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MetaCyc Pathway: CMP-N-acetylneuraminate biosynthesis I (eukaryotes)
Traceable author statement to experimental support

Enzyme View:

Pathway diagram: CMP-N-acetylneuraminate biosynthesis I (eukaryotes)

Note: a dashed line (without arrowheads) between two compound names is meant to imply that the two names are just different instantiations of the same compound -- i.e. one may be a specific name and the other a general name, or they may both represent the same compound in different stages of a polymerization-type pathway. This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Synonyms: CMP-N-acetylneuraminic acid biosynthesis I (eukaryotes)

Superclasses: BiosynthesisCarbohydrates BiosynthesisSugars BiosynthesisSugar Nucleotides BiosynthesisCMP-sugar BiosynthesisCMP-N-acetylneuraminate Biosynthesis

Some taxa known to possess this pathway include : Homo sapiens, Mus musculus, Rattus norvegicus

Expected Taxonomic Range: Eukaryota

General Background

Sialic acids are a family of polyhydroxylated α-keto acids that contain nine carbon atoms. Most sialic acids are derivatives of N-acetylneuraminate or 2-keto-3-deoxy-D-glycero-D-galacto-nononate (KDN). N-acetylneuraminate is the most common sialic acid in mammals (this pathway), while KDN is abundant in lower vertebrates (see pathway CMP-2-keto-3-deoxy-D-glycero-D-galacto-nononate biosynthesis). Their core structures can be modified at the hydroxyl groups, lactonized, or hydroxylated at the acetamido group, generating many derivatives. CMP-N-glycoloyl-β-neuraminate is a derivative of CMP-N-acetyl-β-neuraminate (see pathway CMP-N-glycoloylneuraminate biosynthesis). Reviewed in [Tanner05, Inoue06, Koles08] and [Angata02].

Sialic acids are found mainly in vertebrates and a few higher invertebrates (ascidians and echinoderms). These acidic sugars are usually the terminal sugar residue in the glycan chains of vertebrate glycoconjugates (mostly glycoproteins and glycolipids, but also proteoglycans and glycosylphosphatidylinositol anchors). They function in mediating cellular recognition and adhesion events for many important processes such as development, the immune and inflammatory responses, and oncogenesis. Sialic acid occurs rarely in invertebrates. Endogenous sialylation has been shown to occur in Drosophila , but details of sialic acid biosynthesis in this organism remain to be determined [Koles08]. However, it is possible the sialic acids might be biosynthesized by other eukaryotes in a species and/or life cycle-dependent manner. In [Schneckenburger94] and reviewed in [Tanner05, Inoue06, Koles08] and [Angata02].

Most bacteria do not biosynthesize sialic acids, but some pathogenic, or symbiotic bacteria biosynthesize sialic acids as a means of evading a host's immune system (see pathway CMP-N-acetylneuraminate biosynthesis II (bacteria)). The sialic acid is displayed on the bacterial cell surface (in capsular polysaccharides) in order to mimic mammalian cells. Pathogens that biosynthesize sialic acids include Neisseria meningitidis, Escherichia coli K1 and Campylobacter jejuni. In addition, the human gut symbiont Bacteroides thetaiotaomicron has been shown to synthesize 2-keto-3-deoxy-D-glycero-D-galacto-nononate [Wang08a] (see pathway CMP-2-keto-3-deoxy-D-glycero-D-galacto-nononate biosynthesis). Whether or not archaea contain sialic acids remains to be determined. Reviewed in [Tanner05, Inoue06, Koles08] and [Angata02]. Other sialic acid-like sugars biosynthesized by bacteria include the nonulosonic acids 5,7-diacetamido-3,5,7,9-tetradeoxy-L-glycero-α-L-manno-nonulosonate [Schoenhofen06] (see pathway CMP-pseudaminate biosynthesis) and legionaminic acid [Glaze08].

Protists are thought to lack the ability to biosynthesize sialic acids although more genome data are needed to confirm this. Sialic acids have been thought to be absent in plants but some studies raise the possibility [Bakker08]. Fungi appear to lack any known sialic acid biosynthetic pathway, although strain-specific, or novel pathways could exist. Reviewed in [Tanner05, Inoue06, Koles08] and [Angata02]. Also see superpathway of CMP-sialic acids biosynthesis.

