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Glycobiology Oct 2022N-glycolylated carbohydrates are amino sugars with an N-glycolyl amide group. These glycans have not been well studied due to their surprising rarity in nature in... (Review)
Review
N-glycolylated carbohydrates are amino sugars with an N-glycolyl amide group. These glycans have not been well studied due to their surprising rarity in nature in comparison with N-acetylated carbohydrates. Recently, however, there has been increasing interest in N-glycolylated sugars because the non-human sialic acid N-glycolylneuraminic acid (Neu5Gc), apparently the only source of all N-glycolylated sugars in deuterostomes, appears to be involved in xenosialitis (inflammation associated with consumption of Neu5Gc-rich red meats). Xenosialitis has been implicated in cancers as well as other diseases including atherosclerosis. Furthermore, metabolites of Neu5Gc have been shown to be incorporated into glycosaminoglycans (GAGs), resulting in N-glycolylated GAGs. These N-glycolylated GAGs have important potential applications, such as dating the loss of the Neu5Gc-generating CMAH gene in humans and being explored as a xenosialitis biomarker and/or estimate of the body burden of diet-derived Neu5Gc, to understand the risks associated with the consumption of red meats. This review explores N-glycolylated carbohydrates, how they are metabolized to N-glycolylglucosamine and N-glycolylgalactosamine, and how these metabolites can be incorporated into N-glycolylated GAGs in human tissues. We also discuss other sources of N-glycolylated sugars, such as recombinant production from microorganisms using metabolic engineering as well as chemical synthesis.
Topics: Humans; Neuraminic Acids; N-Acetylneuraminic Acid; Amino Sugars; Polysaccharides; Inflammation
PubMed: 35925816
DOI: 10.1093/glycob/cwac048 -
Molecules (Basel, Switzerland) Mar 2018Nucleic acids and carbohydrates are essential biomolecules involved in numerous biological and pathological processes. Development of multifunctional building blocks... (Review)
Review
Nucleic acids and carbohydrates are essential biomolecules involved in numerous biological and pathological processes. Development of multifunctional building blocks based on nucleosides and sugars is in high demand for the generation of novel oligonucleotide mimics and glycoconjugates for biomedical applications. Recently, aminooxyl-functionalized compounds have attracted increasing research interest because of their easy derivatization through oxime ligation or -oxyamide formation reactions. Various biological applications have been reported for -amino carbohydrate- and nucleoside-derived compounds. Here, we report our efforts in the design and synthesis of glyco-, glycosyl, nucleoside- and nucleo-aminooxy acid derivatives from readily available sugars and amino acids, and their use for the generation of -oxyamide-linked oligosaccharides, glycopeptides, glycolipids, oligonucleosides and nucleopeptides as novel glycoconjugates or oligonucleotide mimics. Delicate and key points in the synthesis will be emphasized.
Topics: Amino Sugars; Molecular Structure; Nucleosides; Oximes
PubMed: 29534554
DOI: 10.3390/molecules23030641 -
Nature Sep 2022Bacterial cell wall components provide various unique molecular structures that are detected by pattern recognition receptors (PRRs) of the innate immune system as...
Bacterial cell wall components provide various unique molecular structures that are detected by pattern recognition receptors (PRRs) of the innate immune system as non-self. Most bacterial species form a cell wall that consists of peptidoglycan (PGN), a polymeric structure comprising alternating amino sugars that form strands cross-linked by short peptides. Muramyl dipeptide (MDP) has been well documented as a minimal immunogenic component of peptidoglycan. MDP is sensed by the cytosolic nucleotide-binding oligomerization domain-containing protein 2 (NOD2). Upon engagement, it triggers pro-inflammatory gene expression, and this functionality is of critical importance in maintaining a healthy intestinal barrier function. Here, using a forward genetic screen to identify factors required for MDP detection, we identified N-acetylglucosamine kinase (NAGK) as being essential for the immunostimulatory activity of MDP. NAGK is broadly expressed in immune cells and has previously been described to contribute to the hexosamine biosynthetic salvage pathway. Mechanistically, NAGK functions upstream of NOD2 by directly phosphorylating the N-acetylmuramic acid moiety of MDP at the hydroxyl group of its C6 position, yielding 6-O-phospho-MDP. NAGK-phosphorylated MDP-but not unmodified MDP-constitutes an agonist for NOD2. Macrophages from mice deficient in NAGK are completely deficient in MDP sensing. These results reveal a link between amino sugar metabolism and innate immunity to bacterial cell walls.
