Sialic acid metabolism (Homo sapiens)

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43, 463, 39, 478, 284, 9, 35, 44, 526, 5343152, 5, 10, 16, 20...2, 5, 10, 16, 20...40, 42437, 27, 4818, 25, 26, 41, 45...22431113, 30, 361, 14, 17, 19, 23...12, 21, 24, 38, 514343Golgi lumenlysosomal lumencytosolnucleoplasmST3GAL1-6glycoconjugatesH2ONPL tetramerCMPPEPGal-R ST6GALNAC3 NEU2 substratesNeu5Ac-2,8-Neu5Ac-R ST8SIA1-6H2OCMP-Neu5AcST6GAL2 CMPST8SIA3 Neu5Ac-RST3GAL6 H2OSLC17A5UDPNeu5Ac-2,8-Neu5Ac-R Neu5Ac-2,8-Neu5Ac-R ST8SIA2 ST6GAL1,2ST3GAL3 GalNAc-RNeu5Ac-2,3-Gal-R Neu5Ac-2,3-Gal-R Neu5Ac-2,6-GalNAc-R ST8SIA6 ST3GAL2 Neu5Ac, Neu5GcUDP-GlcNAcST6GALNAC2 Mg2+ Neu5Ac-2,6-Gal-R glycoconjugatesGalNAc-R ManNAc NEU2Neu5Ac-2,6-GalNAc-R PiST6GALNAC5 Neu5Ac-2,3-Gal-R Neu5Ac-2,8-Neu5Ac-RGal-RSLC35A1Neu5Ac-2,3-Gal-R Neu5Ac-R Neu5Ac-2,8-Neu5Ac-R ST6GALNAC6 Neu5Ac-2,3-Gal-R Neu5Ac-2,8-Neu5Ac-R ManNGc ST6GALNAC1-6Neu5Ac-2,6-GalNAc-R Neu5Ac-2,6-GalNAc-R Neu5AcH2ONANP Neu5Ac glycoconjugatesST6GALNAC4 Neu5Ac-2,3-Gal-R CTSA(29-326) Neu5Ac-2,6-GalNAc-R CTPST6GAL1 Neu5Ac-9-PST3GAL4 PYRNeu5Gc ST8SIA4 Neu5AcST8SIA1 Neu5Ac-2,3-Gal-RNeu5Ac-2,6-Gal-RManNAc-6-PGalNAc-R CMAS Gal-R,GalNAc-R,Neu5Ac-RNANSNeu5Ac-2,6-Gal-R ST3GAL5 Neu5Ac-2,8-Neu5Ac-R NANP:Mg2+Neu5Ac-R H2OGal-R,GalNAc-R,Neu5Ac-RGNE hexamerH+ADPH2ONeu5AcNEU3Neu5Ac-2,6-GalNAc-R ManNAc,ManNGcNEU4 CTSA(327-480) NEU1,4 substratesCMP-Neu5AcCMAS tetramerPiCMP-Neu5AcGal-R NEU1 ST3GAL1 Neu5Ac-2,8-Neu5Ac-R Gal-R CMPST8SIA5 Neu5Ac-2,3-Gal-R PPiNEU1:GLB1:CTSA,NEU4GNE Neu5Ac-R ATPCMPNeu5Ac-2,6-Gal-R GLB1 NEU3 substratesNeu5Ac-2,6-Gal-R Neu5Ac-2,6-GalNAc-RNPL Neu5AcNeu5Ac-2,6-Gal-R H+Neu5Ac-2,6-Gal-R Gal-R, Neu5Ac-RST6GALNAC1 ManNAcNeu5Acglycoconjugates


Description

Sialic acids are a family of 9 carbon alpha-keto acids that are usually present in the non reducing terminal of glycoconjuates on the cell surface of eukaryotic cells. These sialylated conjugates play important roles in cell recognition and signaling, neuronal development, cancer metastasis and bacterial or viral infection. More than 50 forms of sialic acid are found in nature, the most abundant being N-acetylneuraminic acid (Neu5Ac, N-acetylneuraminate) (Li & Chen 2012, Wickramasinghe & Medrano 2011). The steps below describe the biosynthesis, transport, utilization and degradation of Neu5Ac in humans. View original pathway at:Reactome.

