N-Acetylmannosamine

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N-Acetylmannosamine
Alpha N-acetylmannosamine.svg
Names
IUPAC name
2-(Acetylamino)-2-deoxy-β-D-mannopyranose
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.127.007 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • 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/s1 Yes check.svgY
    Key: OVRNDRQMDRJTHS-OZRXBMAMSA-N Yes check.svgY
  • 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/s1
    Key: OVRNDRQMDRJTHS-OZRXBMAMBC
  • O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1NC(C)=O
Properties
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 [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

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).

Contents

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

ManNAc is now manufactured in large quantities by New Zealand Pharmaceuticals Ltd, [4] 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. [5] Keppler et al. [6] 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. [7] 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 [8] to the therapeutic glycoprotein. [9]

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 [formerly known as hereditary Inclusion Body Myopathy (HIBM), and Distal Myopathy with Rimmed Vacuoles (DMRV)] is manifested as progressive muscle weakness. GNE myopathy is a rare genetic disorder caused by hyposialylated muscle proteins and glycosphingolipids [10] because there is insufficient metabolic ManNAc to form the Neu5Ac terminal sugar. There is no available therapy [11] [12] 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, [13] [14] 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. [15]

Related Research Articles

<span class="mw-page-title-main">Glycoprotein</span> Protein with oligosaccharide modifications

Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. Secreted extracellular proteins are often glycosylated.

<span class="mw-page-title-main">Sialic acid</span> Class of keto acid sugars

Sialic acids are a class of alpha-keto acid sugars with a nine-carbon backbone. The term "sialic acid" was first introduced by Swedish biochemist Gunnar Blix in 1952. The most common member of this group is N-acetylneuraminic acid found in animals and some prokaryotes.

<span class="mw-page-title-main">Glycosaminoglycan</span> Polysaccharides found in animal tissue

Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units. The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case of the sulfated glycosaminoglycan keratan, where, in place of the uronic sugar there is a galactose unit. GAGs are found in vertebrates, invertebrates and bacteria. Because GAGs are highly polar molecules and attract water; the body uses them as lubricants or shock absorbers.

<span class="mw-page-title-main">Ganglioside</span> Class of chemical compounds

A ganglioside is a molecule composed of a glycosphingolipid with one or more sialic acids linked on the sugar chain. NeuNAc, an acetylated derivative of the carbohydrate sialic acid, makes the head groups of gangliosides anionic at pH 7, which distinguishes them from globosides.

Hereditary inclusion body myopathies (HIBM) are a group of rare genetic disorders which have different symptoms. Generally, they are neuromuscular disorders characterized by muscle weakness developing in young adults. Hereditary inclusion body myopathies comprise both autosomal recessive and autosomal dominant muscle disorders that have a variable expression (phenotype) in individuals, but all share similar structural features in the muscles.

<span class="mw-page-title-main">Tunicamycin</span> Chemical compound

Tunicamycin is a mixture of homologous nucleoside antibiotics that inhibits the UDP-HexNAc: polyprenol-P HexNAc-1-P family of enzymes. In eukaryotes, this includes the enzyme GlcNAc phosphotransferase (GPT), which catalyzes the transfer of N-acetylglucosamine-1-phosphate from UDP-N-acetylglucosamine to dolichol phosphate in the first step of glycoprotein synthesis. Tunicamycin blocks N-linked glycosylation (N-glycans) and treatment of cultured human cells with tunicamycin causes cell cycle arrest in G1 phase. It is used as an experimental tool in biology, e.g. to induce unfolded protein response. Tunicamycin is produced by several bacteria, including Streptomyces clavuligerus and Streptomyces lysosuperificus.