Topics: Acetylmuramyl-Alanyl-Isoglutamine; Animals; Bacteria; Cell Wall; Hexosamines; Immunity, Innate; Macrophages; Mice; Nod2 Signaling Adaptor Protein; Peptidoglycan; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor)
PubMed: 36002575
DOI: 10.1038/s41586-022-05125-x -
BMC Biology Jul 2019Altered metabolism and deregulated cellular energetics are now considered a hallmark of all cancers. Glucose, glutamine, fatty acids, and amino acids are the primary... (Review)
Review
Altered metabolism and deregulated cellular energetics are now considered a hallmark of all cancers. Glucose, glutamine, fatty acids, and amino acids are the primary drivers of tumor growth and act as substrates for the hexosamine biosynthetic pathway (HBP). The HBP culminates in the production of an amino sugar uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) that, along with other charged nucleotide sugars, serves as the basis for biosynthesis of glycoproteins and other glycoconjugates. These nutrient-driven post-translational modifications are highly altered in cancer and regulate protein functions in various cancer-associated processes. In this review, we discuss recent progress in understanding the mechanistic relationship between the HBP and cancer.
Topics: Biosynthetic Pathways; Hexosamines; Neoplasms; Protein Processing, Post-Translational; Proteins
PubMed: 31272438
DOI: 10.1186/s12915-019-0671-3 -
Applied and Environmental Microbiology Dec 2020Amino sugars, particularly glucosamine (GlcN) and -acetylglucosamine (GlcNAc), are abundant carbon and nitrogen sources supplied in host secretions and in the diet to...
Amino sugars, particularly glucosamine (GlcN) and -acetylglucosamine (GlcNAc), are abundant carbon and nitrogen sources supplied in host secretions and in the diet to the biofilms colonizing the human oral cavity. Evidence is emerging that these amino sugars provide ecological advantages to beneficial commensals over oral pathogens and pathobionts. Here, we performed transcriptome analysis on and growing in single-species or dual-species cultures with glucose, GlcN, or GlcNAc as the primary carbohydrate source. Compared to glucose, GlcN caused drastic transcriptomic shifts in each species of bacteria when it was cultured alone. Likewise, cocultivation in the presence of GlcN yielded transcriptomic profiles that were dramatically different from the single-species results from GlcN-grown cells. In contrast, GlcNAc elicited only minor changes in the transcriptome of either organism in single- and dual-species cultures. Interestingly, genes involved in pyruvate metabolism were among the most significantly affected by GlcN in both species, and these changes were consistent with measurements of pyruvate in culture supernatants. Differing from what was found in a previous report, growth of alone with GlcN inhibited the expression of multiple operons required for mutacin production. Cocultivation with consistently increased the expression of two manganese transporter operons ( and ) and decreased expression of mutacin genes in Conversely, appeared to be less affected by the presence of but did show increases in genes for biosynthetic processes in the cocultures. In conclusion, amino sugars profoundly alter the interactions between pathogenic and commensal streptococci by reprogramming central metabolism. Carbohydrate metabolism is central to the development of dental caries. A variety of sugars available to dental microorganisms influence the development of caries by affecting the physiology, ecology, and pathogenic potential of tooth biofilms. Using two well-characterized oral bacteria, one pathogen () and one commensal (), in an RNA deep-sequencing analysis, we studied the impact of two abundant amino sugars on bacterial gene expression and interspecies interactions. The results indicated large-scale remodeling of gene expression induced by GlcN in particular, affecting bacterial energy generation, acid production, protein synthesis, and release of antimicrobial molecules. Our study provides novel insights into how amino sugars modify bacterial behavior, information that will be valuable in the design of new technologies to detect and prevent oral infectious diseases.