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Bibliography

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History

View all...
CompareRevisionActionTimeUserComment
114949view16:47, 25 January 2021ReactomeTeamReactome version 75
113393view11:46, 2 November 2020ReactomeTeamReactome version 74
112598view15:57, 9 October 2020ReactomeTeamReactome version 73
101514view11:37, 1 November 2018ReactomeTeamreactome version 66
101050view21:19, 31 October 2018ReactomeTeamreactome version 65
100581view19:53, 31 October 2018ReactomeTeamreactome version 64
100130view16:38, 31 October 2018ReactomeTeamreactome version 63
99680view15:08, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99273view12:45, 31 October 2018ReactomeTeamreactome version 62
93742view13:33, 16 August 2017ReactomeTeamreactome version 61
93256view11:18, 9 August 2017ReactomeTeamreactome version 61
87197view10:26, 19 July 2016EgonwOntology Term : 'classic metabolic pathway' added !
86334view09:15, 11 July 2016ReactomeTeamreactome version 56
83354view10:56, 18 November 2015ReactomeTeamVersion54
81514view13:03, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
CMAS ProteinQ8NFW8 (Uniprot-TrEMBL)
CMAS tetramerComplexR-HSA-4085413 (Reactome)
CMP-Neu5AcMetaboliteCHEBI:16556 (ChEBI)
CMPMetaboliteCHEBI:17361 (ChEBI)
CTPMetaboliteCHEBI:17677 (ChEBI)
CTSA(29-326) ProteinP10619 (Uniprot-TrEMBL)
CTSA(327-480) ProteinP10619 (Uniprot-TrEMBL)
GLB1 ProteinP16278 (Uniprot-TrEMBL)
GNE ProteinQ9Y223 (Uniprot-TrEMBL)
GNE hexamerComplexR-HSA-3781918 (Reactome)
Gal-R MetaboliteCHEBI:61248 (ChEBI)
Gal-R, Neu5Ac-RComplexR-ALL-4088103 (Reactome)
Gal-R,GalNAc-R,Neu5Ac-RComplexR-ALL-4087987 (Reactome)
Gal-R,GalNAc-R,Neu5Ac-RComplexR-ALL-4088123 (Reactome)
Gal-RMetaboliteCHEBI:61248 (ChEBI)
GalNAc-R MetaboliteCHEBI:21507 (ChEBI)
GalNAc-RMetaboliteCHEBI:21507 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
ManNAc MetaboliteCHEBI:17122 (ChEBI)
ManNAc,ManNGcComplexR-ALL-4088099 (Reactome)
ManNAc-6-PMetaboliteCHEBI:28273 (ChEBI)
ManNAcMetaboliteCHEBI:17122 (ChEBI)
ManNGc MetaboliteCHEBI:28255 (ChEBI)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
NANP ProteinQ8TBE9 (Uniprot-TrEMBL)
NANP:Mg2+ComplexR-HSA-4085395 (Reactome)
NANSProteinQ9NR45 (Uniprot-TrEMBL)
NEU1 ProteinQ99519 (Uniprot-TrEMBL)
NEU1,4 substratesComplexR-ALL-4087983 (Reactome)
NEU1:GLB1:CTSA,NEU4ComplexR-HSA-4088186 (Reactome)
NEU2 substratesComplexR-ALL-4088071 (Reactome)
NEU2ProteinQ9Y3R4 (Uniprot-TrEMBL)
NEU3 substratesComplexR-ALL-4088088 (Reactome)
NEU3ProteinQ9UQ49 (Uniprot-TrEMBL)
