Asparagine N-linked glycosylation (Homo sapiens)

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38, 70, 86, 87, 94...9937, 46, 61, 73, 115...6267, 101, 108395, 76, 13313113, 43, 47, 79, 95...5363, 93, 11816, 60, 1114, 528, 33, 103, 13717, 56, 1043876, 58116128109, 1348218, 32, 68, 9265, 8026, 54, 10211035, 11411859977, 12, 15, 28, 71...29, 7469, 77, 113, 1357, 12, 15, 28, 71...7, 12, 15, 28, 71...5342, 123, 13185, 9864, 1064, 51, 12220, 22, 23, 491251216218, 32, 9213048, 683418, 32, 9283, 90, 10710, 21, 132, 1382519, 2427, 84, 11757, 96, 119, 12030, 100, 11218, 32, 9211, 899, 88, 1395344, 9136, 1402, 40, 55, 6641, 5241, 812, 40, 55, 665231, 45, 72cytosolGolgi lumenlysosomal lumenendoplasmic reticulum lumenendoplasmic reticulum quality control compartmentSRD5A3unfoldedprotein:(Glc)2(GlcNAc)2 (Man)9(Asn)1:malectinST8SIA2,3,6CALR PDIA3Glycoprotein withGlcNAc in position5AcGlcN1PUAP1 (Glc)1 (GlcNAc)2 (Man)9 (GlcNAc)2 (Man)8c L-GlnGlcMAN2A2 SEL1L UTPDOLDPDOLPGFPT1,2B4GALT6 (Glc)3 (GlcNAc)2(Man)9 (Asn)1unfolded protein Gal1,3GlcNAc group(GlcNAc)2 (Man)8b Glycoprotein withbifurcating GlcNAcin position 3E,E-FPP(GlcNAc)2 (Man)8b MAN2:Zn2+CALR,CANXGlc2xGNPNAT1unfoldedprotein:(Glc)1(GlcNAc)2(Man)9(Asn)1:chaperone:ERp57Man6PDbGPunfolded protein (GlcNAc)2 (Man)5 ATP(GlcNAc)2 (Man)7(PP-Dol)1(GlcNAc)2 (Man)5(PP-Dol)1GDPPPiCoA-SHB4GALT5 Gal1,3Fuc1,4GlcNAcgroup(Glc)2 (GlcNAc)2(Man)9 (PP-Dol)1MLEC PRKCSH ALG10 (GlcNAc)2 (Man)8a (GlcNAc)2 (Man)8b UDPunfolded protein unfolded protein DOLPZn2+ (GlcNAc)2 (Man)5(Asn)1UDP-GlcNAc(Glc)2 (GlcNAc)2 (Man)9 (Asn)1 NGP:1,6-GlcNAcPDIA3 UDP-GlcNAcCO2PMM2 DPM3 DOLPunfolded protein GDP-FucH2O(GlcNAc)2 (Man)5(PP-Dol)1(GlcNAc)2 (Man)8a B4GALT3 unfoldedprotein:(Glc)2(GlcNAc)2 (Man)9(Asn)1(un)foldedprotein:(GlcNAc)2(Man)9OST complexUGGT2 CALR:CANXDDOST Manunfoldedprotein:(GlcNAc)2(Man)7aaMGAT2ST8SIA2 UDP-GlcGMPPB unfolded protein DOLKDHDDSpPNOLglucosidase IIGNPNAT1 (GlcNAc)2 (Man)8(PP-Dol)1unfolded protein ALG10B GDPpPPP phosphatase(Glc)1 (GlcNAc)2 (Man)8b GDP-Manunfoldedprotein:(GlcNAc)2(Man)8bFUCA1 tetramerunfolded protein unfoldedprotein:(Glc)3(GlcNAc)2 (Man)9(Asn)1DOLPMGAT4sH2O(GlcNAc)2 (Man)3(PP-Dol)1(un)foldedprotein:(GlcNAc)2(Man)9CANX DOLP(GlcNAc)2 (Man)2(PP-Dol)1OS9 Glycoproteins withMan8 N-glycans(GlcNAc)2 (Man)8b CALR H2Ounfolded protein AcGlcN6PGANAB (GlcNAc)3 (Man)3(Asn)1CDPFUCA1 pPPPSLC35C1unfolded protein CALR (un)foldedprotein:(GlcNAc)2(Man)9(GlcNAc)2 (Man)9 MAN2A1 (GlcNAc)2 (Man)5 ALG2(GlcNAc)2 (Man)8a MVA5PPPRKCSH Neu5AcDOLP-Man(Glc)2 (GlcNAc)2 (Man)9 (Asn)1 UMPALG3STT3A (Glc)1 (GlcNAc)2 (Man)9 GDP-ManGFPT1 unfoldedprotein:glycan (noglucose)MGAT4C (GlcNAc)2 (Man)9unfoldedprotein:(Glc)1(GlcNAc)2 (Man)9(Asn)1:chaperoneunfoldedprotein:(GlcNAc)2(Man)5CANX UGGT1 Glycoprotein-Neu5AcALG13:ALG14ALG14 (GlcNAc)2 (Man)6(PP-Dol)1DERL2 H2OGDPFUT3PiRFT1DPAGT1unfolded protein GDPMPIDPM1 UDP-GlcNAcDAD1 (GlcNAc)2 (Man)7bcGlycoproteins withMan8 N-glycansGFPT2 Glycoprotein withGlcNAc in position4(GlcNAc)2 (Man)8a (Glc)1 (GlcNAc)2(Man)9 (PP-Dol)1MAN1C1 DOLP(GlcNAc)2 (Man)8b CALR unfolded protein (GlcNAc)2 (Man)9 unfolded protein ST8SIA6 (GlcNAc)2 (Man)8c EDEM1 DOLP-ManL-Gluunfoldedprotein:(GlcNAc)2(Man)8cTUSC3(1-348) GTPUDPST8SIA3 NGPB4GALT4 GlcNAcDOLDPMGAT3LMAN1 (Glc)3 (GlcNAc)2 (Man)9 (Asn)1 IPPP(GlcNAc)2 (Man)8(Asn)1EDEM3 (Glc)1 (GlcNAc)2 (Man)8c H2OPDIA3 Man(GlcNAc)2 (Man)9 DPM2 MAN1B1,EDEM2DCHOLGMPPA/BALG6GlcN6PDbGPunfolded protein CTPCANX GMPPA DOLPDPM1:DPM2:DPM3Glycoprotein withgalactose(Glc)1 (GlcNAc)2 (Man)9 ALG11MDCDDGDP-FucSYVN1(1-617) GDP-FucDOLPglucosidase IIPMM1 Sialic acidmetabolism(GlcNAc)2 (Man)7aa MAN1A2 GlycosaminoglycanmetabolismCALR (GlcNAc)2 (Man)8c Ac-CoAUDP-GlcNAcDbGPNADP+EDEM1,3ST6GAL1MVD dimer(GlcNAc)2 (Man)8c unfolded protein DbGPunfolded protein unfoldedprotein:glycan:chaperone:ERp57RPN1 Fru(6)Punfoldedprotein:(GlcNAc)2(Man)8aUGGT1,2unfoldedprotein:(Glc)1(GlcNAc)2 (Man)9(Asn)1CANX ALG9MOGSunfolded protein PPiN,N'-DCDOLDPCANX EDEM2 Man1PMCFD2 ST3GAL4ALG5MPDU1unfolded protein PiL-fucoseunfolded proteinFUT8MGAT4B H2O(Glc)1 (GlcNAc)2 (Man)9 UDP-GalMVD unfoldedprotein:(GlcNAc)2(Man)5B4GALT2 MGAT4A(1-535) unfolded protein (GlcNAc)4 (Man)3(Asn)1MGAT1(GlcNAc)2 (Man)8c (GlcNAc)2 (Man)8glycansALG12DOLPP1(GlcNAc)3 (Man)5(Asn)1(GlcNAc)2 (Man)7bc ALG13(1-165) PGM3ALG1ALG10 homologueMAN1A1 GANAB MGAT5unfolded protein B4GALT1-6 homodimersPPiNGPALG8B4GALT1 GDPPMM1,2(Glc)1 (GlcNAc)2 (Man)8b MAN1B1 unfoldedprotein:(Glc)1(GlcNAc)2 (Man)9ADPMLECunfoldedprotein:(Glc)1(GlcNAc)2 (Man)8bMAN1A1/A2/C1(Glc)3 (GlcNAc)2(Man)9 (PP-Dol)1(Glc)1 (GlcNAc)2 (Man)7bc (Glc)1 (GlcNAc)2 (Man)9 MAGT1 RPN2 unfolded protein LMAN1:MCFD2ER to GolgiAnterogradeTransportMANEA2xUAP1NGP:1,6-GlcNAcNADPH(GlcNAc)2 (Man)9 (GlcNAc)2 (Man)9(PP-Dol)1OS9:SEL1:SYVN1dimer:DERL21, 13650, 105, 12414


