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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Broccolini A, Pescatori M, D'Amico A, Sabino A, Silvestri G, Ricci E, Servidei S, Tonali PA, Mirabella M.; ''An Italian family with autosomal recessive inclusion-body myopathy and mutations in the GNE gene.''; PubMedEurope PMCScholia
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Samyn-Petit B, Krzewinski-Recchi MA, Steelant WF, Delannoy P, Harduin-Lepers A.; ''Molecular cloning and functional expression of human ST6GalNAc II. Molecular expression in various human cultured cells.''; PubMedEurope PMCScholia
Li Y, Chen X.; ''Sialic acid metabolism and sialyltransferases: natural functions and applications.''; PubMedEurope PMCScholia
Nakayama J, Fukuda MN, Hirabayashi Y, Kanamori A, Sasaki K, Nishi T, Fukuda M.; ''Expression cloning of a human GT3 synthase. GD3 AND GT3 are synthesized by a single enzyme.''; PubMedEurope PMCScholia
Wu ZL, Ethen CM, Prather B, Machacek M, Jiang W.; ''Universal phosphatase-coupled glycosyltransferase assay.''; PubMedEurope PMCScholia
Tomimitsu H, Ishikawa K, Shimizu J, Ohkoshi N, Kanazawa I, Mizusawa H.; ''Distal myopathy with rimmed vacuoles: novel mutations in the GNE gene.''; PubMedEurope PMCScholia
Kitagawa H, Paulson JC.; ''Cloning and expression of human Gal beta 1,3(4)GlcNAc alpha 2,3-sialyltransferase.''; PubMedEurope PMCScholia
Krzewinski-Recchi MA, Julien S, Juliant S, Teintenier-Lelièvre M, Samyn-Petit B, Montiel MD, Mir AM, Cerutti M, Harduin-Lepers A, Delannoy P.; ''Identification and functional expression of a second human beta-galactoside alpha2,6-sialyltransferase, ST6Gal II.''; PubMedEurope PMCScholia
Seyrantepe V, Landry K, Trudel S, Hassan JA, Morales CR, Pshezhetsky AV.; ''Neu4, a novel human lysosomal lumen sialidase, confers normal phenotype to sialidosis and galactosialidosis cells.''; PubMedEurope PMCScholia
Aula N, Salomäki P, Timonen R, Verheijen F, Mancini G, Månsson JE, Aula P, Peltonen L.; ''The spectrum of SLC17A5-gene mutations resulting in free sialic acid-storage diseases indicates some genotype-phenotype correlation.''; PubMedEurope PMCScholia
Ikehara Y, Kojima N, Kurosawa N, Kudo T, Kono M, Nishihara S, Issiki S, Morozumi K, Itzkowitz S, Tsuda T, Nishimura SI, Tsuji S, Narimatsu H.; ''Cloning and expression of a human gene encoding an N-acetylgalactosamine-alpha2,6-sialyltransferase (ST6GalNAc I): a candidate for synthesis of cancer-associated sialyl-Tn antigens.''; PubMedEurope PMCScholia
Argov Z, Eisenberg I, Grabov-Nardini G, Sadeh M, Wirguin I, Soffer D, Mitrani-Rosenbaum S.; ''Hereditary inclusion body myopathy: the Middle Eastern genetic cluster.''; PubMedEurope PMCScholia
Miyagi T, Wada T, Yamaguchi K, Hata K, Shiozaki K.; ''Plasma membrane-associated sialidase as a crucial regulator of transmembrane signalling.''; PubMedEurope PMCScholia
Bigi A, Morosi L, Pozzi C, Forcella M, Tettamanti G, Venerando B, Monti E, Fusi P.; ''Human sialidase NEU4 long and short are extrinsic proteins bound to outer mitochondrial membrane and the endoplasmic reticulum, respectively.''; PubMedEurope PMCScholia
Tomimitsu H, Shimizu J, Ishikawa K, Ohkoshi N, Kanazawa I, Mizusawa H.; ''Distal myopathy with rimmed vacuoles (DMRV): new GNE mutations and splice variant.''; PubMedEurope PMCScholia
Wu M, Gu S, Xu J, Zou X, Zheng H, Jin Z, Xie Y, Ji C, Mao Y.; ''A novel splice variant of human gene NPL, mainly expressed in human liver, kidney and peripheral blood leukocyte.''; PubMedEurope PMCScholia
