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:||Biosynthesis → Carbohydrates Biosynthesis → Sugars Biosynthesis → Sugar Nucleotides Biosynthesis → CMP-sugar Biosynthesis → CMP-N-acetylneuraminate Biosynthesis|
Expected Taxonomic Range: Eukaryota
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
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 [Wang08c] (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, Zhao06d, 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 220.127.116.11 through EC 18.104.22.168. 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
Unification Links: KEGG:map00530
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
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