About This Pathway

In both animals (this pathway) and bacteria (see pathway CMP-N-acetylneuraminate biosynthesis II (bacteria)) N-acetylneuraminate biosynthesis begins with the conversion of UDP-N-acetyl-α-D-glucosamine to N-acetyl-β-D-mannosamine. This reaction involves both an inversion of stereochemistry at C-2 of the sugar moiety and hydrolysis of the glycosidic phosphate bond. In animals N-acetyl-β-D-mannosamine is then phosphorylated to its 6-phosphate derivative. Condensation with phosphoenolpyruvate then forms N-acetyl-β-neuraminate 9-phosphate, a distinctive biosynthetic step. After dephosphorylation to N-acetylneuraminate, CTP is used to generate the activated form of sialic acid, CMP-N-acetyl-β-neuraminate. This step is in contrast to activation of other vertebrate monosaccharides, the activated forms of which use uridine or guanine dinucleotides. The CMP-activated form is the sialic acid donor for glycoconjugates. In contrast, in the bacterial pathway N-acetyl-β-D-mannosamine is not phosphorylated, but is converted to N-acetylneuraminate directly by condensation with phosphoenolpyruvate. This is followed by formation of the activated form CMP-N-acetyl-β-neuraminate. Reviewed in [Tanner05, Inoue06, Koles08] and [Angata02].

In animal cells, N-acetylneuraminate is biosynthesized in the cytosol. However, its CMP derivative, CMP-N-acetyl-β-neuraminate, is formed in the nucleus, enters the cytosol and is then transported into the golgi apparatus by a golgi CMP-sialic acid transporter [Lim08, Zhao06c, Eckhardt96]. In the golgi lumen CMP-N-acetyl-β-neuraminate serves as a sialic acid donor for sialyltransferases in the formation of glycoconjugates. For examples of sialyltransferases see EC through EC CMP-N-acetyl-β-neuraminate can also be hydroxylated to CMP-N-glycoloyl-β-neuraminate by the cytidine monophosphate-N-acetylneuraminate hydroxylase system and transferred to glycoconjugates (as shown in the pathway link). Reviewed in [Tanner05, Inoue06] and [Koles08].

In mammals the first two reactions are catalyzed by a bifunctinal enzyme that catalyzes the rate-limiting steps in sialic acid biosynthesis. The supply of N-acetylneuraminate is regulated through feedback inhibition by CMP-N-acetyl-β-neuraminate [Hinderlich97]. Reviewed in [Tanner05, Inoue06] and [Koles08].

Superpathways: superpathway of CMP-sialic acids biosynthesis

Variants: CMP-N-acetylneuraminate biosynthesis II (bacteria)

Unification Links: KEGG:map00530

Created 19-Feb-2009 by Fulcher CA, SRI International


Angata02: Angata T, Varki A (2002). "Chemical diversity in the sialic acids and related alpha-keto acids: an evolutionary perspective." Chem Rev 102(2);439-69. PMID: 11841250

Bakker08: Bakker H, Routier F, Ashikov A, Neumann D, Bosch D, Gerardy-Schahn R (2008). "A CMP-sialic acid transporter cloned from Arabidopsis thaliana." Carbohydr Res 343(12);2148-52. PMID: 18258224

Cox02: Cox AD, Hood DW, Martin A, Makepeace KM, Deadman ME, Li J, Brisson JR, Moxon ER, Richards JC (2002). "Identification and structural characterization of a sialylated lacto-N-neotetraose structure in the lipopolysaccharide of Haemophilus influenzae." Eur J Biochem 269(16);4009-19. PMID: 12180977

Eckhardt96: Eckhardt M, Muhlenhoff M, Bethe A, Gerardy-Schahn R (1996). "Expression cloning of the Golgi CMP-sialic acid transporter." Proc Natl Acad Sci U S A 93(15);7572-6. PMID: 8755516

Ghaderi07: Ghaderi D, Strauss HM, Reinke S, Cirak S, Reutter W, Lucka L, Hinderlich S (2007). "Evidence for dynamic interplay of different oligomeric states of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase by biophysical methods." J Mol Biol 369(3);746-58. PMID: 17448495

Glaze08: Glaze PA, Watson DC, Young NM, Tanner ME (2008). "Biosynthesis of CMP-N,N'-diacetyllegionaminic acid from UDP-N,N'-diacetylbacillosamine in Legionella pneumophila." Biochemistry 47(10);3272-82. PMID: 18275154

Hinderlich97: Hinderlich S, Stasche R, Zeitler R, Reutter W (1997). "A bifunctional enzyme catalyzes the first two steps in N-acetylneuraminic acid biosynthesis of rat liver. Purification and characterization of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase." J Biol Chem 272(39);24313-8. PMID: 9305887