<span class="mw-page-title-main">UDP-glucose 4-epimerase</span> Class of enzymes

The enzyme UDP-glucose 4-epimerase, also known as UDP-galactose 4-epimerase or GALE, is a homodimeric epimerase found in bacterial, fungal, plant, and mammalian cells. This enzyme performs the final step in the Leloir pathway of galactose metabolism, catalyzing the reversible conversion of UDP-galactose to UDP-glucose. GALE tightly binds nicotinamide adenine dinucleotide (NAD+), a co-factor required for catalytic activity.

<span class="mw-page-title-main">UDP-N-acetylglucosamine 2-epimerase</span> Class of enzymes

In enzymology, an UDP-N-acetylglucosamine 2-epimerase is an enzyme that catalyzes the chemical reaction

Nucleotide sugars are the activated forms of monosaccharides. Nucleotide sugars act as glycosyl donors in glycosylation reactions. Those reactions are catalyzed by a group of enzymes called glycosyltransferases.

In enzymology, a beta-galactoside alpha-2,6-sialyltransferase is an enzyme that catalyzes the chemical reaction

In enzymology, a glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase is an enzyme that catalyzes the chemical reaction

In enzymology, a polypeptide N-acetylgalactosaminyltransferase is an enzyme that catalyzes the chemical reaction

In enzymology, an UDP-N-acetylglucosamine—dolichyl-phosphate N-acetylglucosaminephosphotransferase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">GNE (gene)</span> Protein-coding gene in humans

Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase is an enzyme that in humans is encoded by the GNE gene.

<span class="mw-page-title-main">RENBP</span> Mammalian protein found in Homo sapiens

N-acylglucosamine 2-epimerase is an enzyme that in humans is encoded by the RENBP gene.

<span class="mw-page-title-main">DPAGT1</span> Protein-coding gene in the species Homo sapiens

UDP-N-acetylglucosamine—dolichyl-phosphate N-acetylglucosaminephosphotransferase is an enzyme that in humans is encoded by the DPAGT1 gene.

O-linked glycosylation is the attachment of a sugar molecule to the oxygen atom of serine (Ser) or threonine (Thr) residues in a protein. O-glycosylation is a post-translational modification that occurs after the protein has been synthesised. In eukaryotes, it occurs in the endoplasmic reticulum, Golgi apparatus and occasionally in the cytoplasm; in prokaryotes, it occurs in the cytoplasm. Several different sugars can be added to the serine or threonine, and they affect the protein in different ways by changing protein stability and regulating protein activity. O-glycans, which are the sugars added to the serine or threonine, have numerous functions throughout the body, including trafficking of cells in the immune system, allowing recognition of foreign material, controlling cell metabolism and providing cartilage and tendon flexibility. Because of the many functions they have, changes in O-glycosylation are important in many diseases including cancer, diabetes and Alzheimer's. O-glycosylation occurs in all domains of life, including eukaryotes, archaea and a number of pathogenic bacteria including Burkholderia cenocepacia, Neisseria gonorrhoeae and Acinetobacter baumannii.

Alpha-1,6-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase is an enzyme with systematic name UDP-N-acetyl-D-glucosamine:2,6-bis(N-acetyl-beta-D-glucosaminyl)-alpha-D-mannosyl-glycoprotein 4-beta-N-acetyl-D-glucosaminyltransferase. This enzyme catalyses the following chemical reaction

Protein <i>O</i>-GlcNAc transferase Protein-coding gene in the species Homo sapiens

Protein O-GlcNAc transferase also known as OGT or O-linked N-acetylglucosaminyltransferase is an enzyme that in humans is encoded by the OGT gene. OGT catalyzes the addition of the O-GlcNAc post-translational modification to proteins.

UDP-N-acetylglucosamine 2-epimerase (hydrolysing) (EC 3.2.1.183, UDP-N-acetylglucosamine 2-epimerase, GNE (gene), siaA (gene), neuC (gene)) is an enzyme with systematic name UDP-N-acetyl-alpha-D-glucosamine hydrolase (2-epimerising). This enzyme catalyses the following chemical reaction

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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