NEU4 ProteinQ8WWR8 (Uniprot-TrEMBL)
NPL ProteinQ9BXD5 (Uniprot-TrEMBL)
NPL tetramerComplexR-HSA-4088083 (Reactome)
Neu5Ac MetaboliteCHEBI:17012 (ChEBI)
Neu5Ac, Neu5GcComplexR-ALL-4088096 (Reactome)
Neu5Ac-2,3-Gal-R MetaboliteCHEBI:75127 (ChEBI)
Neu5Ac-2,3-Gal-RMetaboliteCHEBI:75127 (ChEBI)
Neu5Ac-2,6-Gal-R MetaboliteCHEBI:75129 (ChEBI)
Neu5Ac-2,6-Gal-RMetaboliteCHEBI:75129 (ChEBI)
Neu5Ac-2,6-GalNAc-R MetaboliteCHEBI:62634 (ChEBI)
Neu5Ac-2,6-GalNAc-RMetaboliteCHEBI:62634 (ChEBI)
Neu5Ac-2,8-Neu5Ac-R MetaboliteCHEBI:75130 (ChEBI)
Neu5Ac-2,8-Neu5Ac-RMetaboliteCHEBI:75130 (ChEBI)
Neu5Ac-9-PMetaboliteCHEBI:27438 (ChEBI)
Neu5Ac-R MetaboliteCHEBI:75133 (ChEBI)
Neu5Ac-RMetaboliteCHEBI:75133 (ChEBI)
Neu5AcMetaboliteCHEBI:17012 (ChEBI)
Neu5Gc MetaboliteCHEBI:29025 (ChEBI)
PEPMetaboliteCHEBI:18021 (ChEBI)
PPiMetaboliteCHEBI:29888 (ChEBI)
PYRMetaboliteCHEBI:32816 (ChEBI)
PiMetaboliteCHEBI:18367 (ChEBI)
SLC17A5ProteinQ9NRA2 (Uniprot-TrEMBL)
SLC35A1ProteinP78382 (Uniprot-TrEMBL)
ST3GAL1 ProteinQ11201 (Uniprot-TrEMBL)
ST3GAL1-6ComplexR-HSA-4086290 (Reactome)
ST3GAL2 ProteinQ16842 (Uniprot-TrEMBL)
ST3GAL3 ProteinQ11203 (Uniprot-TrEMBL)
ST3GAL4 ProteinQ11206 (Uniprot-TrEMBL)
ST3GAL5 ProteinQ9UNP4 (Uniprot-TrEMBL)
ST3GAL6 ProteinQ9Y274 (Uniprot-TrEMBL)
ST6GAL1 ProteinP15907 (Uniprot-TrEMBL)
ST6GAL1,2ComplexR-HSA-975904 (Reactome)
ST6GAL2 ProteinQ96JF0 (Uniprot-TrEMBL)
ST6GALNAC1 ProteinQ9NSC7 (Uniprot-TrEMBL)
ST6GALNAC1-6ComplexR-HSA-4086259 (Reactome)
ST6GALNAC2 ProteinQ9UJ37 (Uniprot-TrEMBL)
ST6GALNAC3 ProteinQ8NDV1 (Uniprot-TrEMBL)
ST6GALNAC4 ProteinQ9H4F1 (Uniprot-TrEMBL)
ST6GALNAC5 ProteinQ9BVH7 (Uniprot-TrEMBL)
ST6GALNAC6 ProteinQ969X2 (Uniprot-TrEMBL)
ST8SIA1 ProteinQ92185 (Uniprot-TrEMBL)
ST8SIA1-6ComplexR-HSA-4086295 (Reactome)
ST8SIA2 ProteinQ92186 (Uniprot-TrEMBL)
ST8SIA3 ProteinO43173 (Uniprot-TrEMBL)
ST8SIA4 ProteinQ92187 (Uniprot-TrEMBL)
ST8SIA5 ProteinO15466 (Uniprot-TrEMBL)
ST8SIA6 ProteinP61647 (Uniprot-TrEMBL)
UDP-GlcNAcMetaboliteCHEBI:16264 (ChEBI)
UDPMetaboliteCHEBI:17659 (ChEBI)
glycoconjugatesComplexR-ALL-4088200 (Reactome)
glycoconjugatesComplexR-ALL-4088202 (Reactome)
glycoconjugatesComplexR-ALL-4088208 (Reactome)
glycoconjugatesComplexR-ALL-4088213 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-4085028 (Reactome)
ATPR-HSA-4085028 (Reactome)
CMAS tetramermim-catalysisR-HSA-4084982 (Reactome)
CMP-Neu5AcArrowR-HSA-4084982 (Reactome)
CMP-Neu5AcArrowR-HSA-4084990 (Reactome)
CMP-Neu5AcArrowR-HSA-727807 (Reactome)
CMP-Neu5AcR-HSA-4084978 (Reactome)
CMP-Neu5AcR-HSA-4084980 (Reactome)
CMP-Neu5AcR-HSA-4084984 (Reactome)
