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MetaCyc Chimeric Pathway: superpathway of CMP-sialic acids biosynthesis

Pathway diagram: superpathway of CMP-sialic acids biosynthesis

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. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Superclasses: BiosynthesisCarbohydrates BiosynthesisSugars BiosynthesisSugar Nucleotides BiosynthesisCMP-sugar Biosynthesis

Some taxa known to possess parts of the pathway include : Aliivibrio salmonicida LFI1238, Asterias rubens, Bacteroides thetaiotaomicron, Campylobacter jejuni, Escherichia coli K1, Homo sapiens, Mus musculus, Neisseria meningitidis, Oncorhynchus mykiss, Rattus norvegicus, Sus scrofa

Expected Taxonomic Range: Bacteria , Eukaryota

Note: This is a chimeric pathway, comprising reactions from multiple organisms, and typically will not occur in its entirety in a single organism. The taxa listed here are likely to catalyze only subsets of the reactions depicted in this pathway.

Please note: This pathway does not represent a single organism. Rather, it is a superpathway assembled from pathways found in a variety of organisms. Its purpose is to provide an overview of the diversity of ways that organisms can biosynthesize sialic acids and their CMP-derivatives.

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 (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 [Wang08d] (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].

Subpathways: CMP-N-acetylneuraminate biosynthesis I (eukaryotes), CMP-N-acetylneuraminate biosynthesis II (bacteria), CMP-N-glycoloylneuraminate biosynthesis, CMP-2-keto-3-deoxy-D-glycero-D-galacto-nononate biosynthesis, CMP-N-acetyl-7-O-acetylneuraminate biosynthesis

Created 02-Mar-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

Cox02a: 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

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

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

Wang08d: 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

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

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

Annunziato95: Annunziato PW, Wright LF, Vann WF, Silver RP (1995). "Nucleotide sequence and genetic analysis of the neuD and neuB genes in region 2 of the polysialic acid gene cluster of Escherichia coli K1." J Bacteriol 177(2);312-9. PMID: 7814319

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

Campbell00: Campbell RE, Mosimann SC, Tanner ME, Strynadka NC (2000). "The structure of UDP-N-acetylglucosamine 2-epimerase reveals homology to phosphoglycosyl transferases." Biochemistry 39(49);14993-5001. PMID: 11106477

Chen02e: 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

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

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

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

Giese05: 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

Gunawan05: Gunawan J, Simard D, Gilbert M, Lovering AL, Wakarchuk WW, Tanner ME, Strynadka NC (2005). "Structural and mechanistic analysis of sialic acid synthase NeuB from Neisseria meningitidis in complex with Mn2+, phosphoenolpyruvate, and N-acetylmannosaminitol." J Biol Chem 280(5);3555-63. PMID: 15516336

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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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