Unsaturated Fatty Acid Synthesis in the Gastric Pathogen Helicobacter pylori Proceeds via a Backtracking Mechanism

Bi, Hongkai; Zhu, Lei; Jia, Jia; Zeng, Liping; Cronan, John E.

doi:10.1016/j.chembiol.2016.10.007

Cited by 21 publications

(11 citation statements)

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“…Alternatively, the different oligomer states observed for the E. coli AcpP 6 -FabZ 6 complex (this work) and the H. pylori ACP 3 -FabZ 6 complex (20) may reflect a real difference in the two FabZ proteins, perhaps arising from distinct strategies for dehydration of β-hydroxyacyl-AcpPs during fatty acid biosynthesis. Indeed, the dual FabA-FabZ DH system does not exist in e-proteobacteria such as H. pylori, which possess only FabZ and use a desaturase to synthesize unsaturated fatty acids (29,30).…”

Section: Resultsmentioning

confidence: 99%

Structural and dynamical rationale for fatty acid unsaturation in Escherichia coli

Dodge

Patel

Jaremko

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Fatty acid biosynthesis in αand γ-proteobacteria requires two functionally distinct dehydratases, FabA and FabZ. Here, mechanistic cross-linking facilitates the structural characterization of a stable hexameric complex of six Escherichia coli FabZ dehydratase subunits with six AcpP acyl carrier proteins. The crystal structure sheds light on the divergent substrate selectivity of FabA and FabZ by revealing distinct architectures of the binding pocket. Molecular dynamics simulations demonstrate differential biasing of substrate orientations and conformations within the active sites of FabA and FabZ such that FabZ is preorganized to catalyze only dehydration, while FabA is primed for both dehydration and isomerization. de novo unsaturated fatty acid biosynthesis | cell membrane homeostasis | chemical biology | structural biology | computational biology Author contributions: J.A.M., J.L.S., and M.D.B. designed research; G.J.D., A.P., and K.L.J. performed research; J.A.M., J.L.S., and M.D.B. contributed new reagents/analytic tools;

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Section: Resultsmentioning

confidence: 99%

Structural and dynamical rationale for fatty acid unsaturation in Escherichia coli

Dodge

Patel

Jaremko

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…This included fatty acid metabolism and beta-lactam resistance to drug due to cytochrome P450. H. pylori depends on unsaturated fatty acid (UFA) biosynthesis for maintaining its membrane structure and function (Bi et al, 2016). The level of microbial UFA is significantly elevated in the blood of patients with H. pylori infection-induced peptic ulceration (Ktsoyan et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Helicobacter pylori Infection Aggravates Dysbiosis of Gut Microbiome in Children With Gastritis

Yang

Zhang

et al. 2019

Front. Cell. Infect. Microbiol.

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Introduction: Helicobacter pylori infection consistently leads to chronic and low degree of inflammatory response in gastric mucosa and is closely related with gastrointestinal and extra-gastric diseases. Effects of local microbiome in the stomach have been studied in adults and children with H. pylori infection. It is, however, not known whether the intestinal microbial community differs in children with varying H. pylori infection. The aim of this study is to characterize the altered composition of microbiome induced by H. pylori infection and in gastritis.Materials and Methods: This study involved 154 individuals, including 50 children affected by H. pylori-induced gastritis, 42 children with H. pylori-negative gastritis, and 62 healthy controls. Gut microbiome composition was analyzed using 16S rRNA gene-based pyrosequencing. Fecal bacterial diversity and composition were then compared.Results: On the basis of an analysis of similarities and differences, we found that children with H. pylori-induced gastritis exhibited gut bacteria dysbiosis. The ratio of Firmicutes/Bacteroidetes (F:B) at the phylum level had dramatically decreased in H. pylori-positive gastritis group (HPG) and H. pylori-negative gastritis group (HNG), compared with the healthy control group (HCG). At the family and genus levels, relative abundance of Bacteroidaceae and Enterobacteriaceae was prevalent in HPG and HNG, whereas relative abundance of Lachnospiraceae, Bifidobacteriaceae, and Lactobacillaceae was seen in HCG. Prevalence of different taxa of gut microbiome at the class, order, family, and genus levels was also observed among the three groups.Conclusions: Gastritis can cause changes in composition of fecal microbiome, which is exacerbated by H. pylori infection. These changes in gut microbiome may be related to drug resistance and development of chronic gastrointestinal diseases.