Topics: Amino Sugars; Gene Expression; Gene Expression Profiling; Genes, Bacterial; Microbiota; Mouth; Streptococcus gordonii; Streptococcus mutans; Symbiosis
PubMed: 33097515
DOI: 10.1128/AEM.01459-20 -
BioTechniques Feb 2021Five established clearing protocols were compared with a modified and simplified method to determine an optimal clearing reagent for three-dimensionally visualizing...
Five established clearing protocols were compared with a modified and simplified method to determine an optimal clearing reagent for three-dimensionally visualizing fluorophores in the murine liver, a challenging organ to clear. We report successful clearing of whole liver lobes by modification of an established protocol (UbasM) using only Ub-1, a urea-based amino sugar reagent, in a simpler protocol that requires only a 24-h processing time. With Ub-1 alone, we observed sufficiently preserved liver tissue structure in three dimensions along with excellent preservation of fluorophore emissions from endogenous protein reporters and lipophilic tracer dyes. This streamlined technique can be used for 3D cell lineage tracing and fluoroprobe-based reporter gene expression to compare various experimental conditions.
Topics: Amino Sugars; Animals; Fluorescence; Fluorescent Dyes; Liver; Mice; Urea
PubMed: 33467918
DOI: 10.2144/btn-2020-0063 -
PloS One 2012Streptococcus mutans is a cariogenic pathogen that produces an extracellular polysaccharide (glucan) from dietary sugars, which allows it to establish a reproductive...
Streptococcus mutans is a cariogenic pathogen that produces an extracellular polysaccharide (glucan) from dietary sugars, which allows it to establish a reproductive niche and secrete acids that degrade tooth enamel. While two enzymes (GlmS and NagB) are known to be key factors affecting the entrance of amino sugars into glycolysis and cell wall synthesis in several other bacteria, their roles in S. mutans remain unclear. Therefore, we investigated the roles of GlmS and NagB in S. mutans sugar metabolism and determined whether they have an effect on virulence. NagB expression increased in the presence of GlcNAc while GlmS expression decreased, suggesting that the regulation of these enzymes, which functionally oppose one another, is dependent on the concentration of environmental GlcNAc. A glmS-inactivated mutant could not grow in the absence of GlcNAc, while nagB-inactivated mutant growth was decreased in the presence of GlcNAc. Also, nagB inactivation was found to decrease the expression of virulence factors, including cell-surface protein antigen and glucosyltransferase, and to decrease biofilm formation and saliva-induced S. mutans aggregation, while glmS inactivation had the opposite effects on virulence factor expression and bacterial aggregation. Our results suggest that GlmS and NagB function in sugar metabolism in opposing directions, increasing and decreasing S. mutans virulence, respectively.
Topics: Aldose-Ketose Isomerases; Amino Sugars; Biofilms; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Enzymologic; Gene Knockout Techniques; Genes, Bacterial; Genetic Complementation Test; Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); Humans; Models, Biological; Mutation; Streptococcus mutans; Virulence; Virulence Factors
PubMed: 22438919
DOI: 10.1371/journal.pone.0033382 -
The Journal of Biological Chemistry 2021The elongated antennae decorating eukaryotic glycans are built from polylactosamine repeats. Polylactosamine forms a lectin recognition site and also acts as a platform...
The elongated antennae decorating eukaryotic glycans are built from polylactosamine repeats. Polylactosamine forms a lectin recognition site and also acts as a platform for presenting diverse additional modifications (e.g., terminal cell-surface antigens); it therefore plays important roles in cell adherence, development, and immunity. Two new papers present a detailed structural and mechanistic investigation of β1-3-N-acetylgucosaminyltransferase 2, a key enzyme in antennae synthesis. The resulting insights will also help decipher other members of GT31, the single largest human glycosyltransferase family.
Topics: Amino Sugars; Glycosylation; N-Acetylglucosaminyltransferases; Polysaccharides
PubMed: 33453284
DOI: 10.1016/j.jbc.2020.100212 -
Scientific Reports Sep 2016The nitrogen-metabolic phosphotransferase system, PTS(Ntr), consists of the enzymes I(Ntr), NPr and IIA(Ntr) that are encoded by ptsP, ptsO, and ptsN, respectively. Due...
