Crystal structure of lipid A disaccharide synthase LpxB from Escherichia coli

Bohl, Thomas E.; Shi, Ke; Lee, John K.; Aihara, Hideki

doi:10.1038/s41467-017-02712-9

Cited by 22 publications

(25 citation statements)

References 65 publications

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“…Abundances of KOs encoding virulence factors such as secretion systems (K03197 VirB2 and K03194 VirB1 [34]) and peptidoglycan biosynthesis (K00790 murA, K01924 murC, K01929 murF, K05364 pbpA, K12556 pbp2X, and K00687 pbp2B [35]) were also observed to be correlated with exposure levels of some PAHs. Specifically, KOs related to lipopolysaccharide synthesis pathways, which are crucial for bacterial virulence [36], were significantly associated with exposure to benzo[a]pyrene.…”

Section: Exposure To Specific Pahs Associated With Different Functionmentioning

confidence: 99%

Changes of the human skin microbiota upon chronic exposure to polycyclic aromatic hydrocarbon pollutants

Leung¹,

Tong²,

Bastien³

et al. 2020

Microbiome

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Background: Polycyclic aromatic hydrocarbons (PAHs) are of environmental and public health concerns and contribute to adverse skin attributes such as premature skin aging and pigmentary disorder. However, little information is available on the potential roles of chronic urban PAH pollutant exposure on the cutaneous microbiota. Given the roles of the skin microbiota have on healthy and undesirable skin phenotypes and the relationships between PAHs and skin properties, we hypothesize that exposure of PAHs may be associated with changes in the cutaneous microbiota. In this study, the skin microbiota of over two hundred Chinese individuals from two cities in China with varying exposure levels of PAHs were characterized by bacterial and fungal amplicon and shotgun metagenomics sequencing. Results: Skin site and city were strong parameters in changing microbial communities and their assembly processes. Reductions of bacterial-fungal microbial network structural integrity and stability were associated with skin conditions (acne and dandruff). Multivariate analysis revealed associations between abundances of Propionibacterium and Malassezia with host properties and pollutant exposure levels. Shannon diversity increase was correlated to exposure levels of PAHs in a dose-dependent manner. Shotgun metagenomics analysis of samples (n = 32) from individuals of the lowest and highest exposure levels of PAHs further highlighted associations between the PAHs quantified and decrease in abundances of skin commensals and increase in oral bacteria. Functional analysis identified associations between levels of PAHs and abundance of microbial genes of metabolic and other pathways with potential importance in host-microbe interactions as well as degradation of aromatic compounds. Conclusions: The results in this study demonstrated the changes in composition and functional capacities of the cutaneous microbiota associated with chronic exposure levels of PAHs. Findings from this study will aid the development of strategies to harness the microbiota in protecting the skin against pollutants.

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Section: Exposure To Specific Pahs Associated With Different Functionmentioning

confidence: 99%

Changes of the human skin microbiota upon chronic exposure to polycyclic aromatic hydrocarbon pollutants

Leung¹,

Tong²,

Bastien³

et al. 2020

Microbiome

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“…The reactions (10 l) were prepared with 62 M UDP-DAG (as measured by A 260 , ⑀ ϭ 9.9 mM Ϫ1 cm Ϫ1 ), 10 nM LpxH or 1 l of dilution buffer, 100 mM Tris-HCl, pH 8.0, 0.1% Triton X-100, and 1 mg/ml BSA. UDP-DAG and lipid X were prepared as reported previously (41). The reactions were run at 30°C and were quenched by spotting onto an HPTLC Silica gel 60 plate (EMD Millipore).…”

Section: Activity Assaysmentioning

confidence: 99%

The substrate-binding cap of the UDP-diacylglucosamine pyrophosphatase LpxH is highly flexible, enabling facile substrate binding and product release

Bohl

Ieong

Lee

et al. 2018

Journal of Biological Chemistry

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Gram-negative bacteria are surrounded by a secondary membrane of which the outer leaflet is composed of the glycolipid lipopolysaccharide (LPS), which guards against hydrophobic toxins, including many antibiotics. Therefore, LPS synthesis in bacteria is an attractive target for antibiotic development. LpxH is a pyrophosphatase involved in LPS synthesis, and previous structures revealed that LpxH has a helical cap that binds its lipid substrates. Here, crystallography and hydrogen-deuterium exchange MS provided evidence for a highly flexible substrate-binding cap in LpxH. Furthermore, molecular dynamics simulations disclosed how the helices of the cap may open to allow substrate entry. The predicted opening mechanism was supported by activity assays of LpxH variants. Finally, we confirmed biochemically that LpxH is inhibited by a previously identified antibacterial compound, determined the potency of this inhibitor, and modeled its binding mode in the LpxH active site. In summary, our work provides evidence that the substrate-binding cap of LpxH is highly dynamic, thus allowing for facile substrate binding and product release between the capping helices. Our results also pave the way for the rational design of more potent LpxH inhibitors.

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“…[92] Structural information about this enzyme was not available until quite recently, when Bohl et al [93] described three crystal structures of a soluble E. coli LpxB variant enzyme (several modifications in the sequence). It is a peripheral membrane enzyme that is essential for the growth of E. coli and is one of the most highly conserved enzymes of the pathway.…”

Section: The Lpxb Enzymementioning

confidence: 99%

“…It is a peripheral membrane enzyme that is essential for the growth of E. coli and is one of the most highly conserved enzymes of the pathway . Structural information about this enzyme was not available until quite recently, when Bohl et al . described three crystal structures of a soluble E. coli LpxB variant enzyme (several modifications in the sequence).…”

Section: The Lpxb Enzymementioning

confidence: 99%

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The Inhibition of Lipid A Biosynthesis—The Antidote Against Superbugs?

González‐Bello

2018

Advanced Therapeutics

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After many years of success in the battle against infectious diseases, ground is being lost in this fight with the worldwide increasing appearance of "superbugs," which are resistant to most antibiotics in clinical use. The impact of superbugs on the older population, healthcare-associated patients or patients with a compromised immune system is highly worrisome since no treatment options are available in some cases, especially for Gram-negative pathogens. Efforts are currently devoted to develop novel chemical entities with new mechanisms of action that can inactivate unexplored or underexplored bacterial objectives and to better understand bacterial behavior. The present article highlights the therapeutic potential of the enzymes involved in the biosynthesis of lipid A, which is the lipidic component of lipopolysaccharide-a lipid-anchored complex carbohydrate and a well-designed natural barrier to protect Gram-negative bacteria from external agents, such as antibiotics. An overview of the state-of-the-art inhibitors currently available along with the biochemical and structural knowledge of the enzyme/ligand complexes available is provided. This insight will contribute to the rational design of the next generation of inhibitors or the development of new ones for those promising targets for which inhibitors have not yet been developed.

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Crystal structure of lipid A disaccharide synthase LpxB from Escherichia coli

Cited by 22 publications

References 65 publications

Changes of the human skin microbiota upon chronic exposure to polycyclic aromatic hydrocarbon pollutants

Changes of the human skin microbiota upon chronic exposure to polycyclic aromatic hydrocarbon pollutants

The substrate-binding cap of the UDP-diacylglucosamine pyrophosphatase LpxH is highly flexible, enabling facile substrate binding and product release

The Inhibition of Lipid A Biosynthesis—The Antidote Against Superbugs?

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