Description

N-linked glycosylation is the most important form of post-translational modification for proteins synthesized and folded in the Endoplasmic Reticulum (Stanley et al. 2009). An early study in 1999 revealed that about 50% of the proteins in the Swiss-Prot database at the time were N-glycosylated (Apweiler et al. 1999). It is now established that the majority of the proteins in the secretory pathway require glycosylation in order to achieve proper folding.
The addition of an N-glycan to a protein can have several roles (Shental-Bechor & Levy 2009). First, glycans enhance the solubility and stability of the proteins in the ER, the golgi and on the outside of the cell membrane, where the composition of the medium is strongly hydrophilic and where proteins, that are mostly hydrophobic, have difficulty folding properly. Second, N-glycans are used as signal molecules during the folding and transport process of the protein: they have the role of labels to determine when a protein must interact with a chaperon, be transported to the golgi, or targeted for degradation in case of major folding defects. Third, and most importantly, N-glycans on completely folded proteins are involved in a wide range of processes: they help determine the specificity of membrane receptors in innate immunity or in cell-to-cell interactions, they can change the properties of hormones and secreted proteins, or of the proteins in the vesicular system inside the cell.
All N-linked glycans are derived from a common 14-sugar oligosaccharide synthesized in the ER, which is attached co-translationally to a protein while this is being translated inside the reticulum. The process of the synthesis of this glycan, known as Synthesis of the N-glycan precursor or LLO, constitutes one of the most conserved pathways in eukaryotes, and has been also observed in some eubacteria. The attachment usually happens on an asparagine residue within the consensus sequence asparagine-X-threonine by an complex called oligosaccharyl transferase (OST).
After being attached to an unfolded protein, the glycan is used as a label molecule in the folding process (also known as Calnexin/Calreticulin cycle) (Lederkremer 2009). The majority of the glycoproteins in the ER require at least one glycosylated residue in order to achieve proper folding, even if it has been shown that a smaller portion of the proteins in the ER can be folded without this modification.
Once the glycoprotein has achieved proper folding, it is transported via the cis-Golgi through all the Golgi compartments, where the glycan is further modified according to the properties of the glycoprotein. This process involves relatively few enzymes but due to its combinatorial nature, can lead to several millions of different possible modifications. The exact topography of this network of reactions has not been established yet, representing one of the major challenges after the sequencing of the human genome (Hossler et al. 2006).
Since N-glycosylation is involved in an great number of different processes, from cell-cell interaction to folding control, mutations in one of the genes involved in glycan assembly and/or modification can lead to severe development problems (often affecting the central nervous system). All the diseases in genes involved in glycosylation are collectively known as Congenital Disorders of Glycosylation (CDG) (Sparks et al. 2003), and classified as CDG type I for the genes in the LLO synthesis pathway, and CDG type II for the others. View original pathway at:Reactome.