Nonaka I, Sunohara N, Ishiura S, Satoyoshi E.; ''Familial distal myopathy with rimmed vacuole and lamellar (myeloid) body formation.''; PubMedEurope PMCScholia
Bergfeld AK, Pearce OM, Diaz SL, Pham T, Varki A.; ''Metabolism of vertebrate amino sugars with N-glycolyl groups: elucidating the intracellular fate of the non-human sialic acid N-glycolylneuraminic acid.''; PubMedEurope PMCScholia
Kim YJ, Kim KS, Do S, Kim CH, Kim SK, Lee YC.; ''Molecular cloning and expression of human alpha2,8-sialyltransferase (hST8Sia V).''; PubMedEurope PMCScholia
Kim YJ, Kim KS, Kim SH, Kim CH, Ko JH, Choe IS, Tsuji S, Lee YC.; ''Molecular cloning and expression of human Gal beta 1,3GalNAc alpha 2,3-sialytransferase (hST3Gal II).''; PubMedEurope PMCScholia
Verheijen FW, Verbeek E, Aula N, Beerens CE, Havelaar AC, Joosse M, Peltonen L, Aula P, Galjaard H, van der Spek PJ, Mancini GM.; ''A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases.''; PubMedEurope PMCScholia
Angata K, Yen TY, El-Battari A, Macher BA, Fukuda M.; ''Unique disulfide bond structures found in ST8Sia IV polysialyltransferase are required for its activity.''; PubMedEurope PMCScholia
Monti E, Bassi MT, Bresciani R, Civini S, Croci GL, Papini N, Riboni M, Zanchetti G, Ballabio A, Preti A, Tettamanti G, Venerando B, Borsani G.; ''Molecular cloning and characterization of NEU4, the fourth member of the human sialidase gene family.''; PubMedEurope PMCScholia
Monti E, Bassi MT, Papini N, Riboni M, Manzoni M, Venerando B, Croci G, Preti A, Ballabio A, Tettamanti G, Borsani G.; ''Identification and expression of NEU3, a novel human sialidase associated to the plasma membrane.''; PubMedEurope PMCScholia
Lawrence SM, Huddleston KA, Pitts LR, Nguyen N, Lee YC, Vann WF, Coleman TA, Betenbaugh MJ.; ''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.''; PubMedEurope PMCScholia
Monti E, Preti A, Rossi E, Ballabio A, Borsani G.; ''Cloning and characterization of NEU2, a human gene homologous to rodent soluble sialidases.''; PubMedEurope PMCScholia
Ishida N, Miura N, Yoshioka S, Kawakita M.; ''Molecular cloning and characterization of a novel isoform of the human UDP-galactose transporter, and of related complementary DNAs belonging to the nucleotide-sugar transporter gene family.''; PubMedEurope PMCScholia
Wickramasinghe S, Medrano JF.; ''Primer on genes encoding enzymes in sialic acid metabolism in mammals.''; PubMedEurope PMCScholia
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.; ''The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy.''; PubMedEurope PMCScholia
Maliekal P, Vertommen D, Delpierre G, Van Schaftingen E.; ''Identification of the sequence encoding N-acetylneuraminate-9-phosphate phosphatase.''; PubMedEurope PMCScholia
Shang J, Qiu R, Wang J, Liu J, Zhou R, Ding H, Yang S, Zhang S, Jin C.; ''Molecular cloning and expression of Galbeta1,3GalNAc alpha2, 3-sialyltransferase from human fetal liver.''; PubMedEurope PMCScholia
Tsuchida A, Okajima T, Furukawa K, Ando T, Ishida H, Yoshida A, Nakamura Y, Kannagi R, Kiso M, Furukawa K.; ''Synthesis of disialyl Lewis a (Le(a)) structure in colon cancer cell lines by a sialyltransferase, ST6GalNAc VI, responsible for the synthesis of alpha-series gangliosides.''; PubMedEurope PMCScholia
Lee YC, Kim YJ, Lee KY, Kim KS, Kim BU, Kim HN, Kim CH, Do SI.; ''Cloning and expression of cDNA for a human Sia alpha 2,3Gal beta 1, 4GlcNA:alpha 2,8-sialyltransferase (hST8Sia III).''; PubMedEurope PMCScholia
Bonten E, van der Spoel A, Fornerod M, Grosveld G, d'Azzo A.; ''Characterization of human lysosomal neuraminidase defines the molecular basis of the metabolic storage disorder sialidosis.''; PubMedEurope PMCScholia