CMP-Neu5AcR-HSA-4084990 (Reactome)
CMP-Neu5AcR-HSA-4085033 (Reactome)
CMP-Neu5AcR-HSA-727807 (Reactome)
CMPArrowR-HSA-4084978 (Reactome)
CMPArrowR-HSA-4084980 (Reactome)
CMPArrowR-HSA-4084984 (Reactome)
CMPArrowR-HSA-4085033 (Reactome)
CMPArrowR-HSA-727807 (Reactome)
CMPR-HSA-727807 (Reactome)
CTPR-HSA-4084982 (Reactome)
GNE hexamermim-catalysisR-HSA-4085021 (Reactome)
GNE hexamermim-catalysisR-HSA-4085028 (Reactome)
Gal-R, Neu5Ac-RArrowR-HSA-4084994 (Reactome)
Gal-R,GalNAc-R,Neu5Ac-RArrowR-HSA-4084999 (Reactome)
Gal-R,GalNAc-R,Neu5Ac-RArrowR-HSA-4085029 (Reactome)
Gal-RR-HSA-4084984 (Reactome)
Gal-RR-HSA-4085033 (Reactome)
GalNAc-RR-HSA-4084980 (Reactome)
H+ArrowR-HSA-428585 (Reactome)
H+R-HSA-428585 (Reactome)
H2OR-HSA-4084976 (Reactome)
H2OR-HSA-4084989 (Reactome)
H2OR-HSA-4084994 (Reactome)
H2OR-HSA-4084999 (Reactome)
H2OR-HSA-4085021 (Reactome)
H2OR-HSA-4085029 (Reactome)
ManNAc,ManNGcArrowR-HSA-4085217 (Reactome)
ManNAc-6-PArrowR-HSA-4085028 (Reactome)
ManNAc-6-PR-HSA-4084976 (Reactome)
ManNAcArrowR-HSA-4085021 (Reactome)
ManNAcR-HSA-4085028 (Reactome)
NANP:Mg2+mim-catalysisR-HSA-4084989 (Reactome)
NANSmim-catalysisR-HSA-4084976 (Reactome)
NEU1,4 substratesR-HSA-4084999 (Reactome)
NEU1:GLB1:CTSA,NEU4mim-catalysisR-HSA-4084999 (Reactome)
NEU2 substratesR-HSA-4085029 (Reactome)
NEU2mim-catalysisR-HSA-4085029 (Reactome)
NEU3 substratesR-HSA-4084994 (Reactome)
NEU3mim-catalysisR-HSA-4084994 (Reactome)
NPL tetramermim-catalysisR-HSA-4085217 (Reactome)
Neu5Ac, Neu5GcR-HSA-4085217 (Reactome)
Neu5Ac-2,3-Gal-RArrowR-HSA-4084984 (Reactome)
Neu5Ac-2,6-Gal-RArrowR-HSA-4085033 (Reactome)
Neu5Ac-2,6-GalNAc-RArrowR-HSA-4084980 (Reactome)
Neu5Ac-2,8-Neu5Ac-RArrowR-HSA-4084978 (Reactome)
Neu5Ac-9-PArrowR-HSA-4084976 (Reactome)
Neu5Ac-9-PR-HSA-4084989 (Reactome)
Neu5Ac-RR-HSA-4084978 (Reactome)
Neu5AcArrowR-HSA-4084989 (Reactome)
Neu5AcArrowR-HSA-4084994 (Reactome)
Neu5AcArrowR-HSA-4084999 (Reactome)
Neu5AcArrowR-HSA-4085020 (Reactome)
Neu5AcArrowR-HSA-4085029 (Reactome)
Neu5AcArrowR-HSA-428585 (Reactome)
Neu5AcR-HSA-4084982 (Reactome)
Neu5AcR-HSA-4085020 (Reactome)
Neu5AcR-HSA-428585 (Reactome)
PEPR-HSA-4084976 (Reactome)
PPiArrowR-HSA-4084982 (Reactome)
PYRArrowR-HSA-4085217 (Reactome)
PiArrowR-HSA-4084976 (Reactome)
PiArrowR-HSA-4084989 (Reactome)
R-HSA-4084976 (Reactome) Sialic acid synthase (NANS, SAS) can convert N-acetylmannosamine 6-phosphate (ManNAc-6-P) to N-acetylneuraminate 9-phosphate (Neu5Ac-9-P) (Lawrence et al. 2000). NANS shows lower activity towards ManNAc and can convert it to Neu5Ac (not shown here, Lawrence et al. 2000).