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  75. Lo NW, Shaper JH, Pevsner J, Shaper NL.; ''The expanding beta 4-galactosyltransferase gene family: messages from the databanks.''; PubMed Europe PMC Scholia
  76. Nyfeler B, Nufer O, Matsui T, Mori K, Hauri HP.; ''The cargo receptor ERGIC-53 is a target of the unfolded protein response.''; PubMed Europe PMC Scholia
  77. Tan J, Dunn J, Jaeken J, Schachter H.; ''Mutations in the MGAT2 gene controlling complex N-glycan synthesis cause carbohydrate-deficient glycoprotein syndrome type II, an autosomal recessive disease with defective brain development.''; PubMed Europe PMC Scholia
  78. Dall'Olio F, Malagolini N, Chiricolo M, Trinchera M, Harduin-Lepers A.; ''The expanding roles of the Sd(a)/Cad carbohydrate antigen and its cognate glycosyltransferase B4GALNT2.''; PubMed Europe PMC Scholia
  79. Ning B, Elbein AD.; ''Cloning, expression and characterization of the pig liver GDP-mannose pyrophosphorylase. Evidence that GDP-mannose and GDP-Glc pyrophosphorylases are different proteins.''; PubMed Europe PMC Scholia
  80. Yagi T, Baroja-Fernández E, Yamamoto R, Muñoz FJ, Akazawa T, Hong KS, Pozueta-Romero J.; ''Cloning, expression and characterization of a mammalian Nudix hydrolase-like enzyme that cleaves the pyrophosphate bond of UDP-glucose.''; PubMed Europe PMC Scholia
  81. Helenius J, Ng DT, Marolda CL, Walter P, Valvano MA, Aebi M.; ''Translocation of lipid-linked oligosaccharides across the ER membrane requires Rft1 protein.''; PubMed Europe PMC Scholia
  82. Arnold SM, Fessler LI, Fessler JH, Kaufman RJ.; ''Two homologues encoding human UDP-glucose:glycoprotein glucosyltransferase differ in mRNA expression and enzymatic activity.''; PubMed Europe PMC Scholia
  83. Ou WJ, Cameron PH, Thomas DY, Bergeron JJ.; ''Association of folding intermediates of glycoproteins with calnexin during protein maturation.''; PubMed Europe PMC Scholia
  84. Peneff C, Ferrari P, Charrier V, Taburet Y, Monnier C, Zamboni V, Winter J, Harnois M, Fassy F, Bourne Y.; ''Crystal structures of two human pyrophosphorylase isoforms in complexes with UDPGlc(Gal)NAc: role of the alternatively spliced insert in the enzyme oligomeric assembly and active site architecture.''; PubMed Europe PMC Scholia
  85. Matthijs G, Schollen E, Pirard M, Budarf ML, Van Schaftingen E, Cassiman JJ.; ''PMM (PMM1), the human homologue of SEC53 or yeast phosphomannomutase, is localized on chromosome 22q13.''; PubMed Europe PMC Scholia
  86. Schallus T, Jaeckh C, Fehér K, Palma AS, Liu Y, Simpson JC, Mackeen M, Stier G, Gibson TJ, Feizi T, Pieler T, Muhle-Goll C.; ''Malectin: a novel carbohydrate-binding protein of the endoplasmic reticulum and a candidate player in the early steps of protein N-glycosylation.''; PubMed Europe PMC Scholia
  87. Angata K, Fukuda M.; ''Polysialyltransferases: major players in polysialic acid synthesis on the neural cell adhesion molecule.''; PubMed Europe PMC Scholia
  88. Kirchhausen T.; ''Three ways to make a vesicle.''; PubMed Europe PMC Scholia
  89. Grubenmann CE, Frank CG, Hülsmeier AJ, Schollen E, Matthijs G, Mayatepek E, Berger EG, Aebi M, Hennet T.; ''Deficiency of the first mannosylation step in the N-glycosylation pathway causes congenital disorder of glycosylation type Ik.''; PubMed Europe PMC Scholia
  90. Wang L, Liang Y, Li Z, Cai X, Zhang W, Wu G, Jin J, Fang Z, Yang Y, Zha X.; ''Increase in beta1-6 GlcNAc branching caused by N-acetylglucosaminyltransferase V directs integrin beta1 stability in human hepatocellular carcinoma cell line SMMC-7721.''; PubMed Europe PMC Scholia
  91. Wedgwood JF, Strominger JL.; ''Enzymatic activities in cultured human lymphocytes that dephosphorylate dolichyl pyrophosphate and dolichyl phosphate.''; PubMed Europe PMC Scholia
  92. Hull E, Sarkar M, Spruijt MP, Höppener JW, Dunn R, Schachter H.; ''Organization and localization to chromosome 5 of the human UDP-N-acetylglucosamine:alpha-3-D-mannoside beta-1,2-N-acetylglucosaminyltransferase I gene.''; PubMed Europe PMC Scholia
  93. Ohyama C, Smith PL, Angata K, Fukuda MN, Lowe JB, Fukuda M.; ''Molecular cloning and expression of GDP-D-mannose-4,6-dehydratase, a key enzyme for fucose metabolism defective in Lec13 cells.''; PubMed Europe PMC Scholia
  94. Kranz C, Jungeblut C, Denecke J, Erlekotte A, Sohlbach C, Debus V, Kehl HG, Harms E, Reith A, Reichel S, Grobe H, Hammersen G, Schwarzer U, Marquardt T.; ''A defect in dolichol phosphate biosynthesis causes a new inherited disorder with death in early infancy.''; PubMed Europe PMC Scholia
  95. Hardt B, Völker C, Mundt S, Salska-Navarro M, Hauptmann M, Bause E.; ''Human endo-alpha1,2-mannosidase is a Golgi-resident type II membrane protein.''; PubMed Europe PMC Scholia
  96. Schwarz M, Thiel C, Lübbehusen J, Dorland B, de Koning T, von Figura K, Lehle L, Körner C.; ''Deficiency of GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase causes congenital disorder of glycosylation type Ik.''; PubMed Europe PMC Scholia
  97. Frank CG, Grubenmann CE, Eyaid W, Berger EG, Aebi M, Hennet T.; ''Identification and functional analysis of a defect in the human ALG9 gene: definition of congenital disorder of glycosylation type IL.''; PubMed Europe PMC Scholia
  98. Cantagrel V, Lefeber DJ, Ng BG, Guan Z, Silhavy JL, Bielas SL, Lehle L, Hombauer H, Adamowicz M, Swiezewska E, De Brouwer AP, Blümel P, Sykut-Cegielska J, Houliston S, Swistun D, Ali BR, Dobyns WB, Babovic-Vuksanovic D, van Bokhoven H, Wevers RA, Raetz CR, Freeze HH, Morava E, Al-Gazali L, Gleeson JG.; ''SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder.''; PubMed Europe PMC Scholia
  99. Quirk S, Seley KL.; ''Substrate discrimination by the human GTP fucose pyrophosphorylase.''; PubMed Europe PMC Scholia
  100. Christianson JC, Shaler TA, Tyler RE, Kopito RR.; ''OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin ligase complex for ERAD.''; PubMed Europe PMC Scholia
  101. Züchner S, Dallman J, Wen R, Beecham G, Naj A, Farooq A, Kohli MA, Whitehead PL, Hulme W, Konidari I, Edwards YJ, Cai G, Peter I, Seo D, Buxbaum JD, Haines JL, Blanton S, Young J, Alfonso E, Vance JM, Lam BL, Peričak-Vance MA.; ''Whole-exome sequencing links a variant in DHDDS to retinitis pigmentosa.''; PubMed Europe PMC Scholia
  102. Lederkremer GZ.; ''Glycoprotein folding, quality control and ER-associated degradation.''; PubMed Europe PMC Scholia
  103. Thiel C, Schwarz M, Peng J, Grzmil M, Hasilik M, Braulke T, Kohlschütter A, von Figura K, Lehle L, Körner C.; ''A new type of congenital disorders of glycosylation (CDG-Ii) provides new insights into the early steps of dolichol-linked oligosaccharide biosynthesis.''; PubMed Europe PMC Scholia
  104. Wada Y, Sakamoto M.; ''Isolation of the human phosphomannomutase gene (PMM1) and assignment to chromosome 22q13.''; PubMed Europe PMC Scholia
  105. Montiel MD, Krzewinski-Recchi MA, Delannoy P, Harduin-Lepers A.; ''Molecular cloning, gene organization and expression of the human UDP-GalNAc:Neu5Acalpha2-3Galbeta-R beta1,4-N-acetylgalactosaminyltransferase responsible for the biosynthesis of the blood group Sda/Cad antigen: evidence for an unusual extended cytoplasmic domain.''; PubMed Europe PMC Scholia
  106. Burda P, Aebi M.; ''The ALG10 locus of Saccharomyces cerevisiae encodes the alpha-1,2 glucosyltransferase of the endoplasmic reticulum: the terminal glucose of the lipid-linked oligosaccharide is required for efficient N-linked glycosylation.''; PubMed Europe PMC Scholia
  107. Kranz C, Denecke J, Lehle L, Sohlbach K, Jeske S, Meinhardt F, Rossi R, Gudowius S, Marquardt T.; ''Congenital disorder of glycosylation type Ik (CDG-Ik): a defect of mannosyltransferase I.''; PubMed Europe PMC Scholia
  108. Intra J, Perotti ME, Pavesi G, Horner D.; ''Comparative and phylogenetic analysis of alpha-L-fucosidase genes.''; PubMed Europe PMC Scholia
  109. Song BL, Sever N, DeBose-Boyd RA.; ''Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase.''; PubMed Europe PMC Scholia
  110. Wickramasinghe S, Medrano JF.; ''Primer on genes encoding enzymes in sialic acid metabolism in mammals.''; PubMed Europe PMC Scholia
  111. Aronson NN, Kuranda MJ.; ''Lysosomal degradation of Asn-linked glycoproteins.''; PubMed Europe PMC Scholia
  112. Kudo T, Nakagawa H, Takahashi M, Hamaguchi J, Kamiyama N, Yokoo H, Nakanishi K, Nakagawa T, Kamiyama T, Deguchi K, Nishimura S, Todo S.; ''N-glycan alterations are associated with drug resistance in human hepatocellular carcinoma.''; PubMed Europe PMC Scholia
  113. Nauseef WM, McCormick SJ, Clark RA.; ''Calreticulin functions as a molecular chaperone in the biosynthesis of myeloperoxidase.''; PubMed Europe PMC Scholia
  114. Furukawa T, Youssef EM, Yatsuoka T, Yokoyama T, Makino N, Inoue H, Fukushige S, Hoshi M, Hayashi Y, Sunamura M, Horii A.; ''Cloning and characterization of the human UDP-N-acetylglucosamine: alpha-1,3-D-mannoside beta-1,4-N-acetylglucosaminyltransferase IV-homologue (hGnT-IV-H) gene.''; PubMed Europe PMC Scholia
  115. Vleugels W, Schollen E, Foulquier F, Matthijs G.; ''Screening for OST deficiencies in unsolved CDG-I patients.''; PubMed Europe PMC Scholia
  116. Lubas WA, Spiro RG.; ''Evaluation of the role of rat liver Golgi endo-alpha-D-mannosidase in processing N-linked oligosaccharides.''; PubMed Europe PMC Scholia
  117. Kasapkara CS, Tümer L, Ezgü FS, Hasanoğlu A, Race V, Matthijs G, Jaeken J.; ''SRD5A3-CDG: a patient with a novel mutation.''; PubMed Europe PMC Scholia
  118. McKnight GL, Mudri SL, Mathewes SL, Traxinger RR, Marshall S, Sheppard PO, O'Hara PJ.; ''Molecular cloning, cDNA sequence, and bacterial expression of human glutamine:fructose-6-phosphate amidotransferase.''; PubMed Europe PMC Scholia
  119. Karaveg K, Siriwardena A, Tempel W, Liu ZJ, Glushka J, Wang BC, Moremen KW.; ''Mechanism of class 1 (glycosylhydrolase family 47) {alpha}-mannosidases involved in N-glycan processing and endoplasmic reticulum quality control.''; PubMed Europe PMC Scholia
  120. Tremblay LO, Herscovics A.; ''Characterization of a cDNA encoding a novel human Golgi alpha 1, 2-mannosidase (IC) involved in N-glycan biosynthesis.''; PubMed Europe PMC Scholia
  121. Angata K, Suzuki M, McAuliffe J, Ding Y, Hindsgaul O, Fukuda M.; ''Differential biosynthesis of polysialic acid on neural cell adhesion molecule (NCAM) and oligosaccharide acceptors by three distinct alpha 2,8-sialyltransferases, ST8Sia IV (PST), ST8Sia II (STX), and ST8Sia III.''; PubMed Europe PMC Scholia
