Structure and mechanism for streptococcal fatty acid kinase (Fak) system dedicated to host fatty acid scavenging

Shi, Yu; Zang, Ning; Lou, Ningjie; Xu, Yongchang; Sun, Jingdu; Huang, Man; Zhang, Huimin; Lü, Huijie; Zhou, Chun; Feng, Youjun

doi:10.1126/sciadv.abq3944

Cited by 12 publications

(23 citation statements)

References 66 publications

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“…46 Staphylococcus and Streptococcus, two groups of major human pathogens, were thought to be able to scavenge host fatty acids. 47 The genus Flavonif ractor such as Flavonif ractor plautii, a potential pathogen, was related with the suppressed immune response in mice. 48 Notably, the genus Desulfovibrio in the gut had the pathogenic effects on fatty liver in diet-induced obese mice and children with obesity.…”

Section: ■ Discussionmentioning

confidence: 99%

Structural Insights into Amelioration Effects of Quercetin and Its Glycoside Derivatives on NAFLD in Mice by Modulating the Gut Microbiota and Host Metabolism

Shi

Zhang

Lei

et al. 2022

J. Agric. Food Chem.

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The sugar moieties of natural flavonoids determine their absorption, bioavailability, and bioactivity in humans. To explore structure-dependent bioactivities of quercetin, isoquercetin, and rutin, which have the same basic skeleton linking different sugar moieties, we systemically investigated the ameliorative effects of dietary these flavonoids on high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) of mice. Our results revealed that isoquercetin exhibits the strongest capability in improving NAFLD phenotypes of mice, including body and liver weight gain, glucose intolerance, and systemic inflammation in comparison with quercetin and rutin. At the molecular level, dietary isoquercetin markedly ameliorated liver dysfunction and host metabolic disorders in mice with NAFLD. At the microbial level, the three flavonoids compounds, especially isoquercetin, can effectively regulate the gut microbiota composition, such as genera Akkermansia, Bifidobacterium, and Lactobacillus, which were significantly disrupted in NAFLD mice. These comparative findings offer new insights into the structure-dependent activities of natural flavonoids for NAFLD treatment.

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Section: ■ Discussionmentioning

confidence: 99%

Structural Insights into Amelioration Effects of Quercetin and Its Glycoside Derivatives on NAFLD in Mice by Modulating the Gut Microbiota and Host Metabolism

Shi

Zhang

Lei

et al. 2022

J. Agric. Food Chem.

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Section: Methodsmentioning

confidence: 99%

“…Multiple sequence alignment of seven BioH homologs was carried out using ClustalOmega (https://www.ebi.ac.uk/Tools/msa/clustalo), and the output was given via the ESPript 3.0 program (https://espript.ibcp.fr/ESPript/cgi-bin/ESPript.cgi) [76]. In addition to the paradigm E. coli BioH (b3412) and P. aeruginosa BioH (PA0502), the remaining 5 orthologs consisted of three BioH-like enzymes (i.e., V. cholerae vc2718, Xanthomonas Xcc0385, plus Lpc_0888 of Legionella pneumophila), and two BioHC fusion proteins, namely i) CJA_0428 (502 aa) of Cellvibrio japonicus, and ii) Sde_3137 (558 aa) of Saccharophagus degradans).…”

Section: Bioinformatic Analysesmentioning

confidence: 99%

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The opportunistic pathogen Pseudomonas aeruginosa exploits bacterial biotin synthesis pathway to benefit its infectivity