R-HSA-4084978 (Reactome) The alpha-2,8-sialyltransferases 1-6 (ST8SIA1-6) are involved in the production of gangliosides, glycoproteins and glycolipids. They transfer N-acetylneuraminate (Neu5Ac) to terminal Neu5Ac-yl groups of these glycoconjugates (Nakayama et al. 1996, Scheidegger et al. 1995, Lee et al. 1998, Angata et al. 2001, Kim et al. 1997). Once sialylated, glycoconjugates translocate to the plasma membrane by an unknown mechanism. For simplicity, Neu5Ac-R is shown in a generic form where R represents other sugars O-linked to proteins which can result in a large variability in glycoconjugate structures.
R-HSA-4084980 (Reactome) The alpha-2,6-sialyltransferases 1-6 (ST6GALNAC1-6) are able to transfer a sialic acid (Neu5Ac) moiety to the terminal N-acetylgalactosaminyl (GalNAc-R) residue of O-glycosylated proteins, glycoproteins and some gangliosides. Neu5Ac is added to GalNAc-R via an alpha-2,6 linkage (Ikehara et al. 1999, Samyn-Petit et al, 2000, Harduin-Lepers et al. 2000, Tsuchida et al. 2003, Senda et al. 2007). Once sialylated, glycoconjugates translocate to the plasma membrane by an unknown mechanism. For simplicity, GalNAc-R is shown in a generic form where R represents other sugars O-linked to proteins which can result in a large variability in glycoconjugate structures.
R-HSA-4084982 (Reactome) Cytidine Monophosphate N-Acetylneuraminic Acid Synthetase1 (CMAS) transfers cytidine 5-monophosphate from a CTP donor to N-acetylneuraminate (Neu5Ac) to form CMP-Neu5Ac. CMAS is ubiquitously expressed and localizes to the nucleus in mammalian cells. The active form of the enzyme is a homotetramer (a dimer of dimers) (Lawrence et al. 2001, Huizing 2005). CMP-Neu5Ac is the donor substrate for sialyltransferases.
R-HSA-4084984 (Reactome) The alpha-2,3-sialyltransferases 1-6 (ST3GAL1-6) are able to transfer a sialic acid (Neu5Ac) moiety to the terminal galactosyl (Gal-R) residue of O-glycosylated proteins and some gangliosides. Neu5Ac is added to Gal-R via an alpha-2,3 linkage (Shang et al. 1999, Kim et al. 1996, Kitagawa & Paulson 1993, Basu et al. 1993, Ishii et al. 1998, Okajima et al. 1999). Once sialylated, glycoconjugates translocate to the plasma membrane by an unknown mechanism. For simplicity, Gal is shown in a generic form where R represents other sugars O-linked to proteins which can result in a large variability in glycoconjugate structures.
