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Abnormal metabolism of mannose in families with carbohydrate-deficient glycoprotein syndrome type 1.Biochemical and Molecular Medicine Aug 1997Patients with carbohydrate-deficient glycoprotein syndrome (CDGS) Type 1 underglycosylate many glycoproteins by failing to add entire N-linked carbohydrate chains to...
Patients with carbohydrate-deficient glycoprotein syndrome (CDGS) Type 1 underglycosylate many glycoproteins by failing to add entire N-linked carbohydrate chains to them. The primary defect in these patients has been reported as a > 90% deficiency in phosphomannomutase activity (PMM), the enzyme that converts mannose-6-phosphate to mannose-1-phosphate. This lesion reduces both the amount and the size of the lipid-linked oligosaccharide precursor. We have now analyzed the activity of PMM and the level of glycosylation in cultured fibroblasts as well as the level of blood mannose in seven CDGS Type 1 patients and their parents. All of these patients were approximately 95% deficient in PMM activity and their parents had an average of 51% of control PMM activity. Furthermore, parental fibroblasts showed reduced glycosylation and a higher proportion of truncated N-linked chains compared to those made by control fibroblasts. Addition of 0.25 mM mannose to the culture medium corrected both the underglycosylation and size of the oligosaccharide chains in CDGS Type 1 patients and their parents. Finally, serum from CDGS patients had considerably reduced mannose levels (5-40 microM) compared to normal controls (40-80 microM) and some parents were below normal (16-103 microM). These results suggest that the reduced blood mannose level is a consequence of the PMM deficiency. This is the first inherited disorder in human metabolism that shows a decrease in available mannose. Increasing blood mannose levels might correct some protein underglycosylation in these patients.
Topics: Carbohydrate Conformation; Case-Control Studies; Cell Line; Congenital Disorders of Glycosylation; Female; Glycosylation; Humans; Male; Mannose; Phosphotransferases (Phosphomutases)
PubMed: 9259981
DOI: 10.1006/bmme.1997.2599 -
Carbohydrate Research Jan 2014Here we present a synthetic route for solid phase synthesis of N-linked glycoconjugates containing high mannose oligosaccharides which allows the incorporation of useful...
Here we present a synthetic route for solid phase synthesis of N-linked glycoconjugates containing high mannose oligosaccharides which allows the incorporation of useful functional handles on the N-terminus of asparagine. In this strategy, the C-terminus of an Fmoc protected aspartic acid residue is first attached to a solid phase support. The side chain of aspartic acid is protected by a 2-phenylisopropyl protecting group, which allows selective deprotection for the introduction of glycosylation. By using a convergent on-resin glycosylamine coupling strategy, an N-glycosidic linkage is successfully formed on the free side chain of the resin bound aspartic acid with a large high mannose oligosaccharide, Man8GlcNAc2, to yield N-linked high mannose glycosylated asparagine. The use of on-resin glycosylamine coupling provides excellent glycosylation yield, can be applied to couple other types of oligosaccharides, and also makes it possible to recover excess oligosaccharides conveniently after the on-resin coupling reaction. Useful functional handles including an alkene (p-vinylbenzoic acid), an alkyne (4-pentynoic acid), biotin, and 5-carboxyfluorescein are then conjugated onto the N-terminal amine of asparagine on-resin after the removal of the Fmoc protecting group. In this way, useful functional handles are introduced onto the glycosylated asparagine while maintaining the structural integrity of the reducing end of the oligosaccharide. The asparagine side chain also serves as a linker between the glycan and the functional group and preserves the native presentation of N-linked glycan which may aid in biochemical and structural studies. As an example of a biochemical study using functionalized high mannose glycosylated asparagine, a fluorescence polarization assay has been utilized to study the binding of the lectin Concanavalin A (ConA) using 5-carboxyfluorescein labeled high mannose glycosylated asparagine.
Topics: Asparagine; Aspartic Acid; Concanavalin A; Fluorescence; Glycosylation; Mannose; Oligosaccharides; Resins, Synthetic; Solid-Phase Synthesis Techniques
PubMed: 24326091
DOI: 10.1016/j.carres.2013.11.002 -
Phytotherapy Research : PTR Feb 2023Atractylodin (ATL) has been reported to exert anti-inflammatory effects. Osteogenic changes induced by inflammation in valve interstitial cells (VICs) play a key role in...
Atractylodin targets GLA to regulate D-mannose metabolism to inhibit osteogenic differentiation of human valve interstitial cells and ameliorate aortic valve calcification.