et al. 2023

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Pseudomonas aeruginosa is an opportunistic pathogen that predominantly causes nosocomial and community-acquired lung infections. As a member of ESKAPE pathogens, carbapenem-resistant P. aeruginosa (CRPA) compromises the limited therapeutic options, raising an urgent demand for the development of lead compounds against previously-unrecognized drug targets. Biotin is an important cofactor, of which the de novo synthesis is an attractive antimicrobial target in certain recalcitrant infections. Here we report genetic and biochemical definition of P. aeruginosa BioH (PA0502) that functions as a gatekeeper enzyme allowing the product pimeloyl-ACP to exit from fatty acid synthesis cycle and to enter the late stage of biotin synthesis pathway. In relative to Escherichia coli, P. aeruginosa physiologically requires 3-fold higher level of cytosolic biotin, which can be attributed to the occurrence of multiple biotinylated enzymes. The BioH protein enables the in vitro reconstitution of biotin synthesis. The repertoire of biotin abundance is assigned to different mouse tissues and/or organ contents, and the plasma biotin level of mouse is around 6-fold higher than that of human. Removal of bioH renders P. aeruginosa biotin auxotrophic and impairs its intra-phagosome persistence. Based on a model of CD-1 mice mimicking the human environment, lung challenge combined with systemic infection suggested that BioH is necessary for the full virulence of P. aeruginosa. As expected, the biotin synthesis inhibitor MAC13772 is capable of dampening the viability of CRPA. Notably, MAC13772 interferes the production of pyocyanin, an important virulence factor of P. aeruginosa. Our data expands our understanding of P. aeruginosa biotin synthesis relevant to bacterial infectivity. In particular, this study represents the first example of an extracellular pathogen P. aeruginosa that exploits biotin cofactor as a fitness determinant, raising the possibility of biotin synthesis as an anti-CRPA target.

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“…DegV proteins bind FA with high affinity indicating that DegV proteins may take part in lipid transport and in FA metabolic processes [ 9 ]. Whereas single fakA genes are found in Firmicutes, degV genes are multiple; two fakB have been identified in Staphylococcus aureus , three in Streptococcus pneumoniae , and four in Streptococcus suis , Enterococcus faecalis and Enterococcus faecium [ 7 , 10 – 12 ]. In S .…”

Section: Introductionmentioning

confidence: 99%

A Streptococcus pyogenes DegV protein regulates the membrane lipid content and limits the formation of extracellular vesicles

et al. 2023

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Membranes contain lipids that are composed of fatty acids (FA) and a polar head. Membrane homeostasis is crucial for optimal bacterial growth and interaction with the environment. Bacteria synthesize their FAs via the FASII pathway. Gram-positive bacteria can incorporate exogenous FAs which need to be phosphorylated to become substrate of the lipid biosynthetic pathway. In many species including staphylococci, streptococci and enterococci, this phosphorylation is carried out by the Fak complex, which is composed of two subunits, FakA and FakB. FakA is the kinase. FakB proteins are members of the DegV family, proteins known to bind FAs. Two or three FakB types have been identified depending on the bacterial species and characterized by their affinity for saturated and/or unsaturated FAs. Some species such as Streptococcus pyogenes, which causes a wide variety of diseases ranging from mild non-invasive to severe invasive infections, possess an uncharacterized additional DegV protein. We identify here this DegV member as a fourth FakB protein, named FakB4. The fakB4 gene is co-regulated with FASII genes suggesting an interaction with endogenous fatty acids. fakB4 deletion has no impact on membrane phospholipid composition nor on the percentage of other major lipids. However, the fakB4 mutant strain produced more lipids and more extracellular membrane vesicles than the wild-type strain. This suggests that FakB4 is involved in endogenous FA binding and controls FA storage or catabolism resulting in a limitation of extracellular FA release via membrane vesicles.

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Structure and mechanism for streptococcal fatty acid kinase (Fak) system dedicated to host fatty acid scavenging

Cited by 12 publications

References 66 publications

Structural Insights into Amelioration Effects of Quercetin and Its Glycoside Derivatives on NAFLD in Mice by Modulating the Gut Microbiota and Host Metabolism

Structural Insights into Amelioration Effects of Quercetin and Its Glycoside Derivatives on NAFLD in Mice by Modulating the Gut Microbiota and Host Metabolism

The opportunistic pathogen Pseudomonas aeruginosa exploits bacterial biotin synthesis pathway to benefit its infectivity

A Streptococcus pyogenes DegV protein regulates the membrane lipid content and limits the formation of extracellular vesicles

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