  122. Schollen E, Dorland L, de Koning TJ, Van Diggelen OP, Huijmans JG, Marquardt T, Babovic-Vuksanovic D, Patterson M, Imtiaz F, Winchester B, Adamowicz M, Pronicka E, Freeze H, Matthijs G.; ''Genomic organization of the human phosphomannose isomerase (MPI) gene and mutation analysis in patients with congenital disorders of glycosylation type Ib (CDG-Ib).''; PubMed Europe PMC Scholia
  123. Sun L, Eklund EA, Chung WK, Wang C, Cohen J, Freeze HH.; ''Congenital disorder of glycosylation id presenting with hyperinsulinemic hypoglycemia and islet cell hyperplasia.''; PubMed Europe PMC Scholia
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  125. Timson DJ, Reece RJ.; ''Identification and characterisation of human aldose 1-epimerase.''; PubMed Europe PMC Scholia
  126. Senderek J, Müller JS, Dusl M, Strom TM, Guergueltcheva V, Diepolder I, Laval SH, Maxwell S, Cossins J, Krause S, Muelas N, Vilchez JJ, Colomer J, Mallebrera CJ, Nascimento A, Nafissi S, Kariminejad A, Nilipour Y, Bozorgmehr B, Najmabadi H, Rodolico C, Sieb JP, Steinlein OK, Schlotter B, Schoser B, Kirschner J, Herrmann R, Voit T, Oldfors A, Lindbergh C, Urtizberea A, von der Hagen M, Hübner A, Palace J, Bushby K, Straub V, Beeson D, Abicht A, Lochmüller H.; ''Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect.''; PubMed Europe PMC Scholia
  127. Suzuki T, Huang C, Fujihira H.; ''The cytoplasmic peptide:N-glycanase (NGLY1) - Structure, expression and cellular functions.''; PubMed Europe PMC Scholia
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  132. Wolf MJ, Rush JS, Waechter CJ.; ''Golgi-enriched membrane fractions from rat brain and liver contain long-chain polyisoprenyl pyrophosphate phosphatase activity.''; PubMed Europe PMC Scholia
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  135. Harduin-Lepers A, Vallejo-Ruiz V, Krzewinski-Recchi MA, Samyn-Petit B, Julien S, Delannoy P.; ''The human sialyltransferase family.''; PubMed Europe PMC Scholia
  136. Cameron HS, Szczepaniak D, Weston BW.; ''Expression of human chromosome 19p alpha(1,3)-fucosyltransferase genes in normal tissues. Alternative splicing, polyadenylation, and isoforms.''; PubMed Europe PMC Scholia
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  140. Winchester B.; ''Lysosomal metabolism of glycoproteins.''; PubMed Europe PMC Scholia
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  142. Pang H, Koda Y, Soejima M, Kimura H.; ''Identification of human phosphoglucomutase 3 (PGM3) as N-acetylglucosamine-phosphate mutase (AGM1).''; PubMed Europe PMC Scholia
  143. Alanen HI, Williamson RA, Howard MJ, Hatahet FS, Salo KE, Kauppila A, Kellokumpu S, Ruddock LW.; ''ERp27, a new non-catalytic endoplasmic reticulum-located human protein disulfide isomerase family member, interacts with ERp57.''; PubMed Europe PMC Scholia
  144. Kumar R, Yang J, Larsen RD, Stanley P.; ''Cloning and expression of N-acetylglucosaminyltransferase I, the medial Golgi transferase that initiates complex N-linked carbohydrate formation.''; PubMed Europe PMC Scholia
  145. Akama TO, Nakagawa H, Wong NK, Sutton-Smith M, Dell A, Morris HR, Nakayama J, Nishimura S, Pai A, Moremen KW, Marth JD, Fukuda MN.; ''Essential and mutually compensatory roles of {alpha}-mannosidase II and {alpha}-mannosidase IIx in N-glycan processing in vivo in mice.''; PubMed Europe PMC Scholia
  146. Brynedal B, Wojcik J, Esposito F, Debailleul V, Yaouanq J, Martinelli-Boneschi F, Edan G, Comi G, Hillert J, Abderrahim H.; ''MGAT5 alters the severity of multiple sclerosis.''; PubMed Europe PMC Scholia
  147. Kelleher DJ, Gilmore R.; ''An evolving view of the eukaryotic oligosaccharyltransferase.''; PubMed Europe PMC Scholia
  148. Hinderlich S, Berger M, Schwarzkopf M, Effertz K, Reutter W.; ''Molecular cloning and characterization of murine and human N-acetylglucosamine kinase.''; PubMed Europe PMC Scholia
  149. Oriol R, Martinez-Duncker I, Chantret I, Mollicone R, Codogno P.; ''Common origin and evolution of glycosyltransferases using Dol-P-monosaccharides as donor substrate.''; PubMed Europe PMC Scholia
  150. Chantret I, Dupré T, Delenda C, Bucher S, Dancourt J, Barnier A, Charollais A, Heron D, Bader-Meunier B, Danos O, Seta N, Durand G, Oriol R, Codogno P, Moore SE.; ''Congenital disorders of glycosylation type Ig is defined by a deficiency in dolichyl-P-mannose:Man7GlcNAc2-PP-dolichyl mannosyltransferase.''; PubMed Europe PMC Scholia
  151. Hansske B, Thiel C, Lübke T, Hasilik M, Höning S, Peters V, Heidemann PH, Hoffmann GF, Berger EG, von Figura K, Körner C.; ''Deficiency of UDP-galactose:N-acetylglucosamine beta-1,4-galactosyltransferase I causes the congenital disorder of glycosylation type IId.''; PubMed Europe PMC Scholia
  152. Granovsky M, Fata J, Pawling J, Muller WJ, Khokha R, Dennis JW.; ''Suppression of tumor growth and metastasis in Mgat5-deficient mice.''; PubMed Europe PMC Scholia
  153. Imbach T, Burda P, Kuhnert P, Wevers RA, Aebi M, Berger EG, Hennet T.; ''A mutation in the human ortholog of the Saccharomyces cerevisiae ALG6 gene causes carbohydrate-deficient glycoprotein syndrome type-Ic.''; PubMed Europe PMC Scholia
  154. Kämpf M, Absmanner B, Schwarz M, Lehle L.; ''Biochemical characterization and membrane topology of Alg2 from Saccharomyces cerevisiae as a bifunctional alpha1,3- and 1,6-mannosyltransferase involved in lipid-linked oligosaccharide biosynthesis.''; PubMed Europe PMC Scholia
  155. Mi Y, Fiete D, Baenziger JU.; ''Ablation of GalNAc-4-sulfotransferase-1 enhances reproduction by altering the carbohydrate structures of luteinizing hormone in mice.''; PubMed Europe PMC Scholia
  156. Tian H, Miyoshi E, Kawaguchi N, Shaker M, Ito Y, Taniguchi N, Tsujimoto M, Matsuura N.; ''The implication of N-acetylglucosaminyltransferase V expression in gastric cancer.''; PubMed Europe PMC Scholia
  157. Serafini-Cessi F, Conte R.; ''Precipitin reaction between Sda-active human Tamm-Horsfall glycoprotein and anti-Sda-serum.''; PubMed Europe PMC Scholia
  158. Takahashi T, Honda R, Nishikawa Y.; ''Cloning of the human cDNA which can complement the defect of the yeast mannosyltransferase I-deficient mutant alg 1.''; PubMed Europe PMC Scholia
  159. Maeda Y, Tanaka S, Hino J, Kangawa K, Kinoshita T.; ''Human dolichol-phosphate-mannose synthase consists of three subunits, DPM1, DPM2 and DPM3.''; PubMed Europe PMC Scholia
  160. Hiraoka N, Misra A, Belot F, Hindsgaul O, Fukuda M.; ''Molecular cloning and expression of two distinct human N-acetylgalactosamine 4-O-sulfotransferases that transfer sulfate to GalNAc beta 1-->4GlcNAc beta 1-->R in both N- and O-glycans.''; PubMed Europe PMC Scholia
  161. Tonetti M, Sturla L, Bisso A, Benatti U, De Flora A.; ''Synthesis of GDP-L-fucose by the human FX protein.''; PubMed Europe PMC Scholia
  162. Gonzalez DS, Karaveg K, Vandersall-Nairn AS, Lal A, Moremen KW.; ''Identification, expression, and characterization of a cDNA encoding human endoplasmic reticulum mannosidase I, the enzyme that catalyzes the first mannose trimming step in mammalian Asn-linked oligosaccharide biosynthesis.''; PubMed Europe PMC Scholia
  163. Arnold SM, Kaufman RJ.; ''The noncatalytic portion of human UDP-glucose: glycoprotein glucosyltransferase I confers UDP-glucose binding and transferase function to the catalytic domain.''; PubMed Europe PMC Scholia
  164. Saxena A, Yik JH, Weigel PH.; ''H2, the minor subunit of the human asialoglycoprotein receptor, trafficks intracellularly and forms homo-oligomers, but does not bind asialo-orosomucoid.''; PubMed Europe PMC Scholia
  165. Clarke JL, Watkins WM.; ''Expression of human alpha-l-fucosyltransferase gene homologs in monkey kidney COS cells and modification of potential fucosyltransferase acceptor substrates by an endogenous glycosidase.''; PubMed Europe PMC Scholia
  166. Ide Y, Miyoshi E, Nakagawa T, Gu J, Tanemura M, Nishida T, Ito T, Yamamoto H, Kozutsumi Y, Taniguchi N.; ''Aberrant expression of N-acetylglucosaminyltransferase-IVa and IVb (GnT-IVa and b) in pancreatic cancer.''; PubMed Europe PMC Scholia
  167. Cipollo JF, Trimble RB, Chi JH, Yan Q, Dean N.; ''The yeast ALG11 gene specifies addition of the terminal alpha 1,2-Man to the Man5GlcNAc2-PP-dolichol N-glycosylation intermediate formed on the cytosolic side of the endoplasmic reticulum.''; PubMed Europe PMC Scholia
  168. Apweiler R, Hermjakob H, Sharon N.; ''On the frequency of protein glycosylation, as deduced from analysis of the SWISS-PROT database.''; PubMed Europe PMC Scholia
  169. Kinoshita T, Inoue N.; ''Dissecting and manipulating the pathway for glycosylphos-phatidylinositol-anchor biosynthesis.''; PubMed Europe PMC Scholia
  170. Lo Presti L, Cabuy E, Chiricolo M, Dall'Olio F.; ''Molecular cloning of the human beta1,4 N-acetylgalactosaminyltransferase responsible for the biosynthesis of the Sd(a) histo-blood group antigen: the sequence predicts a very long cytoplasmic domain.''; PubMed Europe PMC Scholia
  171. Alcock F, Swanton E.; ''Mammalian OS-9 is upregulated in response to endoplasmic reticulum stress and facilitates ubiquitination of misfolded glycoproteins.''; PubMed Europe PMC Scholia
  172. Schaub BE, Berger B, Berger EG, Rohrer J.; ''Transition of galactosyltransferase 1 from trans-Golgi cisterna to the trans-Golgi network is signal mediated.''; PubMed Europe PMC Scholia
  173. Schmid M, Prajczer S, Gruber LN, Bertocchi C, Gandini R, Pfaller W, Jennings P, Joannidis M.; ''Uromodulin facilitates neutrophil migration across renal epithelial monolayers.''; PubMed Europe PMC Scholia
  174. Misago M, Liao YF, Kudo S, Eto S, Mattei MG, Moremen KW, Fukuda MN.; ''Molecular cloning and expression of cDNAs encoding human alpha-mannosidase II and a previously unrecognized alpha-mannosidase IIx isozyme.''; PubMed Europe PMC Scholia
  175. Ciccarelli FD, von Mering C, Suyama M, Harrington ED, Izaurralde E, Bork P.; ''Complex genomic rearrangements lead to novel primate gene function.''; PubMed Europe PMC Scholia
  176. Zhou H, Sun L, Li J, Xu C, Yu F, Liu Y, Ji C, He J.; ''The crystal structure of human GDP-L-fucose synthase.''; PubMed Europe PMC Scholia
  177. Pinho SS, Reis CA, Paredes J, Magalhães AM, Ferreira AC, Figueiredo J, Xiaogang W, Carneiro F, Gärtner F, Seruca R.; ''The role of N-acetylglucosaminyltransferase III and V in the post-transcriptional modifications of E-cadherin.''; PubMed Europe PMC Scholia
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History

