scholarly journals Helicobacter pylori FabX contains a [4Fe-4S] cluster essential for unsaturated fatty acid synthesis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jiashen Zhou ◽  
Lin Zhang ◽  
Liping Zeng ◽  
Lu Yu ◽  
Yuanyuan Duan ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Unsaturated Fatty Acids ◽  
Acyl Carrier Protein ◽  
Acid Synthesis ◽  
Active Site Residue ◽  
Human Pathogen ◽  
Membrane Phospholipids ◽  
Functional Membrane ◽  
H Pylori ◽  
Positively Charged

AbstractUnsaturated fatty acids (UFAs) are essential for functional membrane phospholipids in most bacteria. The bifunctional dehydrogenase/isomerase FabX is an essential UFA biosynthesis enzyme in the widespread human pathogen Helicobacter pylori, a bacterium etiologically related to 95% of gastric cancers. Here, we present the crystal structures of FabX alone and in complexes with an octanoyl-acyl carrier protein (ACP) substrate or with holo-ACP. FabX belongs to the nitronate monooxygenase (NMO) flavoprotein family but contains an atypical [4Fe-4S] cluster absent in all other family members characterized to date. FabX binds ACP via its positively charged α7 helix that interacts with the negatively charged α2 and α3 helices of ACP. We demonstrate that the [4Fe-4S] cluster potentiates FMN oxidation during dehydrogenase catalysis, generating superoxide from an oxygen molecule that is locked in an oxyanion hole between the FMN and the active site residue His182. Both the [4Fe-4S] and FMN cofactors are essential for UFA synthesis, and the superoxide is subsequently excreted by H. pylori as a major resource of peroxide which may contribute to its pathogenic function in the corrosion of gastric mucosa.

scholarly journals The Helicobacter pylori Homologue of the Ferric Uptake Regulator Is Involved in Acid Resistance

2002 ◽  
Vol 70 (2) ◽  
pp. 606-611 ◽  
Author(s):  
Jetta J. E. Bijlsma ◽  
Barbara Waidner ◽  
Arnoud H. M. van Vliet ◽  
Nicky J. Hughes ◽  
Stephanie Häg ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Iron Homeostasis ◽  
Regulatory Protein ◽  
Acid Resistance ◽  
Low Ph ◽  
Main Function ◽  
Ferric Uptake Regulator ◽  
Acidic Ph ◽  
Human Pathogen ◽  
H Pylori

ABSTRACT The only known niche of the human pathogen Helicobacter pylori is the gastric mucosa, where large fluctuations of pH occur, indicating that the bacterial response and resistance to acid are important for successful colonization. One of the few regulatory proteins in the H. pylori genome is a homologue of the ferric uptake regulator (Fur). In most bacteria, the main function of Fur is the regulation of iron homeostasis. However, in Salmonella enterica serovar Typhimurium, Fur also plays an important role in acid resistance. In this study, we determined the role of the H. pylori Fur homologue in acid resistance. Isogenic fur mutants were generated in three H. pylori strains (1061, 26695, and NCTC 11638). At pH 7 there was no difference between the growth rates of mutants and the parent strains. Under acidic conditions, growth of the fur mutants was severely impaired. No differences were observed between the survival of the fur mutant and parent strain 1061 after acid shock. Addition of extra iron or removal of iron from the growth medium did not improve the growth of the fur mutant at acidic pH. This indicates that the phenotype of the fur mutant at low pH was not due to increased iron sensitivity. Transcription of fur was repressed in response to low pH. From this we conclude that Fur is involved in the growth at acidic pH of H. pylori; as such, it is the first regulatory protein implicated in the acid resistance of this important human pathogen.

scholarly journals A Gastric Pathogen Moves Chemotaxis in a New Direction

mBio ◽  
2011 ◽  
Vol 2 (5) ◽  
Author(s):  
Emily Goers Sweeney ◽  
Karen Guillemin
Keyword(s):  
Escherichia Coli ◽  
Helicobacter Pylori ◽  
Chemical Cues ◽  
Swimming Behavior ◽  
Human Pathogen ◽  
Gastric Glands ◽  
Content Type ◽  
Gastric Pathogen ◽  
H Pylori ◽  
Novel Antibiotics

