| Revision as of 10:59, 29 July 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Script assisted update of identifiers from ChemSpider, CommonChemistry and FDA for the Chem/Drugbox validation project - Updated: ChEMBL.← Previous edit |
Latest revision as of 13:46, 19 July 2024 edit undoJWBE (talk | contribs)Extended confirmed users10,111 edits added Category:Acetyl compounds using HotCat |
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{{chembox |
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{{chembox |
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| verifiedrevid = 400319057 |
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| verifiedrevid = 442022210 |
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| Name=''N''-Acetylmannosamine |
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| Name =''N''-Acetylmannosamine |
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| ImageFile = Alfa-D-manosamina.png |
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| ImageFile = Alpha N-acetylmannosamine.svg |
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| ImageSize = 150px |
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| ImageSize = 250px |
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| IUPACName = 2-(Acetylamino)-2-deoxy-β-D-mannopyranose |
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| IUPACName = 2-(Acetylamino)-2-deoxy-β-D-mannopyranose |
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| OtherNames = |
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| OtherNames = |
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| Section1 = {{Chembox Identifiers |
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|Section1={{Chembox Identifiers |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 9271300 |
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| ChemSpiderID = 9271300 |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL = 1210906 |
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| ChEMBL = 1231391 |
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| 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 |
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| 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 |
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| InChIKey = OVRNDRQMDRJTHS-OZRXBMAMBC |
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| InChIKey = OVRNDRQMDRJTHS-OZRXBMAMBC |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = OVRNDRQMDRJTHS-OZRXBMAMSA-N |
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| StdInChIKey = OVRNDRQMDRJTHS-OZRXBMAMSA-N |
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| CASNo_Ref = {{cascite|correct|??}} |
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| CASNo = 7772-94-3 |
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| CASNo = 7772-94-3 |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| PubChem = 11096158 |
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| UNII = 88J1ZMR63L |
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| SMILES = O1O(CO)(O)(O)1NC(C)=O |
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| PubChem = 11096158 |
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| SMILES = O1O(CO)(O)(O)1NC(C)=O |
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| Section2 = {{Chembox Properties |
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|Section2={{Chembox Properties |
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| C=8 | H=15 | N=1 | O=6 |
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| Formula = C<sub>8</sub>H<sub>15</sub>NO<sub>6</sub> |
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| MolarMass = 221.21 g/mol |
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| MolarMass = 221.21 g/mol |
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| MeltingPt = 118-121 °C |
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| MeltingPtC = 118 to 121 |
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'''''N''-Acetylmannosamine''' is a ] involved in a range of metabolic processes. It is an ]/] that consists of ]s, ]s and ]s, and is used for the synthesis of ]. |
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'''''N''-Acetylmannosamine''' is a hexosamine ]. 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). |
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ManNAc is the first committed biological precursor of ] (Neu5Ac, ]) (Figure 1). Sialic acids are the negatively charged, terminal monosaccharides of carbohydrate chains that are attached to ] and ] (glycans). |
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== Biological role of ManNAc == |
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==External links== |
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ManNAc is the first committed biological precursor of ]. |
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The initiation of ] biosynthesis occurs in the ]. The main substrate for this pathway is ], which is derived from ]. 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. |
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{{DEFAULTSORT:Acetylmannosamine, N-}} |
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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. |
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==Synthesis== |
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There are several ways in which ManNAc can be synthesised and three examples follow. |
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# By aldolase treatment of sialic acid.<ref name="1-Roseman 1960">{{cite journal|year=1960 |last1=Comb |first1=D. G. |last2=Roseman |first2=S |title=The sialic acids. I. The structure and enzymatic synthesis of N-acetylneuraminic acid |issue=9 |pages=2529–2537 |journal=Journal of Biological Chemistry |volume=235 |doi=10.1016/S0021-9258(19)76908-7 |pmid=13811398 |doi-access=free }}</ref> to produce ManNAc and pyruvic acid. |
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# By base catalysed epimerization of N-acetyl glucosamine.<ref name="2-Blayer 1999">{{cite journal |last1=Blayer |first1=S. |last2=Woodley |first2=J. |last3=Dawson |first3=M |last4=Lilly |first4=M. |year=1999 |title=Alkaline biocatalysis for the direct synthesis of N-acetyl-D-neuraminic acid (Neu5Ac) from N-acetyl-D-glucosamine (GlcNAc) |journal=Biotechnology and Bioengineering |volume=66 |issue=2 | pages=131–6 and references cited within |pmid=10567071 |doi=10.1002/(sici)1097-0290(1999)66:2<131::aid-bit6>3.0.co;2-x}}</ref> |