Hood99: Hood DW, Makepeace K, Deadman ME, Rest RF, Thibault P, Martin A, Richards JC, Moxon ER (1999). "Sialic acid in the lipopolysaccharide of Haemophilus influenzae: strain distribution, influence on serum resistance and structural characterization." Mol Microbiol 33(4);679-92. PMID: 10447878

Inoue06: Inoue S, Kitajima K (2006). "KDN (deaminated neuraminic acid): dreamful past and exciting future of the newest member of the sialic acid family." Glycoconj J 23(5-6);277-90. PMID: 16897172

Koles08: Koles K, Repnikova E, Pavlova G, Korochkin LI, Panin VM (2008). "Sialylation in protostomes: a perspective from Drosophila genetics and biochemistry." Glycoconj J. PMID: 18568399

Lim08: Lim SF, Lee MM, Zhang P, Song Z (2008). "The Golgi CMP-sialic acid transporter: A new CHO mutant provides functional insights." Glycobiology 18(11);851-60. PMID: 18713811

Schneckenburger94: Schneckenburger P, Shaw L, Schauer R (1994). "Purification, characterization and reconstitution of CMP-N-acetylneuraminate hydroxylase from mouse liver." Glycoconj J 11(3);194-203. PMID: 7841794

Schoenhofen06: Schoenhofen IC, McNally DJ, Brisson JR, Logan SM (2006). "Elucidation of the CMP-pseudaminic acid pathway in Helicobacter pylori: synthesis from UDP-N-acetylglucosamine by a single enzymatic reaction." Glycobiology 16(9);8C-14C. PMID: 16751642

Severi05: Severi E, Randle G, Kivlin P, Whitfield K, Young R, Moxon R, Kelly D, Hood D, Thomas GH (2005). "Sialic acid transport in Haemophilus influenzae is essential for lipopolysaccharide sialylation and serum resistance and is dependent on a novel tripartite ATP-independent periplasmic transporter." Mol Microbiol 58(4);1173-85. PMID: 16262798

Severi08: Severi E, Muller A, Potts JR, Leech A, Williamson D, Wilson KS, Thomas GH (2008). "Sialic acid mutarotation is catalysed by the Escherichia coli beta -propeller protein YJHT." J Biol Chem 283(8):4841-9. PMID: 18063573

Tanner05: Tanner ME (2005). "The enzymes of sialic acid biosynthesis." Bioorg Chem 33(3);216-28. PMID: 15888312

Wang08a: Wang L, Lu Z, Allen KN, Mariano PS, Dunaway-Mariano D (2008). "Human symbiont Bacteroides thetaiotaomicron synthesizes 2-keto-3-deoxy-D-glycero-D- galacto-nononic acid (KDN)." Chem Biol 15(9);893-7. PMID: 18804026

Zhao06c: Zhao W, Chen TL, Vertel BM, Colley KJ (2006). "The CMP-sialic acid transporter is localized in the medial-trans Golgi and possesses two specific endoplasmic reticulum export motifs in its carboxyl-terminal cytoplasmic tail." J Biol Chem 281(41);31106-18. PMID: 16923816

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Banerjee69: Banerjee S, Ghosh S (1969). "Purification and properties of N-acetylmannosamine kinase from Salmonella typhimurium." Eur J Biochem 8(2);200-6. PMID: 4889177

Benie04: Benie AJ, Blume A, Schmidt RR, Reutter W, Hinderlich S, Peters T (2004). "Characterization of ligand binding to the bifunctional key enzyme in the sialic acid biosynthesis by NMR: II. Investigation of the ManNAc kinase functionality." J Biol Chem 279(53);55722-7. PMID: 15498763

Blume02: Blume A, Chen H, Reutter W, Schmidt RR, Hinderlich S (2002). "2',3'-Dialdehydo-UDP-N-acetylglucosamine inhibits UDP-N-acetylglucosamine 2-epimerase, the key enzyme of sialic acid biosynthesis." FEBS Lett 521(1-3);127-32. PMID: 12067740

Blume04: Blume A, Ghaderi D, Liebich V, Hinderlich S, Donner P, Reutter W, Lucka L (2004). "UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, functionally expressed in and purified from Escherichia coli, yeast, and insect cells." Protein Expr Purif 35(2);387-96. PMID: 15135418

Blume04a: Blume A, Benie AJ, Stolz F, Schmidt RR, Reutter W, Hinderlich S, Peters T (2004). "Characterization of ligand binding to the bifunctional key enzyme in the sialic acid biosynthesis by NMR: I. Investigation of the UDP-GlcNAc 2-epimerase functionality." J Biol Chem 279(53);55715-21. PMID: 15498764