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CompareRevisionActionTimeUserComment
115049view16:59, 25 January 2021ReactomeTeamReactome version 75
113493view11:57, 2 November 2020ReactomeTeamReactome version 74
112693view16:08, 9 October 2020ReactomeTeamReactome version 73
101610view11:47, 1 November 2018ReactomeTeamreactome version 66
101147view21:33, 31 October 2018ReactomeTeamreactome version 65
100675view20:07, 31 October 2018ReactomeTeamreactome version 64
100225view16:52, 31 October 2018ReactomeTeamreactome version 63
99776view15:17, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99333view12:47, 31 October 2018ReactomeTeamreactome version 62
93956view13:47, 16 August 2017ReactomeTeamreactome version 61
93552view11:26, 9 August 2017ReactomeTeamreactome version 61
86654view09:23, 11 July 2016ReactomeTeamreactome version 56
83351view10:56, 18 November 2015ReactomeTeamVersion54
81512view13:03, 21 August 2015ReactomeTeamVersion53
78300view14:22, 24 December 2014EgonwGave an unlabeled protein a label matching its identifier ("4836523").
76985view08:27, 17 July 2014ReactomeTeamFixed remaining interactions
76690view12:05, 16 July 2014ReactomeTeamFixed remaining interactions
76016view10:07, 11 June 2014ReactomeTeamRe-fixing comment source
75725view11:19, 10 June 2014ReactomeTeamReactome 48 Update
75075view14:02, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74857view15:15, 2 May 2014EgonwMarked a metabolite as a DataNode type="Metabolite"...
74722view08:48, 30 April 2014ReactomeTeamReactome46
44964view12:49, 6 October 2011MartijnVanIerselOntology Term : 'protein modification pathway' added !
42008view21:49, 4 March 2011MaintBotAutomatic update
39811view05:50, 21 January 2011MaintBotNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
(Glc)1 (GlcNAc)2 (Man)9 (PP-Dol)1MetaboliteCHEBI:59081 (ChEBI)
(Glc)1 (GlcNAc)2 (Man)7bc R-NUL-901056 (Reactome)
(Glc)1 (GlcNAc)2 (Man)8b MetaboliteCHEBI:64046 (ChEBI)
(Glc)1 (GlcNAc)2 (Man)8c R-NUL-901027 (Reactome)
(Glc)1 (GlcNAc)2 (Man)9 MetaboliteCHEBI:59080 (ChEBI)
(Glc)2 (GlcNAc)2 (Man)9 (PP-Dol)1MetaboliteCHEBI:53020 (ChEBI)
(Glc)2 (GlcNAc)2 (Man)9 (Asn)1 MetaboliteCHEBI:59082 (ChEBI)
(Glc)3 (GlcNAc)2 (Man)9 (Asn)1MetaboliteCHEBI:59084 (ChEBI)
(Glc)3 (GlcNAc)2 (Man)9 (PP-Dol)1MetaboliteCHEBI:53019 (ChEBI)
(Glc)3 (GlcNAc)2 (Man)9 (Asn)1 MetaboliteCHEBI:59084 (ChEBI)
(GlcNAc)2 (Man)2 (PP-Dol)1MetaboliteCHEBI:59085 (ChEBI)
(GlcNAc)2 (Man)3 (PP-Dol)1MetaboliteCHEBI:53742 (ChEBI)
(GlcNAc)2 (Man)5 (Asn)1MetaboliteCHEBI:59087 (ChEBI)
(GlcNAc)2 (Man)5 (PP-Dol)1MetaboliteCHEBI:53022 (ChEBI)
(GlcNAc)2 (Man)5 MetaboliteCHEBI:59087 (ChEBI)
(GlcNAc)2 (Man)6 (PP-Dol)1MetaboliteCHEBI:53023 (ChEBI)
(GlcNAc)2 (Man)7 (PP-Dol)1MetaboliteCHEBI:59088 (ChEBI)
(GlcNAc)2 (Man)7aa MetaboliteCHEBI:60640 (ChEBI)
(GlcNAc)2 (Man)7bc R-NUL-901089 (Reactome)
(GlcNAc)2 (Man)7bcMetaboliteCHEBI:60637 (ChEBI)
(GlcNAc)2 (Man)8 (Asn)1MetaboliteCHEBI:59089 (ChEBI)
(GlcNAc)2 (Man)8 (PP-Dol)1MetaboliteCHEBI:59091 (ChEBI)
(GlcNAc)2 (Man)8 glycansComplexR-HSA-R-ALL-964831 (Reactome)
(GlcNAc)2 (Man)8a MetaboliteCHEBI:60627 (ChEBI)
(GlcNAc)2 (Man)8b MetaboliteCHEBI:60628 (ChEBI)
(GlcNAc)2 (Man)8b MetaboliteCHEBI:64048 (ChEBI)
(GlcNAc)2 (Man)8c MetaboliteCHEBI:60629 (ChEBI)
(GlcNAc)2 (Man)8c MetaboliteCHEBI:64052 (ChEBI)
(GlcNAc)2 (Man)9 (PP-Dol)1MetaboliteCHEBI:59093 (ChEBI)
(GlcNAc)2 (Man)9 MetaboliteCHEBI:59092 (ChEBI)
(GlcNAc)2 (Man)9MetaboliteCHEBI:59092 (ChEBI)
(GlcNAc)3 (Man)3 (Asn)1MetaboliteCHEBI:60615 (ChEBI)
(GlcNAc)3 (Man)5 (Asn)1MetaboliteCHEBI:60625 (ChEBI)
(GlcNAc)4 (Man)3 (Asn)1MetaboliteCHEBI:60651 (ChEBI)
(un)folded

