Human Endogenous Metabolite

N-Acetyl-D-mannosamine (ManNAc) and N-acetyl-D-glucosamine (GlcNAc) are the essential precursors of N-acetylneuraminic acid (NeuAc), the specific monomer of polysialic acid (PA), a bacterial pathogenic determinant. Escherichia coli K1 uses both amino sugars as carbon sources and uptake takes place through the mannose phosphotransferase system transporter, a phosphoenolpyruvate-dependent phosphotransferase system that shows a broad range of specificity. Glucose, mannose, fructose, and glucosamine strongly inhibited the transport of these amino-acetylated sugars and GlcNAc and ManNAc strongly affected ManNAc and GlcNAc uptake, respectively. The ManNAc and the GlcNAc phosphorylation that occurs during uptake affected NeuAc synthesis in vitro. These findings account for the low in vivo PA production observed when E. coli K1 uses ManNAc or GlcNAc as a carbon source for growth. [1]

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Orexin neurons regulate critical brain activities for controlling sleep, eating, emotions, and metabolism, and impaired orexin neuron function results in several neurologic disorders. Therefore, restoring normal orexin function and understanding the mechanisms of loss or impairment of orexin neurons represent important goals. As a step toward that end, we generated human orexin neurons from induced pluripotent stem cells (hiPSCs) by treatment with N-acetyl-d-mannosamine (ManNAc) and its derivatives. The generation of orexin neurons was associated with DNA hypomethylation, histone H3/H4 hyperacetylation, and hypo-O-GlcNAcylation on the HCRT gene locus, and, thereby, the treatment of inhibitors of SIRT1 and OGT were effective at inducing orexin neurons from hiPSCs. The prolonged exposure of orexin neurons to high glucose in culture caused irreversible silencing of the HCRT gene, which was characterized by H3/H4 hypoacetylation and hyper-O-GlcNAcylation. The DNA hypomethylation status, once established in orexin neurogenesis, was maintained in the HCRT-silenced orexin neurons, indicating that histone modifications, but not DNA methylation, were responsible for the HCRT silencing. Thus, the epigenetic status of the HCRT gene is unique to the hyperglycemia-induced silencing. Intriguingly, treatment of ManNAc and its derivatives reactivated HCRT gene expression, while inhibitors SIRT1 and the OGT did not. The present study revealed that the HCRT gene was silenced by the hyperglycemia condition, and ManNAc and its derivatives were useful for restoring the orexin neurons.[2]

N-acetyl-D-mannosamine (administered orally in drinking water at 1% once daily for 16 weeks) prevents obesity-induced hypertension in a mouse model of high-fat diet-induced hypertension by increasing sialylation of IgG glycans [3].
N-acetyl-D-mannosamine (administered orally in drinking water at 0.5% for 8 weeks, ad libitum) improves synaptic transmission and long-term potentiation (LTP) in 6- and 14-month-old SAMR1 mice [4].
N-acetyl-D-mannosamine (administered orally in drinking water at 0.5% for 8 weeks, ad libitum) improves synaptic transmission and long-term potentiation (LTP) in 6- and 14-month-old SAMR1 mice [4].

Animal model: C57BL/6 mouse model of high-fat diet-induced hypertension [2]
Dosage: 1% in drinking water Administration: Oral gavage (p.o.), once a day for 16 weeks
Results: Inhibited high-fat diet-induced weight gain and increased sialylation of IgG glycans.

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Animal model: Knock-in C57BL/6J mouse model of GNE myopathy (Gne p.M712T)
Dosage: 1 or 2 g/kg
Administration: Administration via drinking water (4-6 mL per day), once a day for 12 weeks
Results: Significant reduction in proteinuria (2 g/kg) after only one week of treatment

[1]. Transport of N-acetyl-D-mannosamine and N-acetyl-D-glucosamine in Escherichia coli K1: effect on capsular polysialic acid production. FEBS Lett. 2002 Jan 30;511(1-3):97-101.

[2]. Reactivation of hyperglycemia-induced hypocretin (HCRT) gene silencing by N-acetyl-d-mannosamine in the orexin neurons derived from human iPS cells. Epigenetics. 2017 Sep;12(9):764-778.

[3]. Supplementation With the Sialic Acid Precursor N-Acetyl-D-Mannosamine Breaks the Link Between Obesity and Hypertension. Circulation. 2019 Dec 10;140(24):2005-2018.

[4]. Oral monosaccharide therapies to reverse renal and muscle hyposialylation in a mouse model of GNE myopathy. Mol Genet Metab. 2012 Dec;107(4):748-55.

[5]. Chronic administration of N-acetyl-D-mannosamine improves age-associated impairment of long-term potentiation in the senescence-accelerated mouse. Neurosci Lett. 2015 Jun 26;598:41-6.