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“…Similar results have been observed in other microorganisms. For example, Helicobacter pylori , a Gram-negative pathogenic bacterium, relies on UFA biosynthesis for maintaining membrane architecture and function ( 59 ). The ratio of saturated to unsaturated acyl chains is an important factor determining membrane fluidity ( 14 ).…”

Section: Discussionmentioning

confidence: 99%

HapX, an Indispensable bZIP Transcription Factor for Iron Acquisition, Regulates Infection Initiation by Orchestrating Conidial Oleic Acid Homeostasis and Cytomembrane Functionality in Mycopathogen Beauveria bassiana

et al. 2020

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In pathogenic filamentous fungi, conidial germination not only is fundamental for propagation in the environment but is also a critical step of infection. In the insect mycopathogen Beauveria bassiana, we genetically characterized the role of the basic leucine zipper (bZIP) transcription factor HapX (BbHapX) in conidial nutrient reserves and pathogen-host interaction. Ablation of BbHapX resulted in an almost complete loss of virulence in the topical inoculation and intrahemocoel injection assays. Comparative transcriptomic analysis revealed that BbHapX is required for fatty acid (FA)/lipid metabolism, and biochemical analyses indicated that BbHapX loss caused a significant reduction in conidial FA contents. Exogenous oleic acid could partially or completely restore the impaired phenotypes of the ΔBbHapX mutant, including germination rate, membrane integrity, vegetative growth, and virulence. BbHapX mediates fungal iron acquisition which is not required for desaturation of stearic acid. Additionally, inactivation of the Δ9-fatty acid desaturase gene (BbOle1) generated defects similar to those of the ΔBbHapX mutant; oleic acid also had significant restorative effects on the defective phenotypes of the ΔBbOle1 mutant. A gel retarding assay revealed that BbHapX directly regulated the expression of BbOle1. Lipidomic analyses indicated that both BbHapX and BbOle1 contributed to the homeostasis of phospholipids with nonpolar tails derived from oleic acid; therefore, exogenous phospholipids could significantly restore membrane integrity. These data reveal that the HapX-Ole1 pathway contributes to conidial fatty acid/lipid reserves and that there are important links between the lipid biology and membrane functionality involved in the early stages of infection caused by B. bassiana. IMPORTANCE Conidial maturation and germination are highly coupled physiological processes in filamentous fungi that are critical for the pathogenicity of mycopathogens. Compared to the mechanisms involved in conidial germination, those of conidial reserves during maturation are less understood. The insect-pathogenic fungus Beauveria bassiana, as a representative species of filamentous fungi, is important for applied and fundamental research. In addition to its conserved roles in fungal adaptation to iron status, the bZIP transcription factor HapX acts as a master regulator involved in conidial virulence and regulates fatty acid/lipid metabolism. Further investigation revealed that the Δ9-fatty acid desaturase gene (Ole1) is a direct downstream target of HapX. This study reveals the HapX-Ole1 pathway involved in the fatty acid/lipid accumulation associated with conidial maturation and provides new insights into the startup mechanism of infection caused by spores from pathogenic fungi.

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Unsaturated Fatty Acid Synthesis in the Gastric Pathogen Helicobacter pylori Proceeds via a Backtracking Mechanism

Cited by 21 publications

References 50 publications

Structural and dynamical rationale for fatty acid unsaturation in Escherichia coli

Structural and dynamical rationale for fatty acid unsaturation in Escherichia coli

Helicobacter pylori Infection Aggravates Dysbiosis of Gut Microbiome in Children With Gastritis

HapX, an Indispensable bZIP Transcription Factor for Iron Acquisition, Regulates Infection Initiation by Orchestrating Conidial Oleic Acid Homeostasis and Cytomembrane Functionality in Mycopathogen Beauveria bassiana

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