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Microbiology and Molecular Biology... Dec 2021Accumulation of phosphorylated intermediates during cellular metabolism can have wide-ranging toxic effects on many organisms, including humans and the pathogens that...
Accumulation of phosphorylated intermediates during cellular metabolism can have wide-ranging toxic effects on many organisms, including humans and the pathogens that infect them. These toxicities can be induced by feeding an upstream metabolite (a sugar, for instance) while simultaneously blocking the appropriate metabolic pathway with either a mutation or an enzyme inhibitor. Here, we survey the toxicities that can arise in the metabolism of glucose, galactose, fructose, fructose-asparagine, glycerol, trehalose, maltose, mannose, mannitol, arabinose, and rhamnose. Select enzymes in these metabolic pathways may serve as novel therapeutic targets. Some are conserved broadly among prokaryotes and eukaryotes (e.g., glucose and galactose) and are therefore unlikely to be viable drug targets. However, others are found only in bacteria (e.g., fructose-asparagine, rhamnose, and arabinose), and one is found in fungi but not in humans (trehalose). We discuss what is known about the mechanisms of toxicity and how resistance is achieved in order to identify the prospects and challenges associated with targeted exploitation of these pervasive metabolic vulnerabilities.
Topics: Arabinose; Galactose; Humans; Lactose; Phosphates; Xylose
PubMed: 34585982
DOI: 10.1128/MMBR.00123-21 -
Nature Biomedical Engineering Jul 2022The complex gastrointestinal environment and the intestinal epithelial barrier constrain the design and effectiveness of orally administered tumour vaccines. Here we...
The complex gastrointestinal environment and the intestinal epithelial barrier constrain the design and effectiveness of orally administered tumour vaccines. Here we show that outer membrane vesicles (OMVs) fused to a tumour antigen and produced in the intestine by ingested genetically engineered bacteria function as effective tumour vaccines in mice. We modified Escherichia coli to express, under the control of a promoter induced by the monosaccharide arabinose, a specific tumour antigen fused with the protein cytolysin A on the surface of OMVs released by the commensal bacteria. In mice, oral administration of arabinose and the genetically engineered E. coli led to the production of OMVs that crossed the intestinal epithelium into the lamina propria, where they stimulated dendritic cell maturation. In a mouse model of pulmonary metastatic melanoma and in mice bearing subcutaneous colon tumours, the antigen-bearing OMVs inhibited tumour growth and protected the animals against tumour re-challenge. The in situ production of OMVs by genetically modified commensal bacteria for the delivery of stimulatory molecules could be leveraged for the development of other oral vaccines and therapeutics.
Topics: Animals; Antigens, Neoplasm; Arabinose; Cancer Vaccines; Cell Membrane; Escherichia coli; Mice
PubMed: 35501399
DOI: 10.1038/s41551-022-00886-2 -
Cell Chemical Biology Nov 2023Stimulator of interferon genes (STING) agonists are promising candidates for vaccine adjuvants and antitumor immune stimulants. The most potent natural agonist of STING,...
Stimulator of interferon genes (STING) agonists are promising candidates for vaccine adjuvants and antitumor immune stimulants. The most potent natural agonist of STING, 2',3'-cyclic GMP-AMP (2',3'-cGAMP), is subject to nuclease-mediated inherent metabolic instability, thereby placing limits on its clinical efficacy. Here, we report on a new class of chemically synthesized sugar-modified analogs of 2',3'-cGAMP containing arabinose and xylose sugar derivatives that bind mouse and human STING alleles with high affinity. The co-crystal structures demonstrate that such analogs act as 2',3'-cGAMP mimetics that induce the "closed" conformation of human STING. These analogs show significant resistance to hydrolysis mediated by ENPP1 and increased stability in human serum, while retaining similar potency as 2',3'-cGAMP at inducing IFN-β secretion from human THP1 cells. The arabinose- and xylose-modified 2',3'-cGAMP analogs open a new strategy for overcoming the inherent nuclease-mediated vulnerability of natural ribose cyclic nucleotides, with the additional benefit of high translational potential as cancer therapeutics and vaccine adjuvants.