protein:(GlcNAc)2

(Man)9		ComplexR-HSA-909547 (Reactome)
(un)folded

protein:(GlcNAc)2

(Man)9		ComplexR-HSA-912283 (Reactome)
(un)folded

protein:(GlcNAc)2

(Man)9		ComplexR-HSA-915150 (Reactome)
2xGNPNAT1ComplexR-HSA-771697 (Reactome)
2xUAP1ComplexR-HSA-771695 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
ALG10 ProteinQ5BKT4 (Uniprot-TrEMBL)
ALG10 homologueComplexR-HSA-449652 (Reactome)
ALG10B ProteinQ5I7T1 (Uniprot-TrEMBL)
ALG11ProteinQ2TAA5 (Uniprot-TrEMBL)
ALG12ProteinQ9BV10 (Uniprot-TrEMBL)
ALG13(1-165) ProteinQ9NP73 (Uniprot-TrEMBL)
ALG13:ALG14ComplexR-HSA-449326 (Reactome)
ALG14 ProteinQ96F25 (Uniprot-TrEMBL)
ALG1ProteinQ9BT22 (Uniprot-TrEMBL)
ALG2ProteinQ9H553 (Uniprot-TrEMBL)
ALG3ProteinQ92685 (Uniprot-TrEMBL)
ALG5ProteinQ9Y673 (Uniprot-TrEMBL)
ALG6ProteinQ9Y672 (Uniprot-TrEMBL)
ALG8ProteinQ9BVK2 (Uniprot-TrEMBL)
ALG9ProteinQ9H6U8 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
Ac-CoAMetaboliteCHEBI:15351 (ChEBI)
AcGlcN1PMetaboliteCHEBI:7125 (ChEBI)
AcGlcN6PMetaboliteCHEBI:15784 (ChEBI)
B4GALT1 ProteinP15291 (Uniprot-TrEMBL)
B4GALT1-6 homodimersComplexR-HSA-975898 (Reactome)
B4GALT2 ProteinO60909 (Uniprot-TrEMBL)
B4GALT3 ProteinO60512 (Uniprot-TrEMBL)
B4GALT4 ProteinO60513 (Uniprot-TrEMBL)
B4GALT5 ProteinO43286 (Uniprot-TrEMBL)
B4GALT6 ProteinQ9UBX8 (Uniprot-TrEMBL)
CALR ProteinP27797 (Uniprot-TrEMBL)
CALR,CANXComplexR-HSA-901048 (Reactome)
CALR:CANXComplexR-HSA-548862 (Reactome)
CANX ProteinP27824 (Uniprot-TrEMBL)
CDPMetaboliteCHEBI:17239 (ChEBI)
CO2MetaboliteCHEBI:16526 (ChEBI)
CTPMetaboliteCHEBI:17677 (ChEBI)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
DAD1 ProteinP61803 (Uniprot-TrEMBL)
DCHOLMetaboliteCHEBI:16091 (ChEBI)
DDOST ProteinP39656 (Uniprot-TrEMBL)
DERL2 ProteinQ9GZP9 (Uniprot-TrEMBL)
DHDDSProteinQ86SQ9 (Uniprot-TrEMBL)
DOLDPMetaboliteCHEBI:15750 (ChEBI)
DOLKProteinQ9UPQ8 (Uniprot-TrEMBL)
DOLP-ManMetaboliteCHEBI:15809 (ChEBI)
DOLPMetaboliteCHEBI:16214 (ChEBI)
DOLPP1ProteinQ86YN1 (Uniprot-TrEMBL)
DPAGT1ProteinQ9H3H5 (Uniprot-TrEMBL)
DPM1 ProteinO60762 (Uniprot-TrEMBL)
DPM1:DPM2:DPM3ComplexR-HSA-162692 (Reactome)
DPM2 ProteinO94777 (Uniprot-TrEMBL)
DPM3 ProteinQ9P2X0 (Uniprot-TrEMBL)
DbGPMetaboliteCHEBI:15812 (ChEBI)
E,E-FPPMetaboliteCHEBI:17407 (ChEBI)
EDEM1 ProteinQ92611 (Uniprot-TrEMBL)
EDEM1,3ComplexR-HSA-6782691 (Reactome)
EDEM2 ProteinQ9BV94 (Uniprot-TrEMBL)
EDEM3 ProteinQ9BZQ6 (Uniprot-TrEMBL)
ER to Golgi

