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N-Acetylmannosamine

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(Redirected from N-acyl-D-mannosamine)
N-Acetylmannosamine
Names
IUPAC name 2-(Acetylamino)-2-deoxy-β-D-mannopyranose
Identifiers
CAS Number
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.127.007 Edit this at Wikidata
PubChem CID
UNII
CompTox Dashboard (EPA)
InChI
  • InChI=1S/C8H15NO6/c1-3(11)9-5-7(13)6(12)4(2-10)15-8(5)14/h4-8,10,12-14H,2H2,1H3,(H,9,11)/t4-,5+,6-,7-,8-/m1/s1Key: OVRNDRQMDRJTHS-OZRXBMAMSA-N
  • InChI=1/C8H15NO6/c1-3(11)9-5-7(13)6(12)4(2-10)15-8(5)14/h4-8,10,12-14H,2H2,1H3,(H,9,11)/t4-,5+,6-,7-,8-/m1/s1Key: OVRNDRQMDRJTHS-OZRXBMAMBC
SMILES
  • O1O(CO)(O)(O)1NC(C)=O
Properties
Chemical formula C8H15NO6
Molar mass 221.21 g/mol
Melting point 118 to 121 °C (244 to 250 °F; 391 to 394 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C , 100 kPa). ☒N verify (what is  ?) Infobox references
Chemical compound

N-Acetylmannosamine is a hexosamine monosaccharide. It is a neutral, stable naturally occurring compound. N-Acetylmannosamine is also known as N-Acetyl-D-mannosamine monohydrate, (which has the CAS Registry Number: 676347-48-1), N-Acetyl-D-mannosamine which can be abbreviated to ManNAc or, less commonly, NAM). ManNAc is the first committed biological precursor of N-acetylneuraminic acid (Neu5Ac, sialic acid) (Figure 1). Sialic acids are the negatively charged, terminal monosaccharides of carbohydrate chains that are attached to glycoproteins and glycolipids (glycans).

Biological role of ManNAc

ManNAc is the first committed biological precursor of Neu5Ac.

The initiation of sialic acid biosynthesis occurs in the cytoplasm. The main substrate for this pathway is UDP-GlcNAc, which is derived from glucose. In the rate-limiting step of the pathway, UDP-GlcNAc is converted into ManNAc by UDP-GlcNAc 2-epimerase, encoded by the epimerase domain of GNE. ManNAc is phosphorylated by ManNAc kinase encoded by the kinase domain of GNE. Sialic acid becomes “activated” by CMP-sialic acid synthetase in the nucleus. CMP-sialic acid acts as a sialic acid donor to sialylate glycans on nascent glycoproteins and glycolipids in the Golgi apparatus; it also acts as a cytoplasmic feedback inhibitor of the UDP-GlcNAc 2-epimerase enzyme by binding to its allosteric site. The UDP-GlcNAc 2-epimerase kinase is the rate limiting step in sialic acid biosynthesis. If the enzyme does not work efficiently the organism cannot function correctly.

Synthesis

There are several ways in which ManNAc can be synthesised and three examples follow.

  1. By aldolase treatment of sialic acid. to produce ManNAc and pyruvic acid.
  2. By base catalysed epimerization of N-acetyl glucosamine.
  3. By rhodium (II)-catalyzed oxidative cyclization of glucal 3-carbamates.

ManNAc is now manufactured in large quantities by New Zealand Pharmaceuticals Ltd, in a commercial process from N-acetylglucosamine.

Uses

Sialylation of recombinant proteins

There is normally some level of glycan sialylation within a glycoprotein, but with the observation that incomplete sialylation can lead to reduced therapeutic activity, it becomes relevant to assess the cell-lines and culture media to “humanise” the glycoprotein to improve performance and yield and reduce manufacturing costs. Keppler et al. demonstrated that the GNE enzyme was rate limiting in human hematopoietic cell lines and affected efficiency in cell surface sialylation. The activity of the GNE enzyme is now recognised as one of the defining features in the efficient production of sialylated recombinant glycoprotein therapeutic drugs. Improved sialylation after the addition of ManNAc and other supporting ingredients to the culture medium not only increases manufacturing yield, but also improves therapeutic efficacy by increasing solubility, increasing half-life and reducing immunogenicity by reducing the formation of antibodies to the therapeutic glycoprotein.

Therapeutic potential

When the GNE epimerase kinase does not function correctly in the human body thereby reducing the available ManNAc, it is reasonable to assume that treatment with ManNAc could assist with improving health benefits. The therapeutic potential for ManNAc is currently being assessed in several diseases in which therapy could benefit from its ability to enhance the biosynthesis of sialic acid.

GNE myopathy

The disease GNE myopathy is manifested as progressive muscle weakness. GNE myopathy is a rare genetic disorder caused by hyposialylated muscle proteins and glycosphingolipids because there is insufficient metabolic ManNAc to form the Neu5Ac terminal sugar. There is no available therapy to treat GNE myopathy.