Topics: Humans; Animals; Mice; Arabinose; Xylose; Adjuvants, Vaccine; Nucleotides, Cyclic
PubMed: 37536341
DOI: 10.1016/j.chembiol.2023.07.002 -
The Journal of Nutrition Nov 2023L-arabinose has anti-inflammatory and metabolism-promoting properties, and macrophages participate in the alleviation of inflammation; however, the mechanism by which...
BACKGROUND
L-arabinose has anti-inflammatory and metabolism-promoting properties, and macrophages participate in the alleviation of inflammation; however, the mechanism by which they contribute to the anti-inflammatory effects of L-arabinose is unknown.
OBJECTIVES
To investigate the involvement of macrophages in the mitigation of L-arabinose in an intestinal inflammation model induced by lipopolysaccharide (LPS).
METHODS
Five-week-old male C57BL/6 mice were divided into 3 groups: a control and an LPS group that both received normal water supplementation, and an L-arabinose (ARA+LPS) group that received 5% L-arabinose supplementation. Mice in the LPS and ARA+LPS groups were intraperitoneally injected with LPS (10 mg/kg body weight), whereas the control group was intraperitoneally injected with the same volume of saline. Intestinal morphology, cytokines, tight junction proteins, macrophage phenotypes, and microbial communities were profiled at 6 h postinjection.
RESULTS
L-arabinose alleviated LPS-induced damage to intestinal morphology. L-arabinose down-regulated serum tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, and messenger RNA (mRNA) levels of TNF-α, IL-1β, interferon-γ (IFN-γ), and toll-like receptor-4 in jejunum and colon compared with those of the LPS group (P < 0.05). The mRNA and protein levels of occludin and claudin-1 were significantly increased by L-arabinose (P < 0.05). Interferon regulatory factor-5 (IRF-5) and signal transducer and activator of transcription-1 (STAT-1), key genes characterized by M1 macrophages, were elevated in the jejunum and colon of LPS mice (P < 0.05) but decreased in the ARA+LPS mice (P < 0.05). In vitro, L-arabinose decreased the proportion of M1 macrophages and inhibited mRNA levels of TNF-α, IL-1β, IL-6, IFN-γ, as well as IRF-5 and STAT-1 (P < 0.01). Moreover, L-arabinose restored the abundance of norank_f__Muribaculaceae, Faecalibaculum, Dubosiella, Prevotellaceae_UCG-001, and Paraasutterella compared with those of LPS (P < 0.05) and increased the concentration of short-chain fatty acids (P < 0.05).
CONCLUSION
The anti-inflammatory effects of L-arabinose are achieved by reducing M1 macrophage polarization, suggesting that L-arabinose could be a candidate functional food or nutritional strategy for intestinal inflammation and injury.
Topics: Male; Mice; Animals; Lipopolysaccharides; Tumor Necrosis Factor-alpha; Arabinose; Interleukin-6; Mice, Inbred C57BL; Macrophages; Inflammation; Anti-Inflammatory Agents; RNA, Messenger
PubMed: 37717628
DOI: 10.1016/j.tjnut.2023.09.012 -
Journal of Plant Research Sep 2016L-Arabinose (L-Ara) is a plant-specific sugar accounting for 5-10 % of cell wall saccharides in Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa). L-Ara occurs... (Review)
Review
L-Arabinose (L-Ara) is a plant-specific sugar accounting for 5-10 % of cell wall saccharides in Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa). L-Ara occurs in pectic arabinan, rhamnogalacturonan II, arabinoxylan, arabinogalactan-protein (AGP), and extensin in the cell walls, as well as in glycosylated signaling peptides like CLAVATA3 and small glycoconjugates such as quercetin 3-O-arabinoside. This review focuses on recent advances towards understanding the generation of L-Ara and the metabolism of L-Ara-containing molecules in plants.
