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MetaCyc Pathway: CMP-2-keto-3-deoxy-D-glycero-D-galacto-nononate biosynthesis
Inferred from experimentTraceable author statement to experimental support

Enzyme View:

Pathway diagram: CMP-2-keto-3-deoxy-D-glycero-D-galacto-nononate biosynthesis

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-2-keto-3-deoxy-D-glycero-D-galacto-nononic acid biosynthesis, CMP-3-deoxy-D-glycero-D-galacto-nonulosonic acid biosynthesis, CMP-3-deoxy-D-glycero-D-galacto-nonulosonate biosynthesis, CMP-KDN biosynthesis

Superclasses: BiosynthesisCarbohydrates BiosynthesisSugars BiosynthesisSugar Nucleotides BiosynthesisCMP-sugar Biosynthesis

Some taxa known to possess this pathway include : Bacteroides thetaiotaomicron VPI-5482, Oncorhynchus mykiss

Expected Taxonomic Range: Bacteria , 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 (see pathway CMP-N-acetylneuraminate biosynthesis I (eukaryotes)), while KDN is abundant in lower vertebrates (this pathway). 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] (this pathway). 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

The natural occurrence of the deaminated sialic acid 2-keto-3-deoxy-D-glycero-D-galacto-nononate (deaminated neuraminate) was discovered in 1986 ( [Nadano86] and reviewed in [Inoue06]). It is abundant in extracellular glycoconjugates of lower vertebrates such as fish and amphibians and has been well studied in Oncorhynchus mykiss (rainbow trout).

2-keto-3-deoxy-D-glycero-D-galacto-nononate has also been found in mammalian cells and tissues, but in two to three orders of magnitude lower amounts, and mostly as free monosaccharide. Studies with a monoclonal antibody that recognizes 2-keto-3-deoxy-D-glycero-D-galacto-nononate-containing sequences in glycoproteins have shown immunoreactive protein in mammalian tissues, but the presence of 2-keto-3-deoxy-D-glycero-D-galacto-nononate was not confirmed by chemical analysis. In addition, it has been reported that in vitro, human recombinant sialic acid synthase expressed in insect cells can utilize either N-acetyl-D-mannosamine 6-phosphate or α-D-mannose 6-phosphate to synthesize N-acetyl-β-neuraminate 9-phosphate, or 2-keto-3-deoxy-D-glycero-D-galacto-nononate 9-phosphate, respectively. However, it had a much higher efficiency for production of N-acetyl-β-neuraminate 9-phosphate [Lawrence00]. Mutagenesis studies showed that the human 2-keto-3-deoxy-D-glycero-D-galacto-nononate 9-phosphate synthase activity can be eliminated by a single point mutation [Hao06]. In contrast, the mouse N-acetylneuraminate 9-phosphate synthase cannot use α-D-mannose 6-phosphate as substrate. The human CMP-sialic acid synthase shows a broad substrate specificity that includes 2-keto-3-deoxy-D-glycero-D-galacto-nononate. It appears that further work is needed to confirm the biosynthesis and significance of CMP-2-keto-3-deoxy-D-glycero-D-galacto-nononate in mammals. Reviewed in [Tanner05, Inoue06, Koles08] and [Angata02].

In bacteria, 2-keto-3-deoxy-D-glycero-D-galacto-nononate has been reported to occur in the bacterial capsular polysaccharides of the human pathogen Klebsiella ozaenae serotype K4, the human intestinal symbiont Bacteroides thetaiotaomicron VPI-5482 [Wang08a] the plant symbiont Sinorhizobium fredii strain SVQ293, and the cell wall polymers of the plant pathogen Streptomyces sp. MB-8. It appears to have a role in the bacterial-host interaction. Reviewed in [Tanner05, Inoue06, Koles08] and [Angata02].

The biosynthetic pathway for 2-keto-3-deoxy-D-glycero-D-galacto-nononate is hypothesized to be similar to that of N-acetylneuraminate biosynthesis in eukaryotes (see pathway CMP-N-acetylneuraminate biosynthesis I (eukaryotes)). No evidence for direct conversion of N-acetylneuraminate to 2-keto-3-deoxy-D-glycero-D-galacto-nononate has been reported. Enzymes supporting this pathway have been characterized and in some cases may also be N-acetylneuraminate biosynthesizing enzymes. α-D-mannose 6-phosphate is the key precursor for 2-keto-3-deoxy-D-glycero-D-galacto-nononate, although its formation from D-mannose remains hypothetical. α-D-mannose 6-phosphate can be formed in the cytosol from β-D-fructofuranose 6-phosphate by phosphomannose isomerase (EC, or D-mannose can be transported into the cell and phosphorylated by a 6-phosphokinase. Mechanisms regulating this pathway remain to be determined. The activated product, CMP-2-keto-3-deoxy-D-glycero-D-galacto-nononate, can be used to transfer 2-keto-3-deoxy-D-glycero-D-galacto-nononate to the termini of glycoconjugates via sialyltransferases. A sialyltransferase catalyzing this reaction has been identified in Oncorhynchus mykiss [Angata94]. Reviewed in [Tanner05, Inoue06] and [Koles08].