Kidney diseases

There is a growing body of evidence that reduced activity of the GNE enzyme in the sialylation pathway in kidney tissue could contribute to several glomerular kidney diseases, due to the lack of the Neu5Ac terminal sugar on several kidney glycoproteins.

Three kidney diseases that affect both children and adults are minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) and membranous nephropathy (MN). These diseases are characterized by proteinuria (protein in the urine) and in the case of FSGS, a tendency to progressive scarring of the glomerulus (the filtering units of the kidneys) that leads to end-stage kidney disease. Several therapies are available for these diseases, but these therapies do not provide lasting reduction in proteinuria for many subjects and there can be severe side-effects.

There is now substantial pre-clinical evident correlating with human kidney biopsy samples, that some patients with MCD, FSGS or MN have kidney sialic acid insufficiency on their glomerular proteins. ManNAc therapy may increase sialic acid production and subsequently increase sialylation of glomerular proteins.

References

  1. Comb, D. G.; Roseman, S (1960). "The sialic acids. I. The structure and enzymatic synthesis of N-acetylneuraminic acid". Journal of Biological Chemistry. 235 (9): 2529–2537. doi:10.1016/S0021-9258(19)76908-7. PMID 13811398.
  2. Blayer, S.; Woodley, J.; Dawson, M; Lilly, M. (1999). "Alkaline biocatalysis for the direct synthesis of N-acetyl-D-neuraminic acid (Neu5Ac) from N-acetyl-D-glucosamine (GlcNAc)". Biotechnology and Bioengineering. 66 (2): 131–6 and references cited within. doi:10.1002/(sici)1097-0290(1999)66:2<131::aid-bit6>3.0.co;2-x. PMID 10567071.
  3. Bodner, R; Marcellino, B; Severino, A; Smenton, A; Rojas, C (2015). "Alpha-N-acetylmannosamine (ManNAc) synthesis via rhodium(II)-catalyzed oxidative cyclization of glucal 3-carbamates". Journal of Organic Chemistry. 70 (10): 3988–96. doi:10.1021/jo0500129. PMID 15876087.
  4. "New Zealand Pharmaceuticals Ltd". 2015.
  5. Yorke, S (2013). "The application of N-acetylmannosamine to the mammalian cell culture production of recombinant human glycoproteins". Chemistry in New Zealand (January): 18–20.
  6. Keppler, O; Hinderlich, S; Langner, J; Schwartz-Albiez, R; Reutter, W; Pawlita, M (1999). "UDP-GlcNAc 2-epimerase: a regulator of cell surface sialylation". Science. 284 (5418): 1372–6. doi:10.1126/science.284.5418.1372. PMID 10334995.
  7. Gu, X; Wang, D (1998). "Improvement of interferon-gamma sialylation in Chinese hamster ovary cell culture by feeding of N-acetylmannosamine". Biotechnology and Bioengineering. 58 (6): 642–8. doi:10.1002/(sici)1097-0290(19980620)58:6<642::aid-bit10>3.3.co;2-a. PMID 10099302.
  8. Weiss, P; Ashwell, G (1989). "The asialoglycoprotein receptor: properties and modulation by ligand". Progress in Clinical and Biological Research. 300: 169–84. PMID 2674962.
  9. Yorke, S. "ManNAc and Glycoprotein Production Review".
  10. Patzel, K; Yardeni, T; Le Poëc-Celic, E; Leoyklang, P; Dorward, H; Alonzi, D; Kukushkin, N; Xu, B; Zhang, Y; Sollogoub, M; Blériot, Y; Gahl, W; Huizing, M; Butters (2014). "Non-specific accumulation of glycosphingolipids in GNE myopathy". Journal of Inherited Metabolic Disease. 37 (2): –297–308. doi:10.1007/s10545-013-9655-6. PMC 3979983. PMID 24136589.
  11. Huizing, M; Krasnewich, D (2009). "Hereditary inclusion body myopathy a decade of progress". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1792 (9): 881–7. doi:10.1016/j.bbadis.2009.07.001. PMC 2748147. PMID 19596068.
  12. FDA clinical trials database |Identifier=NCT02346461
  13. Galeano, B; Klootwijk, R; Manoli, I; Sun, M; Ciccone, C; Darvish, D; Starost, M; Zerfas, P; Hoffmann, V; Hoogstraten-Miller, S; Krasnewich, D; Gahl, W; Huizing, M (2007). "Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N-acetylmannosamine". Journal of Clinical Investigation. 117 (6): 1585–94. doi:10.1172/jci30954. PMC 1878529. PMID 17549255.
  14. Chugh, S; Macé, C; Clement, L; Del Nogal, A; Marshall, C (2014). "Angiopoietin-like 4 based therapeutics for proteinuria and kidney disease". Frontiers in Pharmacology. 5: 23. doi:10.3389/fphar.2014.00023. PMC 3933785. PMID 24611049.
  15. An FDA IND has been issued to enable a Phase 1 clinical trial to begin.
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