Atractylodin (ATL) has been reported to exert anti-inflammatory effects. Osteogenic changes induced by inflammation in valve interstitial cells (VICs) play a key role in the development of calcified aortic valve disease (CAVD). This study aimed to investigate the anti-calcification effects of ATL on aortic valves. Human VICs (hVICs) were exposed to osteogenic induction medium (OM) containing ATL to investigate cell viability, osteogenic gene and protein expression, and anti-calcification effects. Gas chromatography-mass spectroscopy (GC-MS) metabolomics analysis was used to detect changes in the metabolites of hVICs stimulated with OM before and after ATL administration. The compound-reaction-enzyme-gene network was used to identify drug targets. Gene interference was used to verify the targets. ApoE-/- mice fed a high-fat (HF) diet were used to evaluate the inhibition of aortic valve calcification by ATL. Treatment with 20 μM ATL in OM prevented calcified nodule accumulation and decreases in the gene and protein expression levels of ALP, RUNX2, and IL-1β. Differential metabolite analysis showed that D-mannose was highly associated with the anti-calcification effect of ATL. The addition of D-mannose prevented calcified nodule accumulation and inhibited succinate-mediated HIF-1α activation and IL-1β production. The target of ATL was identified as GLA. Silencing of the GLA gene (si-GLA) reversed the anti-osteogenic differentiation of ATL. In vivo, ATL ameliorated aortic valve calcification by preventing decreases in GLA expression and the up-regulation of IL-1β expression synchronously. In conclusion, ATL is a potential drug for the treatment of CAVD by targeting GLA to regulate D-mannose metabolism, thereby inhibiting succinate-mediated HIF-1α activation and IL-1β production.
Topics: Humans; Mice; Animals; Aortic Valve; Mannose; Mice, Knockout, ApoE; Cell Differentiation; Cells, Cultured; Osteogenesis
PubMed: 36199227
DOI: 10.1002/ptr.7628 -
Science (New York, N.Y.) Feb 1962The so-called ambiguity of taste perception of D-mannose has been traced to actual differences in taste between the two anomers of this substance. Preliminary data...
The so-called ambiguity of taste perception of D-mannose has been traced to actual differences in taste between the two anomers of this substance. Preliminary data indicate strongly that the alpha-anomer is sweet (sucrose-like) and the beta-anomer is bitter (quinine-like). The difference in taste is attributed to the slight difference in structures of the anomers.
Topics: Humans; Mannose; Sucrose; Taste
PubMed: 14037773
DOI: 10.1126/science.135.3501.367 -
Chembiochem : a European Journal of... May 2011We describe the synthesis of multivalent mannose derivatives by using hyperbranched polyglycerols (hPG) as a scaffold with different linker structures. Grafting of...
We describe the synthesis of multivalent mannose derivatives by using hyperbranched polyglycerols (hPG) as a scaffold with different linker structures. Grafting of protected mannose (Man) units is achieved by using Cu(I) -catalyzed Huisgen click chemistry with either an anomeric azide or propargyl ether onto complementarily functionalized alkyne or azido polymer surfaces. NMR spectroscopy, dynamic light scattering (DLS), IR spectroscopy, size-exclusion chromatography (SEC), and elemental analysis have been used to characterize the hPG-Man compounds. The surface availability and bioactivity of Man-modified polymers were evaluated by using a competitive surface plasmon resonance (SPR)-based binding assay by interactions of the glycopolymers with concanavalin A (Con A), a lectin that binds mannose containing molecules. The results indicated that the novel glycoarchitectures presented in this work are efficient inhibitors of Con A-mannose recognition and resulted in inhibitor concentrations (mean IC(50)) from the micro- to the nanomolar range, whereas the corresponding monovalent mannoside (methyl-Man) requires millimolar concentrations. The results provide an interesting structure-activity relationship for libraries of materials that differ in the linkage of the sugar moiety presented on a biocompatible polyglycerol scaffold.
Topics: Concanavalin A; Glycerol; Mannose; Molecular Structure; Polymers; Surface Plasmon Resonance
PubMed: 21480454
DOI: 10.1002/cbic.201000718 -
Chemistry (Weinheim An Der Bergstrasse,... Jan 2015Terminal "high-mannose oligosaccharides" are involved in a broad range of biological and pathological processes, from sperm-egg fusion to influenza and human...
Terminal "high-mannose oligosaccharides" are involved in a broad range of biological and pathological processes, from sperm-egg fusion to influenza and human immunodeficiency virus infections. In spite of many efforts, their synthesis continues to be very challenging and actually represents a major bottleneck in the field. Whereas multivalent presentation of mannopyranosyl motifs onto a variety of scaffolds has proven to be a successful way to interfere in recognition processes involving high-mannose oligosaccharides, such constructs fail at reproducing the subtle differences in affinity towards the variety of protein receptors (lectins) and antibodies susceptible to binding to the natural ligands. Here we report a family of functional high-mannose oligosaccharide mimics that reproduce not only the terminal mannopyranosyl display, but also the core structure and the branching pattern, by replacing some inner mannopyranosyl units with triazole rings. Such molecular design can be implemented by exploiting "click" ligation strategies, resulting in a substantial reduction of synthetic cost. The binding affinities of the new "click" high-mannose oligosaccharide mimics towards two mannose specific lectins, namely the plant lectin concanavalin A (ConA) and the human macrophage mannose receptor (rhMMR), have been studied by enzyme-linked lectin assays and found to follow identical trends to those observed for the natural oligosaccharide counterparts. Calorimetric determinations against ConA, and X-ray structural data support the conclusion that these compounds are not just another family of multivalent mannosides, but real "structural mimics" of the high-mannose oligosaccharides.