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# By rhodium (II)-catalyzed oxidative cyclization of glucal 3-carbamates.<ref name="3-Bodner 2015">{{cite journal |pmid=15876087 |year=2015 |last1=Bodner |first1=R |last2=Marcellino |first2=B |last3=Severino |first3=A |last4=Smenton |first4=A |last5=Rojas |first5=C |title=Alpha-N-acetylmannosamine (ManNAc) synthesis via rhodium(II)-catalyzed oxidative cyclization of glucal 3-carbamates | journal=Journal of Organic Chemistry |volume= 70|issue=10 |pages=3988–96 |doi=10.1021/jo0500129}}</ref> |
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ManNAc is now manufactured in large quantities by New Zealand Pharmaceuticals Ltd,<ref name="NZP 2015">{{cite web |year=2015 |title=New Zealand Pharmaceuticals Ltd |url=http://www.nzp.co.nz/index.php/products/carbohydrates/n-acetyl-d-mannosamine-mannac-2.html }}</ref> in a commercial process from N-acetylglucosamine. |
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==Uses== |
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{{organic-compound-stub}} |
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===Sialylation of recombinant proteins=== |
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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.<ref name="5-Yorke 2013">{{cite journal |last1=Yorke |first1=S |year=2013 |title=The application of N-acetylmannosamine to the mammalian cell culture production of recombinant human glycoproteins |journal= Chemistry in New Zealand |issue=January |pages=18–20 }}</ref> Keppler et al.<ref name="6-Keppler 1999">{{cite journal |pmid=10334995 |year=1999 |last1=Keppler |first1=O |last2=Hinderlich |first2=S |last3=Langner |first3=J |last4=Schwartz-Albiez |first4=R |last5=Reutter |first5=W |last6=Pawlita |first6=M |title=UDP-GlcNAc 2-epimerase: a regulator of cell surface sialylation |journal=Science |volume=284 |issue=5418 |pages=1372–6 |doi=10.1126/science.284.5418.1372}}</ref> 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.<ref name="7-Gu 1998">{{cite journal |pmid=10099302 |last1=Gu |first1=X |last2=Wang |first2=D |year=1998 |title=Improvement of interferon-gamma sialylation in Chinese hamster ovary cell culture by feeding of N-acetylmannosamine |journal=Biotechnology and Bioengineering |volume=58 |issue=6 |pages=642–8 |doi=10.1002/(sici)1097-0290(19980620)58:6<642::aid-bit10>3.3.co;2-a}}</ref> 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 <ref name="8-Weiss 1989">{{cite journal |last1=Weiss |first1=P |last2=Ashwell |first2=G |year=1989 |title=The asialoglycoprotein receptor: properties and modulation by ligand |journal=Progress in Clinical and Biological Research |volume=300 |pages=169–84 |pmid=2674962}}</ref> to the therapeutic glycoprotein.<ref name="9-Yorke 2013">{{cite web |last1=Yorke |first1=S |title=ManNAc and Glycoprotein Production Review |url=http://www.nzp.co.nz/index.php/component/content/article/7-news/113-mannac-and-glycoprotein-production-review.html}}</ref> |
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===Therapeutic potential=== |
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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. |
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===GNE myopathy=== |
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The disease ] is manifested as progressive muscle weakness. GNE myopathy is a rare genetic disorder caused by hyposialylated muscle proteins and glycosphingolipids<ref name="10-Patzel 2014">{{cite journal |pmid=24136589 | last1=Patzel |first1=K |last2=Yardeni |first2=T |last3=Le Poëc-Celic |first3=E |last4=Leoyklang |first4=P |last5=Dorward |first5=H |last6=Alonzi |first6=D |last7=Kukushkin |first7=N |last8=Xu |first8=B |last9=Zhang |first9=Y |last10=Sollogoub |first10=M |last11=Blériot |first11=Y |last12=Gahl |first12=W |last13=Huizing |first13=M |last14=Butters |year=2014 |title=Non-specific accumulation of glycosphingolipids in GNE myopathy |journal=Journal of Inherited Metabolic Disease |volume=37 |issue=2 |pages=–297–308 |doi=10.1007/s10545-013-9655-6 |pmc=3979983}}</ref> because there is insufficient metabolic ManNAc to form the Neu5Ac terminal sugar. There is no available therapy<ref name="11-Huizing 2009">{{cite journal |last1=Huizing |first1=M |last2=Krasnewich |first2=D |year=2009 |title= Hereditary inclusion body myopathy a decade of progress |journal=Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease |volume=1792 |issue=9 |pages=881–7 |doi=10.1016/j.bbadis.2009.07.001 |pmid=19596068 |pmc=2748147}}</ref><ref> |Identifier=NCT02346461</ref> to treat GNE myopathy. |
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===Kidney diseases=== |
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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,<ref name="12-Galeano 2007">{{cite journal |pmid=17549255 |last1=Galeano |first1=B |last2=Klootwijk |first2=R |last3=Manoli |first3=I |last4=Sun |first4=M |last5=Ciccone |first5=C |last6=Darvish |first6=D |last7=Starost |first7=M |last8=Zerfas |first8=P |last9=Hoffmann |first9=V |last10=Hoogstraten-Miller |first10=S |last11=Krasnewich |first11=D |last12=Gahl |first12=W |last13=Huizing |first13=M |year=2007 |title=Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N-acetylmannosamine |journal=Journal of Clinical Investigation |volume=117 |issue=6 |pages=1585–94 |doi=10.1172/jci30954 |pmc=1878529}}</ref><ref name="13-Chugh 2014">{{cite journal |pmid=24611049 |last1=Chugh |first1=S |last2=Macé |first2=C |last3=Clement |first3=L |last4=Del Nogal |first4=A |last5=Marshall |first5=C |year=2014 |title=Angiopoietin-like 4 based therapeutics for proteinuria and kidney disease |journal=Frontiers in Pharmacology |volume=5 |pages=23 |doi=10.3389/fphar.2014.00023 |pmc=3933785|doi-access=free }}</ref> due to the lack of the Neu5Ac terminal sugar on several kidney glycoproteins. |
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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. |
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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.<ref name="15-Clinical trial">An FDA IND has been issued to enable a Phase 1 clinical trial to begin.</ref> |
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==References== |
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{{reflist}} |
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