Topics: Arabinose; Models, Biological; Phylogeny; Plants; Pollen; Uridine Diphosphate
PubMed: 27220955
DOI: 10.1007/s10265-016-0834-z -
Microbial Biotechnology Jun 2022Filamentous fungi produce a wide variety of enzymes in order to efficiently degrade plant cell wall polysaccharides. The production of these enzymes is controlled by...
Filamentous fungi produce a wide variety of enzymes in order to efficiently degrade plant cell wall polysaccharides. The production of these enzymes is controlled by transcriptional regulators, which also control the catabolic pathways that convert the released monosaccharides. Two transcriptional regulators, GalX and GalR, control d-galactose utilization in the model filamentous fungus Aspergillus nidulans, while the arabinanolytic regulator AraR regulates l-arabinose catabolism. d-Galactose and l-arabinose are commonly found together in polysaccharides, such as arabinogalactan, xylan and rhamnogalacturonan I. Therefore, the catabolic pathways that convert d-galactose and l-arabinose are often also likely to be active simultaneously. In this study, we investigated the interaction between GalX, GalR and AraR in d-galactose and l-arabinose catabolism. For this, we generated single, double and triple mutants of the three regulators, and analysed their growth and enzyme and gene expression profiles. Our results clearly demonstrated that GalX, GalR and AraR co-regulate d-galactose catabolism in A. nidulans. GalX has a prominent role on the regulation of genes of d-galactose oxido-reductive pathway, while AraR can compensate for the absence of GalR and/or GalX.
Topics: Arabinose; Aspergillus nidulans; Galactose; Gene Expression Regulation, Fungal; Polysaccharides; Transcription Factors
PubMed: 35213794
DOI: 10.1111/1751-7915.14025 -
Current Opinion in Chemical Biology Apr 2019In 2014, the first fungal pyrroloquinoline-quinone (PQQ)-dependent enzyme was discovered as a pyranose dehydrogenase from the basidiomycete Coprinopsis cinerea (CcPDH).... (Review)
Review
In 2014, the first fungal pyrroloquinoline-quinone (PQQ)-dependent enzyme was discovered as a pyranose dehydrogenase from the basidiomycete Coprinopsis cinerea (CcPDH). This discovery laid the foundation for a new Auxiliary Activities (AA) family, AA12, in the Carbohydrate-Active enZymes (CAZy) database and revealed a novel enzymatic activity potentially involved in biomass conversion. This review summarizes recent progress made in research on this fungal oxidoreductase and related enzymes. CcPDH consists of the catalytic PQQ-binding AA12 domain, an N-terminal cytochrome b AA8 domain, and a C-terminal family 1 carbohydrate-binding module (CBM1). CcPDH oxidizes 2-keto-d-glucose (d-glucosone), l-fucose, and rare sugars such as d-arabinose and l-galactose, and can activate lytic polysaccharide monooxygenases (LPMOs). Bioinformatic studies suggest a widespread occurrence of quinoproteins in eukaryotes as well as prokaryotes.
Topics: Arabinose; Basidiomycota; Biocatalysis; Fucose; Galactose; Ketoses; Oxidation-Reduction; Oxidoreductases; PQQ Cofactor; Substrate Specificity
PubMed: 30580186
DOI: 10.1016/j.cbpa.2018.12.001 -
FEMS Microbiology Reviews Aug 2021Pentose sugars are widespread in nature and two of them, D-xylose and L-arabinose belong to the most abundant sugars being the second and third by abundance sugars in... (Review)
Review
Pentose sugars are widespread in nature and two of them, D-xylose and L-arabinose belong to the most abundant sugars being the second and third by abundance sugars in dry plant biomass (lignocellulose) and in general on planet. Therefore, it is not surprising that metabolism and bioconversion of these pentoses attract much attention. Several different pathways of D-xylose and L-arabinose catabolism in bacteria and yeasts are known. There are even more common and really ubiquitous though not so abundant pentoses, D-ribose and 2-deoxy-D-ribose, the constituents of all living cells. Thus, ribose metabolism is example of endogenous metabolism whereas metabolism of other pentoses, including xylose and L-arabinose, represents examples of the metabolism of foreign exogenous compounds which normally are not constituents of yeast cells. As a rule, pentose degradation by the wild-type strains of microorganisms does not lead to accumulation of high amounts of valuable substances; however, productive strains have been obtained by random selection and metabolic engineering. There are numerous reviews on xylose and (less) L-arabinose metabolism and conversion to high value substances; however, they mostly are devoted to bacteria or the yeast Saccharomyces cerevisiae. This review is devoted to reviewing pentose metabolism and bioconversion mostly in non-conventional yeasts, which naturally metabolize xylose. Pentose metabolism in the recombinant strains of S. cerevisiae is also considered for comparison. The available data on ribose, xylose, L-arabinose transport, metabolism, regulation of these processes, interaction with glucose catabolism and construction of the productive strains of high-value chemicals or pentose (ribose) itself are described. In addition, genome studies of the natural xylose metabolizing yeasts and available tools for their molecular research are reviewed. Metabolism of other pentoses (2-deoxyribose, D-arabinose, lyxose) is briefly reviewed.