Wada T, Yoshikawa Y, Tokuyama S, Kuwabara M, Akita H, Miyagi T.; ''Cloning, expression, and chromosomal mapping of a human ganglioside sialidase.''; PubMedEurope PMCScholia
Fu C, Bardhan S, Cetateanu ND, Wamil BD, Wang Y, Yan HP, Shi E, Carter C, Venkov C, Yakes FM, Page DL, Lloyd RS, Mernaugh RL, Hellerqvist CG.; ''Identification of a novel membrane protein, HP59, with therapeutic potential as a target of tumor angiogenesis.''; PubMedEurope PMCScholia
Seppala R, Lehto VP, Gahl WA.; ''Mutations in the human UDP-N-acetylglucosamine 2-epimerase gene define the disease sialuria and the allosteric site of the enzyme.''; PubMedEurope PMCScholia
Okajima T, Fukumoto S, Miyazaki H, Ishida H, Kiso M, Furukawa K, Urano T, Furukawa K.; ''Molecular cloning of a novel alpha2,3-sialyltransferase (ST3Gal VI) that sialylates type II lactosamine structures on glycoproteins and glycolipids.''; PubMedEurope PMCScholia
Takashima S, Tsuji S, Tsujimoto M.; ''Characterization of the second type of human beta-galactoside alpha 2,6-sialyltransferase (ST6Gal II), which sialylates Galbeta 1,4GlcNAc structures on oligosaccharides preferentially. Genomic analysis of human sialyltransferase genes.''; PubMedEurope PMCScholia
Kayashima T, Matsuo H, Satoh A, Ohta T, Yoshiura K, Matsumoto N, Nakane Y, Niikawa N, Kishino T.; ''Nonaka myopathy is caused by mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase gene (GNE).''; PubMedEurope PMCScholia
Senda M, Ito A, Tsuchida A, Hagiwara T, Kaneda T, Nakamura Y, Kasama K, Kiso M, Yoshikawa K, Katagiri Y, Ono Y, Ogiso M, Urano T, Furukawa K, Oshima S, Furukawa K.; ''Identification and expression of a sialyltransferase responsible for the synthesis of disialylgalactosylgloboside in normal and malignant kidney cells: downregulation of ST6GalNAc VI in renal cancers.''; PubMedEurope PMCScholia
Basu SS, Basu M, Li Z, Basu S.; ''Characterization of two glycolipid: alpha 2-3sialyltransferases, SAT-3 (CMP-NeuAc:nLcOse4Cer alpha 2-3sialyltransferase) and SAT-4 (CMP-NeuAc:GgOse4Cer alpha 2-3sialyltransferase), from human colon carcinoma (Colo 205) cell line.''; PubMedEurope PMCScholia
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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).
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.
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.
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.
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.
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).
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.
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).
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).
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).
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).
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).
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).
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.
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).
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).
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).
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).
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).
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).
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).
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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).