R-HSA-4084989 (Reactome) N-acylneuraminate 9-phosphatase (NANP) dephosphorylates N-acetylneuraminate -9-phosphate (Neu5Ac-9-P) to produce N-acetylneuraminate (Neu5Ac). NANP requires Mg2+ as a cofactor (Maliekal et al. 2006).
R-HSA-4084990 (Reactome) Once CMP-N-acetylneuraminate (CMP-Neu5Ac) is formed, it leaves the nucleus through nuclear pores to be further modified or used in conjugation reactions in the Golgi apparatus (Li & Chen 2012). The mechanism of translocation is unknown.
R-HSA-4084994 (Reactome) Sialidases 1-4 (NEU1-4, neuraminidases, receptor-destroying enzymes, RDEs) hydrolyze sialic acids (N-acetylneuraminic acid, Neu5Ac) to produce asialo compounds, a step in the degradation process of glycoproteins and gangliosides and are expressed in a variety of cellular locations. NEU3 localizes to the plasma membrane and hydrolyses Neu5Ac especially from gangliosides with alpha2,3- or alpha2,8-linkages present in the lipid bilayer (Wada et al. 1999, Monti et al. 2000). By regulating the composition of the lipid bilayer, NEU3 has been identified as an important regulator of trans-membrane signaling (Miyagi et al. 2008).
R-HSA-4084999 (Reactome) Sialidases 1-4 (NEU1-4, neuraminidases, receptor-destroying enzymes, RDEs) hydrolyse sialic acids (N-acetylneuraminic acid, Neu5Ac) to produce asialo compounds, a step in the degradation process of glycoproteins and gangliosides and are expressed in a variety of cellular locations. NEU4 is an extrinsic membrane protein associated with lysosomes, mitochondria and endoplasmic reticulum. It has broad sialidase activity against glycoconjugates with alpha2,3-, alpha2,6- or alpha2,8-linkages (Bigi et al. 2010, Monti et al. 2004, Seyrantepe et al. 2004). NEU1 (lysosomal sialidase) hydrolyses Neu5Ac from glycoconjugates with alpha2,3-, alpha2,6- or alpha2,8-linked terminal sialated residues in the lysosomal lumen. NEU1 is active in a multienzyme complex comprising cathepsin A protective protein (CTSA) and beta-galactosidase (Bonten et al. 1996, Rudenko et al. 1995). Defects in NEU1 cause Sialidosis (MIM:256550), a lysosomal storage disorder manifesting as type I (late-onset) or type II (earlier-onset) (Bonten et al. 1996). CTSA is thought to exert a protective function necessary for stability and activity of these enzymes (Galjart et al. 1988). Defects in CTSA are the cause of galactosialidosis (GSL; MIM:256540) (Zhou et al. 1991).
R-HSA-4085020 (Reactome) N-acetylneuraminate (Neu5Ac) translocates to the nucleus through nuclear pores to be converted to CMP-Neu5Ac. The mechanism of translocation is unknown (Li & Chen 2012).
R-HSA-4085021 (Reactome) UDP-N-acetylglucosamine 2-epimerase, N-acetylmannosamine kinase (GNE) is a bifunctional enzyme in the cytosol that is involved in the first two critical, rate-limiting steps of sialic acid (Neu5Ac, N-acetylneuraminic acid) biosynthesis, a main constituent of glycoconjugates. Because Neu5Ac is found at terminal positions of glycoconjugates, this molecule is involved in most cell-cell or cell-extracellular matrix interactions, serving as recognition sites. Thus, Neu5Ac plays critical roles in health and disease. In the first reaction, GNE hydrolyses and epimerises UDP-N-acetylglucosamine (UDP-GlcNAc) to N-acetylmannosamine (ManNAc) (Lucka et al. 1999, Keppler et al. 1999).