ABSTRACTFor almost 50 years,Escherichia colihas been the model for understanding how bacteria orient their movement in response to chemical cues, but recent studies of chemotaxis in other bacteria have revealed interesting variations from prevailing paradigms. Investigating the human pathogenHelicobacter pylori, Amieva and colleagues [mBio 2(4):e00098-11, 2011] discovered a new chemotaxis regulator, ChePep, which modulates swimming behavior through the canonical histidine-aspartate phosphorelay system. Functionally conserved among the epsilonproteobacteria, ChePep is essential forH. pylorito navigate deep into the stomach’s gastric glands and may be an attractive target for novel antibiotics.

scholarly journals Helicobacter pylori Association with Amoeba: A Natural Reservoir of the Bacteria?

2012 ◽  
Vol 18 (S5) ◽  
pp. 27-28
Author(s):  
A. P. Alves de Matos ◽  
F. F. Vale ◽  
J. M. B. Vitor
Keyword(s):  
Helicobacter Pylori ◽  
Aquatic Environments ◽  
Human Pathogen ◽  
Human Pathogens ◽  
Natural Reservoir ◽  
Hospital Acquired Infections ◽  
Route Of Transmission ◽  
Mode Of Transmission ◽  
H Pylori ◽  
Hospital Acquired

Helicobacter pylori is a human pathogen involved in gastritis and gastric cancer whose mode of transmission remains unknown. Association of H. pylori with humans is thought to date from remote antiquity and the bacterium has apparently evolved together with the human host. A few studies have shown the presence of H. pylori in aquatic environments, which might provide a route of transmission of the bacteria to humans. A recent study has also disclosed the association of the bacteria with Acantamoeba castellanii. Amoeba are known to harbor and promote the persistence of several human pathogens in the environment, representing a significant source of contamination in community and hospital acquired infections.

scholarly journals Permissive Fatty Acid Incorporation in Host Environments Promotes Staphylococcal Adaptation to FASII Antibiotics

2019 ◽  
Author(s):  
Gérald Kénanian ◽  
Claire Morvan ◽  
Antonin Weckel ◽  
Amit Pathania ◽  
Jamila Anba-Mondoloni ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Acid Synthesis ◽  
Human Pathogen ◽  
Membrane Phospholipids ◽  
Exogenous Fatty Acid ◽  
Adaptation Capacity ◽  
Future Drug

SummaryDevelopment of fatty acid synthesis pathway (FASII) inhibitors against the major human pathogen Staphylococcus aureus hinges on the accepted but unproven postulate that an endogenously synthesized branched chain fatty acid is required to complete membrane phospholipids. Evidence for anti-FASII efficacy in animal models supported this view. However, restricted test conditions used previously to show FASII antibiotic efficacy led us to investigate these questions in a broader, host-relevant context. We report that S. aureus rapidly adapts to FASII antibiotics without FASII mutations when exposed to host environments. Treatment with a lead FASII antibiotic upon signs of infection, rather than just after inoculation as commonly practiced, failed to eliminate S. aureus from infected organs in a septicemia model. In vitro, addition of serum facilitated rapid S. aureus FASII bypass by environmental fatty acid (eFA) replacement in phospholipids. Serum lowers membrane stress, leading to increased retention of the two substrates required for exogenous fatty acid (eFA) utilization. In these conditions, eFA occupy both phospholipid positions 1 and 2, regardless of anti-FASII selection. This study revises conclusions on S. aureus fatty acid requirements by disproving the postulate of fatty acid stringency, and reveals an Achilles’ heel for using FASII antibiotics to treat infection in monotherapy.Significance statementAntibiotic discovery to overcome treatment failure has huge socio-medical and economic stakes. The fatty acid synthesis (FASII) pathway is considered an ideal druggable target against the human pathogen Staphylococcus aureus, based on evidence of anti-FASII efficacy in infection models, and the postulate that S. aureus synthesizes an irreplaceable fatty acid. We report that S. aureus alters its behavior in host-relevant conditions. Administering FASII antibiotics upon signs of infection, rather than just after inoculation as frequently practiced, failed to clear septicemic infections. In serum, S. aureus rapidly overcomes FASII antibiotics by incorporating alternative fatty acids. We conclude that previously, premature antibiotic treatments and experimental constraints masked S. aureus antibiotic adaptation capacity. These findings should help streamline future drug development programs.

