helicobacter pylori arginase in clinical isolates

Hovey, Justin G; Watson, Emily L; Langford, Melanie L.; Hildebrandt, Ellen; Bathala, Sangeetha; Bolland, Jeffrey R.; Spadafora, Domenico; Mendz, George L.; McGee, David J.

doi:10.1186/1471-2180-7-26

Cited by 23 publications

(21 citation statements)

References 64 publications

(53 reference statements)

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“…It has been reported that H. pylori RocF in clinical isolates has genetic microheterogeneity and phenotypic variation (Hovey et al, 2007). To avoid genetic variation in RocF affecting our PCR performance, we designed real-time PCR primers for RocF in its conserved region suggested by gene sequencing (Hovey et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Expression of three essential antioxidants of Helicobacter pylori in clinical isolates

Shi

Chen

Zhang

et al. 2014

J. Zhejiang Univ. Sci. B

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Abstract:Objective: Helicobacter pylori maintains long-term persistence in the host and combats oxidative stress via many antioxidant proteins, which are expected to be relevant to bacterial-associated gastric diseases. We aimed to investigate the expression of three essential antioxidants in H. pylori strains isolated from patients with different clinical outcomes. Methods: Forty H. pylori strains were isolated from endoscopic biopsy specimens of gastric mucosa from 13 patients with gastric cancer, 13 with peptic ulcer, and 14 with gastritis. The expression of thioredoxin 1 (Trx1), arginase (RocF), and alkyl hydroperoxide reductase (AhpC) in H. pylori was measured by real-time PCR. Comparisons among multiple sample sets were analyzed using a one-way ANOVA test. Pearson's correlation test was used to assess relationships among multiple continuous variables. Results: Trx1 expression of H. pylori in gastric cancer and peptic ulcer tissues was higher than that in tissues with gastritis. RocF expression of H. pylori in gastric cancer tissues was higher than that in tissues exhibiting peptic ulcer and gastritis. However, we did not find any differences in AhpC expression in samples from patients with different clinical outcomes. The expression of Trx1 and RocF had a positive, linear correlation. The expression of Trx1 and AhpC had a positive correlation without a linear trend. We found no correlation between the expression of RocF and AhpC. Conclusions: Our observations indicate that the expression of Trx1 and RocF in H. pylori might be related to gastric carcinogenesis. In H. pylori, the expression of members of the antioxidant system may be correlated and relevant to gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Expression of three essential antioxidants of Helicobacter pylori in clinical isolates

Shi

Chen

Zhang

et al. 2014

J. Zhejiang Univ. Sci. B

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“…This protein plays important role in L-arginine homeostasis, regulating L-arginine or L-ornithine, which are essential for critical metabolic processes such as formation of polyamines and protein synthesis (7,8). H. pylori arginase is reported to be crucial for acid protection in vitro but is moderately important for in vivo colonization in the gastric epithelial cells (9,10). NO is known to be an essential component of innate immunity and an effective antimicrobial agent (11).…”

Section: Introductionmentioning

confidence: 99%

Insight into the role of a unique SSEHA motif in the activity and stability of Helicobacter pylori arginase

et al. 2011

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SummaryArginase is a binuclear Mn 21 -metalloenzyme of urea cycle that hydrolyzes arginine to ornithine and urea. Unlike other arginases, the Helicobacter pylori enzyme is selective for Co 21 and has all conserved motifs except 88 SSEHA 92 (instead of GGDHS). To examine the role of this motif in the activity and stability, steady-state kinetics, mutational analysis, thermal denaturation, and homology modeling were carried out. With a series of single and double mutants, we show that mutations of Ser88 and Ala92 to its analogous residues in other arginases individually enhance the catalytic activity. This is supported by the modeling studies, where the motif plays a role in alteration at the active site structure compared to other arginases. Mutational analysis further shows that both Glu90 and His91 are important for the activity, as their mutations lead to significant decrease in the catalytic efficiency but they appear to act in two different ways; Glu90 has a more catalytic role as its mutant displays binding of the two metal ions per monomer of the protein, but His91 plays a critical role in retaining the metal ion at the active site as its mutation exhibits a loss of one metal ion. Thermal denaturation studies demonstrated that Ser88 and His91 both play crucial roles in the stability of the protein as their mutants showed a decrease in the T m by 10-118. Unlike wild type, the metal ions have larger role in providing the stability to the mutant proteins. Thus, our data demonstrate that the motif not only plays an important role in the activity but also critical in the stability of the protein.