There are various disorders associated with defects in the GNE gene. Defects in GNE can cause sialuria (MIM:269921), an inborn error of metabolism characterised by cytoplasmic accumulation and increased urinary excretion of Neu5Ac (Seppala et al. 1999). Mutations causing sialuria are R266W, R266Q and R263L (Seppala et al. 1999). Defects in GNE can also cause hereditary inclusion body myopathy (IBM2; MIM:600737), an autosomal recessive neuromuscular disorder characterised by adult-onset, progressive distal and proximal muscle weakness and wastage. Muscle pathology shows rimmed vacuoles and filamentous inclusions (Eisenberg et al. 2001). The common M712T mutation can cause IBM2, as well as heterozygosity with the mutation M171V (Eisenberg et al. 2001, Argov et al. 2003, Broccolini et al. 2002). Defects in GNE can also cause Nonaka myopathy (NM; MIM:605820), an early adulthood-onset muscular disorder characterised by weakness and wastage of the lower limbs and rimmed vacuoles (Nonaka et al. 1981, Eisenberg et al. 2001). Mutations causing NK include the common V572L, either homozygous or heterozygous with C303V (Tomimitsu et al. 2002, Kayashima et al. 2002) and the heterozygous M712T with A631V indicated that NK and IBM2 are allelic, if not identical, disorders (Tomimitsu et al. 2004).
R-HSA-4085028 (Reactome) UDP N acetylglucosamine 2 epimerase, N acetylmannosamine kinase (GNE) is a bifunctional enzyme in the cytosol that is involved in the first two critical, rate limiting steps of sialic acid (Neu5Ac, N acetylneuraminic acid) biosynthesis. In the second reaction, GNE phosphorylates N-acetylmannosamine (ManNAc) to ManNAc-6-P. There are various disorders associated with defects in the GNE gene. Defects in GNE can cause sialuria (MIM:269921), an inborn error of metabolism characterised by cytoplasmic accumulation and increased urinary excretion of Neu5Ac (Seppala et al. 1999). Mutations causing sialuria are R266W, R266Q and R263L (Seppala et al. 1999). Defects in GNE can also cause hereditary inclusion body myopathy (IBM2; MIM:600737), an autosomal recessive neuromuscular disorder characterised by adult-onset, progressive distal and proximal muscle weakness and wastage. Muscle pathology shows rimmed vacuoles and filamentous inclusions (Eisenberg et al. 2001). The common M712T mutation can cause IBM2, as well as heterozygosity with the mutation M171V (Eisenberg et al. 2001, Argov et al. 2003, Broccolini et al. 2002). Defects in GNE can also cause Nonaka myopathy (NM; MIM:605820), an early adulthood-onset muscular disorder characterised by weakness and wastage of the lower limbs and rimmed vacuoles (Nonaka et al. 1981, Eisenberg et al. 2001). Mutations causing NK include the common V572L, either homozygous or heterozygous with C303V (Tomimitsu et al. 2002, Kayashima et al. 2002) and the heterozygous M712T with A631V indicated that NK and IBM2 are allelic, if not identical, disorders (Tomimitsu et al. 2004).
R-HSA-4085029 (Reactome) Sialidases 1-4 (NEU1-4, neuraminidases, receptor-destroying enzymes, RDEs) hydrolyze sialic acids (N-acetylneuraminic acid, Neu5Ac) to produce asialo compounds, a step in the degradation process of glycoproteins and gangliosides and are expressed in a variety of cellular locations. NEU2 (cytosolic sialidase) hydrolyzes Neu5Ac from glycoconjugates with alpha2,3-, alpha2,6- or alpha2,8-linked terminal sialated residues in the cytosol (Monti et al. 1999, Chavas et al. 2005).
R-HSA-4085033 (Reactome) The beta-galactoside alpha-2,6-sialyltransferases 1 and 2 (ST6GAL1,2) are able to transfer a sialic acid (Neu5Ac) moiety to the terminal galactosyl (Gal-R) residue of O-glycosylated proteins and some gangliosides. Neu5Ac is added to Gal-R via an alpha-2,6 linkage (Wu et al. 2011, Takashima et al. 2002, Krzewinski-Recchi et al. 2003). Once sialylated, glycoconjugates translocate to the plasma membrane by an unknown mechanism. For simplicity, Gal is shown in a generic form where R represents other sugars O-linked to proteins. Highest activity is observed toward oligosaccharides that have the Gal-beta-1,4-GlcNAc sequence at the non-reducing end of their carbohydrate groups.