Anterograde

Transport		PathwayR-HSA-199977 (Reactome) Secretory cargo destined to be secreted or to arrive at the plasma membrane (PM) leaves the ER via distinct exit sites. This cargo is ultimately destined for the Golgi apparatus.
FUCA1 ProteinP04066 (Uniprot-TrEMBL)
FUCA1 tetramerComplexR-HSA-5693805 (Reactome)
FUT3ProteinP21217 (Uniprot-TrEMBL)
FUT8ProteinQ9BYC5 (Uniprot-TrEMBL)
Fru(6)PMetaboliteCHEBI:15946 (ChEBI)
GANAB ProteinQ14697 (Uniprot-TrEMBL)
GDP-FucMetaboliteCHEBI:17009 (ChEBI)
GDP-ManMetaboliteCHEBI:15820 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GFPT1 ProteinQ06210 (Uniprot-TrEMBL)
GFPT1,2ComplexR-HSA-532205 (Reactome)
GFPT2 ProteinO94808 (Uniprot-TrEMBL)
GMPPA ProteinQ96IJ6 (Uniprot-TrEMBL)
GMPPA/BComplexR-HSA-532536 (Reactome)
GMPPB ProteinQ9Y5P6 (Uniprot-TrEMBL)
GNPNAT1 ProteinQ96EK6 (Uniprot-TrEMBL)
GTPMetaboliteCHEBI:15996 (ChEBI)
Gal1,3Fuc1,4GlcNAc groupMetaboliteCHEBI:18914 (ChEBI)
Gal1,3GlcNAc groupMetaboliteCHEBI:18915 (ChEBI)
GlcMetaboliteCHEBI:17925 (ChEBI)
GlcN6PMetaboliteCHEBI:15873 (ChEBI)
GlcNAcDOLDPMetaboliteCHEBI:18278 (ChEBI)
Glycoprotein with

GlcNAc in position

4		R-NUL-981616 (Reactome)
Glycoprotein with

GlcNAc in position

5		R-NUL-981617 (Reactome)
Glycoprotein with

bifurcating GlcNAc

in position 3		R-NUL-981613 (Reactome)
Glycoprotein with galactoseR-NUL-981618 (Reactome)
Glycoprotein-Neu5AcR-NUL-981615 (Reactome)
Glycoproteins with Man8 N-glycansComplexR-HSA-948002 (Reactome)
Glycoproteins with Man8 N-glycansComplexR-HSA-948022 (Reactome)
Glycosaminoglycan metabolismPathwayR-HSA-1630316 (Reactome) Glycosaminoglycans (GAGs) are long, unbranched polysaccharides containing a repeating disaccharide unit composed of a hexosamine (either N-acetylgalactosamine (GalNAc) or N-acetylglucosamine (GlcNAc)) and a uronic acid (glucuronate or iduronate). They can be heavily sulfated. GAGs are located primarily in the extracellular matrix (ECM) and on cell membranes, acting as a lubricating fluid for joints and as part of signalling processes. They have structural roles in connective tissue, cartilage, bone and blood vessels (Esko et al. 2009). GAGs are degraded in the lysosome as part of their natural turnover. Defects in the lysosomal enzymes responsible for the metabolism of membrane-associated GAGs lead to lysosomal storage diseases called mucopolysaccharidoses (MPS). MPSs are characterised by the accumulation of GAGs in lysosomes resulting in chronic, progressively debilitating disorders that in many instances lead to severe psychomotor retardation and premature death (Cantz & Gehler 1976, Clarke 2008). The biosynthesis and breakdown of the main GAGs (hyaluronate, keratan sulfate, chondroitin sulfate, dermatan sulfate and heparan sulfate) is described here.
H2OMetaboliteCHEBI:15377 (ChEBI)
IPPPMetaboliteCHEBI:16584 (ChEBI)
L-GlnMetaboliteCHEBI:18050 (ChEBI)
L-GluMetaboliteCHEBI:16015 (ChEBI)
L-fucoseMetaboliteCHEBI:2181 (ChEBI)
LMAN1 ProteinP49257 (Uniprot-TrEMBL)
LMAN1:MCFD2ComplexR-HSA-1017219 (Reactome)
MAGT1 ProteinQ9H0U3 (Uniprot-TrEMBL)
MAN1A1 ProteinP33908 (Uniprot-TrEMBL)
MAN1A1/A2/C1ComplexR-HSA-964764 (Reactome)
MAN1A2 ProteinO60476 (Uniprot-TrEMBL)
MAN1B1 ProteinQ9UKM7 (Uniprot-TrEMBL)
MAN1B1,EDEM2ComplexR-HSA-6782581 (Reactome)
MAN1C1 ProteinQ9NR34 (Uniprot-TrEMBL)
MAN2:Zn2+ComplexR-HSA-975821 (Reactome)
MAN2A1 ProteinQ16706 (Uniprot-TrEMBL)
MAN2A2 ProteinP49641 (Uniprot-TrEMBL)
MANEAProteinQ5SRI9 (Uniprot-TrEMBL)
MCFD2 ProteinQ8NI22 (Uniprot-TrEMBL)
MDCDDMetaboliteCHEBI:18396 (ChEBI)
MGAT1ProteinP26572 (Uniprot-TrEMBL)
MGAT2ProteinQ10469 (Uniprot-TrEMBL)
MGAT3ProteinQ09327 (Uniprot-TrEMBL)
MGAT4A(1-535) ProteinQ9UM21 (Uniprot-TrEMBL)
MGAT4B ProteinQ9UQ53 (Uniprot-TrEMBL)
MGAT4C ProteinQ9UBM8 (Uniprot-TrEMBL)
MGAT4sComplexR-HSA-975913 (Reactome)
MGAT5ProteinQ09328 (Uniprot-TrEMBL)
MLEC ProteinQ14165 (Uniprot-TrEMBL)
MLECProteinQ14165 (Uniprot-TrEMBL)
MOGSProteinQ13724 (Uniprot-TrEMBL)
MPDU1ProteinO75352 (Uniprot-TrEMBL)
MPIProteinP34949 (Uniprot-TrEMBL)
MVA5PPMetaboliteCHEBI:15899 (ChEBI)
MVD ProteinP53602 (Uniprot-TrEMBL)
MVD dimerComplexR-HSA-191341 (Reactome)
Man1PMetaboliteCHEBI:35374 (ChEBI)
Man6PMetaboliteCHEBI:17369 (ChEBI)
ManMetaboliteCHEBI:4208 (ChEBI)
N,N'-DCDOLDPMetaboliteCHEBI:18341 (ChEBI)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NGP:1,6-GlcNAcR-NUL-1028779 (Reactome)
NGP:1,6-GlcNAcR-NUL-6784247 (Reactome)
NGPMetaboliteCHEBI:59520 (ChEBI)
Neu5AcMetaboliteCHEBI:17012 (ChEBI)
OS9 ProteinQ13438 (Uniprot-TrEMBL)
OS9:SEL1:SYVN1 dimer:DERL2ComplexR-HSA-6781872 (Reactome)
OST complexComplexR-HSA-532516 (Reactome)
PDIA3 ProteinP30101 (Uniprot-TrEMBL)
PDIA3ProteinP30101 (Uniprot-TrEMBL)
PGM3ProteinO95394 (Uniprot-TrEMBL)
PMM1 ProteinQ92871 (Uniprot-TrEMBL)
PMM1,2ComplexR-HSA-532532 (Reactome)
PMM2 ProteinO15305 (Uniprot-TrEMBL)
PPiMetaboliteCHEBI:29888 (ChEBI)
PRKCSH ProteinP14314 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
RFT1ProteinQ96AA3 (Uniprot-TrEMBL)
RPN1 ProteinP04843 (Uniprot-TrEMBL)
RPN2 ProteinP04844 (Uniprot-TrEMBL)
SEL1L ProteinQ9UBV2 (Uniprot-TrEMBL)
SLC35C1ProteinQ96A29 (Uniprot-TrEMBL)
SRD5A3ProteinQ9H8P0 (Uniprot-TrEMBL)
ST3GAL4ProteinQ11206 (Uniprot-TrEMBL)
ST6GAL1ProteinP15907 (Uniprot-TrEMBL)
ST8SIA2 ProteinQ92186 (Uniprot-TrEMBL)
ST8SIA2,3,6ComplexR-HSA-1022134 (Reactome)
ST8SIA3 ProteinO43173 (Uniprot-TrEMBL)
ST8SIA6 ProteinP61647 (Uniprot-TrEMBL)
STT3A ProteinP46977 (Uniprot-TrEMBL)
SYVN1(1-617) ProteinQ86TM6 (Uniprot-TrEMBL)
Sialic acid metabolismPathwayR-HSA-4085001 (Reactome) 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.
TUSC3(1-348) ProteinQ13454 (Uniprot-TrEMBL)
UAP1 ProteinQ16222 (Uniprot-TrEMBL)
UDP-GalMetaboliteCHEBI:18307 (ChEBI)
UDP-GlcMetaboliteCHEBI:18066 (ChEBI)
UDP-GlcNAcMetaboliteCHEBI:16264 (ChEBI)
UDPMetaboliteCHEBI:17659 (ChEBI)
UGGT1 ProteinQ9NYU2 (Uniprot-TrEMBL)
UGGT1,2ComplexR-HSA-548881 (Reactome)
UGGT2 ProteinQ9NYU1 (Uniprot-TrEMBL)
UMPMetaboliteCHEBI:16695 (ChEBI)
UTPMetaboliteCHEBI:15713 (ChEBI)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
glucosidase IIComplexR-HSA-532671 (Reactome)
pPNOLMetaboliteCHEBI:67132 (ChEBI)
pPPP phosphataseR-HSA-4420020 (Reactome)
pPPPMetaboliteCHEBI:37531 (ChEBI)
unfolded