Superpathways: superpathway of CMP-sialic acids biosynthesis

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

Angata94: Angata T, Kitazume S, Terada T, Kitajima K, Inoue S, Troy FA, Inoue Y (1994). "Identification, characterization, and developmental expression of a novel alpha 2-->8-KDN-transferase which terminates elongation of alpha 2-->8-linked oligo-polysialic acid chain synthesis in trout egg polysialoglycoproteins." Glycoconj J 11(5);493-9. PMID: 7696852

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

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

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

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

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

Nadano86: Nadano D, Iwasaki M, Endo S, Kitajima K, Inoue S, Inoue Y (1986). "A naturally occurring deaminated neuraminic acid, 3-deoxy-D-glycero-D-galacto-nonulosonic acid (KDN). Its unique occurrence at the nonreducing ends of oligosialyl chains in polysialoglycoprotein of rainbow trout eggs." J Biol Chem 261(25);11550-7. PMID: 3745155

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

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

Angata99: Angata T, Nakata D, Matsuda T, Kitajima K, Troy FA (1999). "Biosynthesis of KDN (2-keto-3-deoxy-D-glycero-D-galacto-nononic acid). Identification and characterization of a KDN-9-phosphate synthetase activity from trout testis." J Biol Chem 274(33);22949-56. PMID: 10438460

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

Giese, 2005: Giese JO, Herbers K, Hoffmann M, Klosgen RB, Sonnewald U (2005). "Isolation and functional characterization of a novel plastidic hexokinase from Nicotiana tabacum." FEBS Lett 579(3);827-31. PMID: 15670855

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

Nakata00: Nakata D, Close BE, Colley KJ, Matsuda T, Kitajima K (2000). "Molecular cloning and expression of the mouse N-acetylneuraminic acid 9-phosphate synthase which does not have deaminoneuraminic acid (KDN) 9-phosphate synthase activity." Biochem Biophys Res Commun 273(2);642-8. PMID: 10873658

Nakata01: Nakata D, Munster AK, Gerardy-Schahn R, Aoki N, Matsuda T, Kitajima K (2001). "Molecular cloning of a unique CMP-sialic acid synthetase that effectively utilizes both deaminoneuraminic acid (KDN) and N-acetylneuraminic acid (Neu5Ac) as substrates." Glycobiology 11(8);685-92. PMID: 11479279

Renz93: Renz A., Stitt M. "Substrate specificity and product inhibition of different forms of fructokinases and hexokinases in developing potato tubers." Planta (1993) 190 : 166-175.

Sebastian67: Sebastian J, Asensio C (1967). "Identification of mannokinase in Escherichia coli." Biochem Biophys Res Commun 28(2);197-202. PMID: 5342371

Sebastian72: Sebastian J, Asensio C (1972). "Purification and properties of the mannokinase from Escherichia coli." Arch Biochem Biophys 151(1);227-33. PMID: 4557975

Stoop94: Stoop J.M.H., Pharr D.M. "Growth substrate and nutrient salt environment alter mannitol-to-hexose partitioning in celery petioles." J Amer Soc Hort Sci (1994) 119(2) : 237-242.

Terada93: Terada T, Kitazume S, Kitajima K, Inoue S, Ito F, Troy FA, Inoue Y (1993). "Synthesis of CMP-deaminoneuraminic acid (CMP-KDN) using the CTP:CMP-3-deoxynonulosonate cytidylyltransferase from rainbow trout testis. Identification and characterization of a CMP-KDN synthetase." J Biol Chem 268(4);2640-8. PMID: 8381411

Terada96: Terada T, Kitajima K, Inoue S, Koppert K, Brossmer R, Inoue Y (1996). "Substrate specificity of rainbow trout testis CMP-3-deoxy-D-glycero-D-galacto-nonulosonic acid (CMP-Kdn) synthetase: kinetic studies of the reaction of natural and synthetic analogues of nonulosonic acid catalyzed by CMP-Kdn synthetase." Eur J Biochem 236(3);852-5. PMID: 8665905

Tiralongo07: Tiralongo J, Fujita A, Sato C, Kitajima K, Lehmann F, Oschlies M, Gerardy-Schahn R, Munster-Kuhnel AK (2007). "The rainbow trout CMP-sialic acid synthetase utilises a nuclear localization signal different from that identified in the mouse enzyme." Glycobiology 17(9);945-54. PMID: 17580313

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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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