Topics: Arabinose; Biofuels; Pentoses; Saccharomyces cerevisiae; Xylose
PubMed: 33316044
DOI: 10.1093/femsre/fuaa069 -
Journal of the Science of Food and... Nov 2022Taro, a staple food for residents in Africa and parts of Asia, is an important source of carbohydrate. China has abundant taro resources. Taro contains polysaccharide,... (Review)
Review
Taro, a staple food for residents in Africa and parts of Asia, is an important source of carbohydrate. China has abundant taro resources. Taro contains polysaccharide, vitamins, minerals and other substances. Taro polysaccharides, as a significant active ingredient in taro, are mainly composed of monosaccharide units such as glucose, galactose, arabinose, mannose, and so on. Taro polysaccharides have antioxidant, lipid-lowering, and immunomodulatory effects. In today's world, people are interested in food containing natural ingredients, which stimulates the potential of taro polysaccharides in the food, pharmaceutical, medical, and other fields. Herein, the extraction and purification, structural characterization, functional activity, and application of taro polysaccharides are reviewed to strengthen the cognition of taro polysaccharides. It provides references for further research and development of taro polysaccharides. © 2022 Society of Chemical Industry.
Topics: Antioxidants; Arabinose; Colocasia; Galactose; Glucose; Humans; Lipids; Mannose; Monosaccharides; Pharmaceutical Preparations; Polysaccharides; Vitamins
PubMed: 35679352
DOI: 10.1002/jsfa.12058 -
Gut Microbes 2023The pathogenicity of O157:H7 is predominantly associated with Shiga toxin 2 (Stx2) that poses a huge threat to human and animal intestinal health. Production of Stx2...
The pathogenicity of O157:H7 is predominantly associated with Shiga toxin 2 (Stx2) that poses a huge threat to human and animal intestinal health. Production of Stx2 requires expression of gene, which is located in the genome of lambdoid Stx2 prophage. Growing evidence has implicated that many commonly consumed foods participate in the regulation of prophage induction. In this study, we aimed to explore whether specific dietary functional sugars could inhibit Stx2 prophage induction in O157:H7, thereby preventing Stx2 production and promoting intestinal health. We demonstrated that Stx2 prophage induction in O157:H7 was strongly inhibited by L-arabinose both and in a mouse model. Mechanistically, L-arabinose at doses of 9, 12, or 15 mM diminished RecA protein levels, a master mediator of the SOS response, contributing to reduced Stx2-converting phage induction. L-Arabinose inhibited quorum sensing and oxidative stress response, which are known as positive regulators of the SOS response and subsequent Stx2 phage production. Furthermore, L-arabinose impaired O157:H7 arginine transport and metabolism that were involved in producing Stx2 phage. Collectively, our results suggest that L-arabinose may be exploited as a novel Stx2 prophage induction inhibitor against O157:H7 infection.
Topics: Humans; Animals; Mice; Shiga Toxin 2; Bacteriophages; Escherichia coli O157; Arabinose; Gastrointestinal Microbiome
PubMed: 37332116
DOI: 10.1080/19490976.2023.2221778