Chen02c: Chen H, Blume A, Zimmermann-Kordmann M, Reutter W, Hinderlich S (2002). "Purification and characterization of N-acetylneuraminic acid-9-phosphate synthase from rat liver." Glycobiology 12(2);65-71. PMID: 11886839

Chou03: Chou WK, Hinderlich S, Reutter W, Tanner ME (2003). "Sialic acid biosynthesis: stereochemistry and mechanism of the reaction catalyzed by the mammalian UDP-N-acetylglucosamine 2-epimerase." J Am Chem Soc 125(9);2455-61. PMID: 12603133

Effertz99: Effertz K, Hinderlich S, Reutter W (1999). "Selective loss of either the epimerase or kinase activity of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase due to site-directed mutagenesis based on sequence alignments." J Biol Chem 274(40);28771-8. PMID: 10497249

Eisenberg01: Eisenberg I, Avidan N, Potikha T, Hochner H, Chen M, Olender T, Barash M, Shemesh M, Sadeh M, Grabov-Nardini G, Shmilevich I, Friedmann A, Karpati G, Bradley WG, Baumbach L, Lancet D, Asher EB, Beckmann JS, Argov Z, Mitrani-Rosenbaum S (2001). "The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy." Nat Genet 29(1);83-7. PMID: 11528398

Fujita05: Fujita A, Sato C, Munster-Kuhnel AK, Gerardy-Schahn R, Kitajima K (2005). "Development of a simple and efficient method for assaying cytidine monophosphate sialic acid synthetase activity using an enzymatic reduced nicotinamide adenine dinucleotide/oxidized nicotinamide adenine dinucleotide converting system." Anal Biochem 337(1);12-21. PMID: 15649371

Fujita07: Fujita A, Sato C, Kitajima K (2007). "Identification of the nuclear export signals that regulate the intracellular localization of the mouse CMP-sialic acid synthetase." Biochem Biophys Res Commun 355(1);174-80. PMID: 17292865

Galeano07: Galeano B, Klootwijk R, Manoli I, Sun M, Ciccone C, Darvish D, Starost MF, Zerfas PM, Hoffmann VJ, Hoogstraten-Miller S, Krasnewich DM, Gahl WA, Huizing M (2007). "Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N-acetylmannosamine." J Clin Invest 117(6);1585-94. PMID: 17549255

Hao06: Hao J, Vann WF, Hinderlich S, Sundaramoorthy M (2006). "Elimination of 2-keto-3-deoxy-D-glycero-D-galacto-nonulosonic acid 9-phosphate synthase activity from human N-acetylneuraminic acid 9-phosphate synthase by a single mutation." Biochem J 397(1);195-201. PMID: 16503877

Horstkorte99: Horstkorte R, Nohring S, Wiechens N, Schwarzkopf M, Danker K, Reutter W, Lucka L (1999). "Tissue expression and amino acid sequence of murine UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase." Eur J Biochem 260(3);923-7. PMID: 10103025

Kean04: Kean EL, Munster-Kuhnel AK, Gerardy-Schahn R (2004). "CMP-sialic acid synthetase of the nucleus." Biochim Biophys Acta 1673(1-2);56-65. PMID: 15238249

Krapp03: Krapp S, Munster-Kuhnel AK, Kaiser JT, Huber R, Tiralongo J, Gerardy-Schahn R, Jacob U (2003). "The crystal structure of murine CMP-5-N-acetylneuraminic acid synthetase." J Mol Biol 334(4);625-37. PMID: 14636592

Krause05: Krause S, Hinderlich S, Amsili S, Horstkorte R, Wiendl H, Argov Z, Mitrani-Rosenbaum S, Lochmuller H (2005). "Localization of UDP-GlcNAc 2-epimerase/ManAc kinase (GNE) in the Golgi complex and the nucleus of mammalian cells." Exp Cell Res 304(2);365-79. PMID: 15748884

Larion07: Larion M, Moore LB, Thompson SM, Miller BG (2007). "Divergent evolution of function in the ROK sugar kinase superfamily: role of enzyme loops in substrate specificity." Biochemistry 46(47);13564-72. PMID: 17979299

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Lawrence00: Lawrence SM, Huddleston KA, Pitts LR, Nguyen N, Lee YC, Vann WF, Coleman TA, Betenbaugh MJ (2000). "Cloning and expression of the human N-acetylneuraminic acid phosphate synthase gene with 2-keto-3-deoxy-D-glycero- D-galacto-nononic acid biosynthetic ability." J Biol Chem 275(23);17869-77. PMID: 10749855

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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