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“…This variability in MICs could be considered somewhat unexpected for what is essentially a novel antibiotic compound being administered to a naive population. However, recent studies have reported significant phenotypic and genotypic diversity within clinical populations, suggesting that adaptation to environmental or host-related factors may be widespread (46)(47)(48). While the mechanism of action of statin antimicrobial and antivirulence activity remains to be elucidated, some reports suggest the involvement of isoprenoids and membrane integrity (49).…”

Section: Effects Of Statins On In Vitro Bacterial Growthmentioning

confidence: 99%

Is There Potential for Repurposing Statins as Novel Antimicrobials?

Hennessy

Adams

Reen

et al. 2016

Antimicrob Agents Chemother

100

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bStatins are members of a class of pharmaceutical widely used to reduce high levels of serum cholesterol. In addition, statins have so-called "pleiotropic effects," which include inflammation reduction, immunomodulation, and antimicrobial effects. An increasing number of studies are emerging which detail the attenuation of bacterial growth and in vitro and in vivo virulence by statin treatment. In this review, we describe the current information available concerning the effects of statins on bacterial infections and provide insight regarding the potential use of these compounds as antimicrobial therapeutic agents. O ne of the major undisputed clinical breakthroughs of the 20th century was the discovery of the statin family of drugs. These compounds are renowned for their ability to lower cholesterol levels and are used to treat approximately 40 million individuals with high cholesterol levels worldwide. Since the discovery of mevastatin as a metabolic product of Penicillium citrinum in 1976 (1, 2), a total of nine statins have been characterized, seven of which are approved by the FDA to treat patients with high cholesterol. Structurally, statins are characterized by the presence of a conserved lactone ring (3). This structure is present as a hydrolyzed (active) form in all statins except for mevastatin, lovastatin, and simvastatin; in those statins, the lactone ring is hydrolyzed in the liver (4). Statins can be divided into two broad classes (Fig. 1). Type 1 statins are lipophilic and possess a butyryl side chain-they are said to structurally resemble mevastatin (3). Lovastatin, pravastatin, and simvastatin are type 1 statins. Type 2 statins are classically lipophobic and are distinguished from type 1 by the replacement of the butyryl side chain with a fluorophenol group and typically possess larger side chains than type 1 statins (3). Atorvastatin, cerivastatin, fluvastatin, pitavastatin, and rosuvastatin are type 2 statins.Statins exert their cholesterol-lowering effect by binding to the active site of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR), a rate-limiting enzyme involved in cholesterol biosynthesis (3). HMGR is an integral part of the mevalonate pathway, which not only is essential for cholesterol biosynthesis but also contributes to the production of isoprenoids, lipid compounds that are essential for cell signaling and structure. As well as inhibition of cholesterol, statins have also been found to have a number of cholesterol-independent, socalled "pleiotropic" effects. Statins have been reported to confer anti-inflammatory, immunomodulatory, and anticancer effects on host cells, and these effects are well characterized (5-9). Furthermore, several studies have explored the pleiotropic effects of statins in combating multisystem microbial infections, such as sepsis and pneumonia, and a growing number of studies are demonstrating that statins can directly influence the growth and virulence of bacterial pathogens. With the global increase in antibiotic resistance to existing antib...

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Genetic microheterogeneity and phenotypic variation of Helicobacter pylori arginase in clinical isolates

Cited by 23 publications

References 64 publications

Expression of three essential antioxidants of Helicobacter pylori in clinical isolates

Expression of three essential antioxidants of Helicobacter pylori in clinical isolates

Insight into the role of a unique SSEHA motif in the activity and stability of Helicobacter pylori arginase

Is There Potential for Repurposing Statins as Novel Antimicrobials?

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