Background: Obesity-related hypertension is a common disease, and treatments targeting underlying obesity are often ineffective. We previously found that mice systemically lacking the inhibitory immunoglobulin G (IgG) receptor FcγRIIB are protected from obesity-induced hypertension. However, how FcγRIIB is involved remains unclear. This study aimed to determine whether alterations in IgG are involved in the pathogenesis of obesity-induced hypertension. Methods: We used IgG μ-heavy chain knockout mice lacking mature B cells and investigated the involvement of IgG via IgG transfer. We used mice with systemic or endothelial cell-specific knockout of the FcγRIIB receptor to investigate the involvement of FcγRIIB. We induced obesity in mice using a high-fat diet (HFD) and measured blood pressure via wireless telemetry or tail-cuffing. We assessed the sialylation level of Fc glycans on mouse IgG using elderberry lectin blot, which affects IgG activation of the Fc receptor. This study evaluated the effect of IgG on endothelial nitric oxide synthase (eNOS) in human aortic endothelial cells. Mass spectrometry was used to detect the IgG Fc glycan sialylation levels in 3442 subjects, and the relationship between sialylation and blood pressure (BP) was assessed. In mice fed a high-fat diet (HFD), the effect of administration of the sialic acid precursor N-acetyl-D-mannosamine (ManNAc) was determined to normalize IgG sialylation. Results showed that B-cell deficient mice were protected from obesity-induced hypertension. Compared with control mice fed a normal diet, high-fat diet mice had reduced IgG sialylation levels, and when transferred to IgG-deficient recipient mice, they increased blood pressure; however, no hypertensive response was observed in recipient mice simultaneously lacking FcγRIIB. IgG treated with neuraminidase and lacking Fc terminal sialic acid also increased blood pressure. In cultured endothelial cells, both IgG from high-fat diet-fed mice and neuraminidase-treated IgG inhibited vascular endothelial growth factor-activated endothelial nitric oxide synthase (VEGS) via FcγRIIB, through an alteration in VEGS phosphorylation levels. In humans, obesity is associated with decreased IgG sialylation levels, and systolic blood pressure is negatively correlated with IgG sialylation levels. Mice deficient in FcγRIIB in endothelial cells are protected from obesity-induced hypertension. Furthermore, in mice fed a high-fat diet, ManNAc can restore IgG sialylation levels to normal and prevent obesity-induced hypertension. Conclusion: Low sialylation of IgG and FcγRIIB in endothelial cells plays a key role in obesity-induced hypertension in mice, and supporting evidence has been obtained in humans. Interventions targeting these mechanisms, such as ManNAc supplementation, may provide new avenues for breaking the link between obesity and hypertension. 3]

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N-acetyl-D-mannosamine (ManNAc) is a precursor of sialic acid and has recently been reported to improve cognitive function in aged animals. However, the long-term effects of ManNAc administration on impaired synaptic transmission and plasticity in aged animals remain unclear. This study used hippocampal slices from the aging-prone SAMP8 mouse strain to investigate the effects of long-term ManNAc administration on synaptic transmission and plasticity impairment in aged animals using electrophysiological methods. SAMP8 mice exhibited age-related learning and memory impairments. After 8 weeks of oral ManNAc administration, field excitatory postsynaptic potentials (fEPSPs) were improved in both 14-month-old SAMP8 mice and their control strain, the SAM-resistant mouse 1 (SAMR1), but this phenomenon was not observed in 6-month-old mice. On the other hand, ManNAc administration improved long-term potentiation (LTP, representing long-term synaptic plasticity) in 6-month-old SAMP8 mice, but did not improve it in age-matched SAMR1 mice. Furthermore, ManNAc improved LTP in 14-month-old SAMR1 mice, but did not improve it in age-matched SAMP8 mice. Simultaneously, we measured PPR, and the results showed that ManNAc did not affect PPR before or after LTP-induced high-frequency stimulation. These results suggest that long-term use of ManNAc can improve age-related synaptic transmission and LTP decline, and indicate that ManNAc treatment may be a potential treatment for cognitive impairment. [5]

C8H15NO6

221.2078

221.09

C, 40.17; H, 7.16; N, 5.86; O, 46.82

3615-17-6

Cyclic N-Acetyl-D-mannosamine;7772-94-3;N-Acetyl-D-mannosamine-13C;N-Acetyl-D-mannosamine-13C-1;N-Acetyl-D-mannosamine-15N

22952041

White to off-white solid powder

1.423g/cm3

636.4ºC at 760mmHg

205ºC

338.7ºC

1.575

5

6

6

15

221

4

CC(N[C@@H]([C@@H](O)[C@H](O)[C@H](O)CO)C=O)=O

KVWIBLJBIFTKIZ-XNJRRJNCSA-N

InChI=1S/C8H15NO6.H2O/c1-4(12)9-5(2-10)7(14)8(15)6(13)3-11;/h2,5-8,11,13-15H,3H2,1H3,(H,9,12);1H2/t5-,6-,7-,8-;/m1./s1

N-((2S,3R,4S,5R)-3,4,5,6-tetrahydroxy-1-oxohexan-2-yl)acetamide hydrate

N-Acetyl-D-mannosamine (ManNAc); DEX-M-74; DEX M-74; DEXM74; DEX M 74; ManNAc;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~125 mg/mL (~565.07 mM)

Solubility in Formulation 1: 25 mg/mL (113.01 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)