R-HSA-4085217 (Reactome) Once in the cytosol, sialic acids are either reutilized or degraded. N-acetylneuraminate lyase (NPL) is a cytosolic, tetrameric enzyme that can cleave the major sialic acids N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc) to form N-acetylmannosamine (ManNAc) and N-glycolylmannosamine (ManNGc) respectively (Wu et al. 2005). Although humans cannot form Neu5Gc due to a non-functional CMAHP enzyme, Neu5Gc can be ingested by dietary means and must therefore be degraded to avoid accumulation of this immunoreactive sialic acid (Bergfeld et al. 2012).
R-HSA-4088205 (Reactome) Glycoconjugates have to translocate to the cytosol for degradation by cytosol-specific sialidase 2 (NEU2). The mechanism of translocation is unknown but could simply be by diffusion (Li & Chen 2012).
R-HSA-4088207 (Reactome) Once glycoconjugates are sialylated, they translocate to the plasma membrane to carry out their various functions. The mechanism of translocation is unknown (Li & Chen 2012).
R-HSA-4088210 (Reactome) Glycoconjugates have to translocate to the lysosomal lumen for degradation by lysosomal-specific sialidases 1 and 4 (NEU1,4). The mechanism of translocation is unknown but could simply be by diffusion (Li & Chen 2012).
R-HSA-428585 (Reactome) SLC17A5 encodes a lysosomal sialic acid transporter, Sialin (AST, membrane glycoprotein HP59) (Verheijen et al. 1999, Fu et al. 2001). SLC17A5 exports sialic acid (N-acetylneuraminic acid, Neu5Ac) which is derived from the degradation of glycoconjugates. This export is dependent on the proton electrochemical gradient across the lysosomal membrane. SLC17A5 is present in the pathological tumor vasculature of the lung, breast, colon, and ovary, but not in the normal vasculature, suggesting that the protein may be critical to pathological angiogenesis. Sialin is not expressed in a variety of normal tissues, but is significantly expressed in human fetal lung. Defects in SLC17A5 cause Salla disease (SD) and infantile sialic acid storage disorder (ISSD aka N-acetylneuraminic acid storage disease, NSD). These belong to the sialic acid storage disease (SASD) group and are autosomal recessive neurodegenerative disorders characterised by hypotonia, cerebellar ataxia and mental retardation in very young infants (Verheijen et al. 1999, Aula et al. 2000).
R-HSA-727807 (Reactome) The human gene SLC35A1 encodes the CMP-sialic acid transporter which mediates the antiport of CMP-sialic acid (CMP-Neu5Ac) into the Golgi lumen in exchange for CMP (Ishida et al. 1996). Defects in SLC35A1 are the cause of congenital disorder of glycosylation type 2F (CDG2F; MIM:603585). CDGs are a family of severe inherited diseases caused by a defect in protein N-glycosylation (Martinez-Duncker et al. 2005).
SLC17A5mim-catalysisR-HSA-428585 (Reactome)
SLC35A1mim-catalysisR-HSA-727807 (Reactome)
ST3GAL1-6mim-catalysisR-HSA-4084984 (Reactome)
ST6GAL1,2mim-catalysisR-HSA-4085033 (Reactome)
ST6GALNAC1-6mim-catalysisR-HSA-4084980 (Reactome)
ST8SIA1-6mim-catalysisR-HSA-4084978 (Reactome)
UDP-GlcNAcR-HSA-4085021 (Reactome)
UDPArrowR-HSA-4085021 (Reactome)
glycoconjugatesArrowR-HSA-4088205 (Reactome)
glycoconjugatesArrowR-HSA-4088207 (Reactome)
glycoconjugatesArrowR-HSA-4088210 (Reactome)
glycoconjugatesR-HSA-4088205 (Reactome)
glycoconjugatesR-HSA-4088207 (Reactome)
glycoconjugatesR-HSA-4088210 (Reactome)
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