Topics: Click Chemistry; Humans; Lectins; Mannose; Oligosaccharides
PubMed: 25483029
DOI: 10.1002/chem.201405481 -
FEMS Microbiology Letters Feb 1989The secreted invertase (EC 3.2.1.26) of Saccharomyces cerevisiae is a glycoenzyme that contains N- and O-linked mannoses in 40/1 proportion. The small amount of mannose...
The secreted invertase (EC 3.2.1.26) of Saccharomyces cerevisiae is a glycoenzyme that contains N- and O-linked mannoses in 40/1 proportion. The small amount of mannose chains O-linked to invertase is distributed as follows: mannose (20%), mannobiose (50%), mannotriose (6%), mannotetraose (7%) and mannopentaose (17%).
Topics: Glycoside Hydrolases; Glycosylation; Mannose; Saccharomyces cerevisiae; beta-Fructofuranosidase
PubMed: 2656387
DOI: 10.1016/0378-1097(89)90312-1 -
ACS Applied Materials & Interfaces Jun 2024Mannose-binding lectin (MBL) activates the complement system lectin pathway and subsequent inflammatory mechanisms. The incidence and outcome of many human diseases,...
Mannose-binding lectin (MBL) activates the complement system lectin pathway and subsequent inflammatory mechanisms. The incidence and outcome of many human diseases, such as brain ischemia and infections, are associated with and influenced by the activity and serum concentrations of MBL in body fluids. To quantify MBL levels, tests based on ELISA are used, requiring several incubation and washing steps and lengthy turnaround times. Here, we aimed to develop a nanoplasmonic assay for direct MBL detection in human serum at the point of care. Our assay is based on gold nanorods (GNRs) functionalized with mannose (Man-GNRs) an amphiphilic linker. We experimentally determined the effective amount of sugar linked to the nanorods' surface, resulting in an approximate grafting density of 4 molecules per nm, and an average number of 11 to 13 MBL molecules binding to a single nanoparticle. The optimal Man-GNRs concentration to achieve the highest sensitivity in MBL detection was 15 μg·mL. The specificity of the assay for MBL detection both in simple buffer and in complex pooled human sera was confirmed. Our label-free biosensor is able to detect MBL concentrations as low as 160 ng·mL within 15 min directly in human serum a one-step reaction and by using a microplate reader. Hence, it forms the basis for a fast, noninvasive, point-of-care assay for diagnostic indications and monitoring of disease and therapy.
Topics: Humans; Gold; Mannose-Binding Lectin; Point-of-Care Systems; Biosensing Techniques; Nanotubes; Mannose; Metal Nanoparticles
PubMed: 38806166
DOI: 10.1021/acsami.4c04018 -
European Journal of Pediatrics Jul 1998
Topics: Congenital Disorders of Glycosylation; Dietary Supplements; Humans; Infant; Male; Mannose; Phosphotransferases (Phosphomutases)
PubMed: 9686827
DOI: 10.1007/s004310050889 -
Biochemical and Molecular Medicine Apr 1997Carbohydrate-deficient glycoprotein syndrome type I (CDGS) is an inherited metabolic disorder with multisystemic abnormalities resulting from a failure to add entire...
Carbohydrate-deficient glycoprotein syndrome type I (CDGS) is an inherited metabolic disorder with multisystemic abnormalities resulting from a failure to add entire N-linked oligosaccharide chains to many glycoproteins. Fibroblasts from these patients also abnormally glycosylate proteins, but this lesion is corrected by providing 250 microM mannose to the culture medium. This correction of protein glycosylation suggests that providing dietary mannose to elevate blood mannose concentrations might also remedy some of the underglycosylation observed in these patients. We find that ingested mannose is efficiently absorbed and increases blood mannose levels in both normal subjects and CDGS patients. Blood mannose levels increased in a dose-dependent fashion with increasing oral doses of mannose (0.07-0.21 g mannose/kg body weight). Peak blood mannose concentrations occurred at 1-2 h following ingestion and the clearance half-time was approximately 4 h. Doses of 0.1 g mannose/ kg body weight given at 3-h intervals maintained blood mannose concentrations at levels 3- to 5-fold higher than the basal level in both normal controls (approximately 55 microM) and CDGS patients. No side effects were observed for this dosage regimen. These results establish the feasibility of using mannose as a potential therapeutic dietary supplement (nutraceutical) to treat CDGS patients.
Topics: Administration, Oral; Adult; Child; Congenital Disorders of Glycosylation; Dietary Carbohydrates; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Infant; Kinetics; Mannose
PubMed: 9169093
DOI: 10.1006/bmme.1997.2574