scholarly journals Suppression offabBMutation byfabF1Is Mediated by Transcription Read-through in Shewanella oneidensis

2016 ◽  
Vol 198 (22) ◽  
pp. 3060-3069 ◽  
Author(s):  
Meng Li ◽  
Qiu Meng ◽  
Huihui Fu ◽  
Qixia Luo ◽  
Haichun Gao
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Tandem Repeats ◽  
Unsaturated Fatty Acids ◽  
Acyl Carrier Protein ◽  
Shewanella Oneidensis ◽  
Acid Synthesis ◽  
Carrier Protein ◽  
Type Ii ◽  
Content Type

ABSTRACTAs type II fatty acid synthesis is essential for the growth ofEscherichia coli, its many components are regarded as potential targets for novel antibacterial drugs. Among them, β-ketoacyl-acyl carrier protein (ACP) synthase (KAS) FabB is the exclusive factor for elongation of thecis-3-decenoyl-ACP (cis-3-C10-ACP). In our previous study, we presented evidence to suggest that this may not be the case inShewanella oneidensis, an emerging model gammaproteobacterium renowned for its respiratory versatility. Here, we identified FabF1, another KAS, as a functional replacement for FabB inS. oneidensis. InfabB+ordesA+(encoding a desaturase) cells, which are capable of making unsaturated fatty acids (UFA), FabF1 is barely produced. However, UFA auxotroph mutants devoid of bothfabBanddesAgenes can be spontaneously converted to suppressor strains, which no longer require exogenous UFAs for growth. Suppression is caused by a TGTTTT deletion in the region upstream of thefabF1gene, resulting in enhanced FabF1 production. We further demonstrated that the deletion leads to transcription read-through of the terminator foracpP, an acyl carrier protein gene immediately upstream offabF1. There are multiple tandem repeats in the region covering the terminator, and the TGTTTT deletion, as well as others, compromises the terminator efficacy. In addition, FabF2 also shows an ability to complement the FabB loss, albeit substantially less effectively than FabF1.IMPORTANCEIt has been firmly established that FabB for UFA synthesis via type II fatty acid synthesis in FabA-containing bacteria such asE. coliis essential. However,S. oneidensisappears to be an exception. In this bacterium, FabF1, when sufficiently expressed, is able to fully complement the FabB loss. Importantly, such a capability can be obtained by spontaneous mutations, which lead to transcription read-through. Therefore, our data, by identifying the functional overlap between FabB and FabFs, provide new insights into the current understanding of KAS and help reveal novel ways to block UFA synthesis for therapeutic purposes.

scholarly journals Deciphering the Unusual Acylation Pattern of Helicobacter pylori Lipid A

2008 ◽  
Vol 190 (21) ◽  
pp. 7012-7021 ◽  
Author(s):  
Christopher M. Stead ◽  
Ashley Beasley ◽  
Robert J. Cotter ◽  
M. Stephen Trent
Keyword(s):  
Helicobacter Pylori ◽  
Lipid A ◽  
Acyl Carrier Protein ◽  
Acyl Chain ◽  
Fatty Acyl ◽  
Hydroxyl Group ◽  
Fatty Acyl Chain ◽  
Acyl Donor ◽  
H Pylori ◽  
K 12

ABSTRACT The synthesis of “typical” hexa-acylated lipid A occurs via a nine-step enzymatic pathway, which is generally well conserved throughout all gram-negative bacteria. One exception to the rule is Helicobacter pylori, which has only eight homologs to the nine lipid A biosynthetic enzymes. The discrepancy occurs toward the end of the pathway, with H. pylori containing only a single putative secondary acyltransferase encoded by jhp0265. In Escherichia coli K-12, two late acyltransferases, termed LpxL and LpxM, are required for the biosynthesis of hexa-acylated lipid A. Detailed biochemical and genetic analyses reveal that H. pylori Jhp0265 (the protein encoded by jhp0265) is in fact an LpxL homolog, capable of transferring a stearoyl group to the hydroxyl group of the 2′ linked fatty acyl chain of lipid A. Despite the lack of a homolog to LpxM in the H. pylori genome, the organism synthesizes a hexa-acylated lipid A species, suggesting that an equivalent enzyme exists. Using radiolabeled lipid A substrates and acyl-acyl carrier protein as the fatty acyl donor, we were able to confirm the presence of a second H. pylori late acyl transferase by biochemical assays. After synthesis of the hexa-acylated lipid A species, several modification enzymes then function to produce the major lipid A species of H. pylori that is tetra-acylated. Jhp0634 was identified as an outer membrane deacylase that removes the 3′-linked acyl chains of H. pylori lipid A. Together, this work elucidates the biochemical machinery required for the acylation and deacylation of the lipid A domain of H. pylori lipopolysaccharide.