The nitrogen-metabolic phosphotransferase system, PTS(Ntr), consists of the enzymes I(Ntr), NPr and IIA(Ntr) that are encoded by ptsP, ptsO, and ptsN, respectively. Due to the proximity of ptsO and ptsN to rpoN, the PTS(Ntr) system has been postulated to be closely related with nitrogen metabolism. To define the correlation between PTS(Ntr) and nitrogen metabolism, we performed ligand fishing with EIIA(Ntr) as a bait and revealed that D-glucosamine-6-phosphate synthase (GlmS) directly interacted with EIIA(Ntr). GlmS, which converts D-fructose-6-phosphate (Fru6P) into D-glucosamine-6-phosphate (GlcN6P), is a key enzyme producing amino sugars through glutamine hydrolysis. Amino sugar is an essential structural building block for bacterial peptidoglycan and LPS. We further verified that EIIA(Ntr) inhibited GlmS activity by direct interaction in a phosphorylation-state-dependent manner. EIIA(Ntr) was dephosphorylated in response to excessive nitrogen sources and was rapidly degraded by Lon protease upon amino sugar depletion. The regulation of GlmS activity by EIIA(Ntr) and the modulation of glmS translation by RapZ suggest that the genes comprising the rpoN operon play a key role in maintaining amino sugar homeostasis in response to nitrogen availability and the amino sugar concentration in the bacterial cytoplasm.
Topics: Amino Sugars; Bacterial Proteins; Cytoplasm; Fructosephosphates; Glucosamine; Glucose-6-Phosphate; Homeostasis; Nitrogen; Phosphoenolpyruvate Sugar Phosphotransferase System; Phosphorylation; Salmonella typhimurium
PubMed: 27628932
DOI: 10.1038/srep33055 -
Applied and Environmental Microbiology May 2019-Acetylglucosamine (GlcNAc) and glucosamine (GlcN) enhance the competitiveness of the laboratory strain DL1 of against the caries pathogen Here, we examine how amino...
-Acetylglucosamine (GlcNAc) and glucosamine (GlcN) enhance the competitiveness of the laboratory strain DL1 of against the caries pathogen Here, we examine how amino sugars affect the interaction of five low-passage-number clinical isolates of abundant commensal streptococci with by utilizing a dual-species biofilm model. Compared to that for glucose, growth on GlcN or GlcNAc significantly reduced the viability of in cocultures with most commensals, shifting the proportions of species. Consistent with these results, production of HO was increased in most commensals when growing on amino sugars, and inhibition of by , , or was enhanced by amino sugars on agar plates. All commensals except had higher arginine deiminase activities when grown on GlcN and, in some cases, GlcNAc. In biofilms formed using pooled cell-containing saliva (CCS), the proportions of were drastically diminished when GlcNAc was the primary carbohydrate. Increased production of HO could account in large part for the inhibitory effects of CCS biofilms. Surprisingly, amino sugars appeared to improve mutacin production by on agar plates, suggesting that the commensals have mechanisms to actively subvert antagonism by in cocultures. Collectively, these findings demonstrate that amino sugars can enhance the beneficial properties of low-passage-number commensal oral streptococci and highlight their potential for moderating the cariogenicity of oral biofilms. Dental caries is driven by dysbiosis of oral biofilms in which dominance by acid-producing and acid-tolerant bacteria results in loss of tooth mineral. Our previous work demonstrated the beneficial effects of amino sugars GlcNAc and GlcN in promoting the antagonistic properties of a health-associated oral bacterium, , in competition with the major caries pathogen Here, we investigated 5 low-passage-number clinical isolates of the most common streptococcal species to establish how amino sugars may influence the ecology and virulence of oral biofilms. Using multiple models, including a human saliva-derived microcosm biofilm, experiments showed significant enhancement by at least one amino sugar in the ability of most of these bacteria to suppress the caries pathogen. Therefore, our findings demonstrated the mechanism of action by which amino sugars may affect human oral biofilms to promote health.
Topics: Amino Sugars; Biofilms; Dental Caries; Dental Plaque; Saliva; Streptococcal Infections; Streptococcus gordonii; Streptococcus mutans; Symbiosis
PubMed: 30877119
DOI: 10.1128/AEM.00370-19