scholarly journals Extradigestive Manifestation of Helicobacter Pylori Infection in Children and Adolescents

2005 ◽  
Vol 19 (7) ◽  
pp. 421-424 ◽  
Author(s):  
Philip M Sherman ◽  
Frank YH Lin
Keyword(s):  
Helicobacter Pylori ◽  
Molecular Mimicry ◽  
Case Reports ◽  
Case Series ◽  
Helicobacter Pylori Infection ◽  
Deficiency Anemia ◽  
Extraintestinal Manifestations ◽  
Human Pathogen ◽  
Chronic Active Gastritis ◽  
H Pylori

Helicobacter pylori infection fulfills each of Koch's postulates as a human pathogen causing chronic active gastritis. Disease consequences that develop in a subset of infected subjects include peptic ulcerations, gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma. More recently, multiple publications have advocated a role for H pylori infection in causing a variety of extraintestinal manifestations. Many of these reports suffer from being case reports or case series without adequate controls. As a result, purported manifestations may simply be coincidental in nature. On the other hand, increasing evidence supports H pylori infection as a cause of sideropenic (refractory iron deficiency) anemia. Moderate evidence supports H pylori gastric infection as a cause of some cases of immune thrombocytopenic purpura due to molecular mimicry. Guidelines should be adjusted in accordance with advancing knowledge in the field.

Association between Helicobacter pylori and open angle glaucoma: current perspective

1970 ◽  
Vol 1 (2) ◽  
pp. 129-135 ◽  
Author(s):  
M Zaidi ◽  
FA Jilani ◽  
Y Gupta ◽  
S Umair ◽  
M Gupta
Keyword(s):  
Nitric Oxide ◽  
Helicobacter Pylori ◽  
Free Radicals ◽  
Oxygen Free Radicals ◽  
Open Angle Glaucoma ◽  
Open Angle ◽  
Human Pathogen ◽  
Gram Negative ◽  
Current Perspective ◽  
H Pylori

Helicobacter pylori is a Gram negative, spiral-shaped, strictly micro-aerophilic and flagellate human pathogen that can inhabit many areas of stomach. H. pylori infection leads to the generation of oxygen free radicals. H. pylori infection might also aggravate the course of glaucoma by increasing the levels of nitric oxide, endothelin-1 and free radicals indirectly. This article briefly reviews the current perspectives on this issue. Keywords: Helicobacter pylori; glaucoma; free radicals DOI: 10.3126/nepjoph.v1i2.3688 Nep J Oph 2009;1(2):129-135

The rod-to-coccoid body transformation in cultures of Helicobacter pylori

1990 ◽  
Vol 48 (3) ◽  
pp. 626-627
Author(s):  
A. R. Crooker ◽  
W. G. Kraft ◽  
T. L. Beard ◽  
M. C. Myers
Keyword(s):  
Helicobacter Pylori ◽  
Growth Cycle ◽  
Negative Bacterium ◽  
Body Formation ◽  
Coccoid Form ◽  
Spiral Form ◽  
Prolonged Culture ◽  
H Pylori ◽  
Upper Gastrointestinal

Helicobacter pylori is a microaerophilic, gram-negative bacterium found in the upper gastrointestinal tract of humans. There is strong evidence that H. pylori is important in the etiology of gastritis; the bacterium may also be a major predisposing cause of peptic ulceration. On the gastric mucosa, the organism exists as a spiral form with one to seven sheathed flagella at one (usually) or both poles. Short spirals were seen in the first successful culture of the organism in 1983. In 1984, Marshall and Warren reported a coccoid form in older cultures. Since that time, other workers have observed rod and coccal forms in vitro; coccoid forms predominate in cultures 3-7 days old. We sought to examine the growth cycle of H. pylori in prolonged culture and the mode of coccoid body formation.

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