protein:(Glc)1 (GlcNAc)2 (Man)9

(Asn)1:chaperone:ERp57		ComplexR-HSA-909545 (Reactome)
unfolded

protein:(Glc)1

(GlcNAc)2 (Man)8b		ComplexR-HSA-6781883 (Reactome)
unfolded

protein:(Glc)1 (GlcNAc)2 (Man)9

(Asn)1:chaperone		ComplexR-HSA-909542 (Reactome)
unfolded

protein:(Glc)1 (GlcNAc)2 (Man)9

(Asn)1		ComplexR-HSA-532672 (Reactome)
unfolded

protein:(Glc)1

(GlcNAc)2 (Man)9		ComplexR-HSA-912297 (Reactome)
unfolded

protein:(Glc)2 (GlcNAc)2 (Man)9

(Asn)1:malectin		ComplexR-HSA-901051 (Reactome)
unfolded

protein:(Glc)2 (GlcNAc)2 (Man)9

(Asn)1		ComplexR-HSA-532669 (Reactome)
unfolded

protein:(Glc)3 (GlcNAc)2 (Man)9

(Asn)1		ComplexR-HSA-532534 (Reactome)
unfolded

protein:(GlcNAc)2

(Man)5		ComplexR-HSA-6782684 (Reactome)
unfolded

protein:(GlcNAc)2

(Man)5		ComplexR-HSA-6782692 (Reactome)
unfolded

protein:(GlcNAc)2

(Man)7aa		ComplexR-HSA-912280 (Reactome)
unfolded

protein:(GlcNAc)2

(Man)8a		ComplexR-HSA-912285 (Reactome)
unfolded

protein:(GlcNAc)2

(Man)8b		ComplexR-HSA-912284 (Reactome)
unfolded

protein:(GlcNAc)2

(Man)8c		ComplexR-HSA-912295 (Reactome)
unfolded

protein:glycan (no

glucose)		ComplexR-HSA-901021 (Reactome)
unfolded protein:glycan:chaperone:ERp57ComplexR-HSA-901040 (Reactome)
unfolded protein R-HSA-381130 (Reactome)
unfolded protein R-HSA-912296 (Reactome)
unfolded protein R-HSA-915147 (Reactome)
unfolded protein R-NUL-1022114 (Reactome)
unfolded proteinR-HSA-381130 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
(Glc)1 (GlcNAc)2 (Man)9 (PP-Dol)1ArrowR-HSA-446202 (Reactome)
(Glc)1 (GlcNAc)2 (Man)9 (PP-Dol)1R-HSA-446189 (Reactome)
(Glc)2 (GlcNAc)2 (Man)9 (PP-Dol)1ArrowR-HSA-446189 (Reactome)
(Glc)2 (GlcNAc)2 (Man)9 (PP-Dol)1R-HSA-446194 (Reactome)
(Glc)3 (GlcNAc)2 (Man)9 (Asn)1R-HSA-964759 (Reactome)
(Glc)3 (GlcNAc)2 (Man)9 (PP-Dol)1ArrowR-HSA-446194 (Reactome)
(Glc)3 (GlcNAc)2 (Man)9 (PP-Dol)1R-HSA-446209 (Reactome)
(GlcNAc)2 (Man)2 (PP-Dol)1ArrowR-HSA-446208 (Reactome)
(GlcNAc)2 (Man)2 (PP-Dol)1R-HSA-449718 (Reactome)
(GlcNAc)2 (Man)3 (PP-Dol)1ArrowR-HSA-449718 (Reactome)
(GlcNAc)2 (Man)3 (PP-Dol)1R-HSA-446187 (Reactome)
(GlcNAc)2 (Man)5 (Asn)1ArrowR-HSA-964737 (Reactome)
(GlcNAc)2 (Man)5 (Asn)1ArrowR-HSA-964825 (Reactome)
(GlcNAc)2 (Man)5 (Asn)1ArrowR-HSA-964830 (Reactome)
(GlcNAc)2 (Man)5 (Asn)1R-HSA-964768 (Reactome)
(GlcNAc)2 (Man)5 (PP-Dol)1ArrowR-HSA-446187 (Reactome)
(GlcNAc)2 (Man)5 (PP-Dol)1ArrowR-HSA-446212 (Reactome)
(GlcNAc)2 (Man)5 (PP-Dol)1R-HSA-446188 (Reactome)
(GlcNAc)2 (Man)5 (PP-Dol)1R-HSA-446212 (Reactome)
(GlcNAc)2 (Man)6 (PP-Dol)1ArrowR-HSA-446188 (Reactome)
(GlcNAc)2 (Man)6 (PP-Dol)1R-HSA-446215 (Reactome)
(GlcNAc)2 (Man)7 (PP-Dol)1ArrowR-HSA-446215 (Reactome)
(GlcNAc)2 (Man)7 (PP-Dol)1R-HSA-446198 (Reactome)
(GlcNAc)2 (Man)7bcR-HSA-964830 (Reactome)
(GlcNAc)2 (Man)8 (Asn)1ArrowR-HSA-964759 (Reactome)
(GlcNAc)2 (Man)8 (PP-Dol)1ArrowR-HSA-446198 (Reactome)
(GlcNAc)2 (Man)8 (PP-Dol)1R-HSA-446216 (Reactome)
(GlcNAc)2 (Man)8 glycansR-HSA-964825 (Reactome)
(GlcNAc)2 (Man)9 (PP-Dol)1ArrowR-HSA-446216 (Reactome)
(GlcNAc)2 (Man)9 (PP-Dol)1R-HSA-446202 (Reactome)
(GlcNAc)2 (Man)9R-HSA-964737 (Reactome)
(GlcNAc)3 (Man)3 (Asn)1ArrowR-HSA-975814 (Reactome)
(GlcNAc)3 (Man)3 (Asn)1R-HSA-975829 (Reactome)
(GlcNAc)3 (Man)5 (Asn)1ArrowR-HSA-964768 (Reactome)
(GlcNAc)3 (Man)5 (Asn)1R-HSA-975814 (Reactome)
(GlcNAc)4 (Man)3 (Asn)1ArrowR-HSA-975829 (Reactome)
(un)folded

protein:(GlcNAc)2

(Man)9		ArrowR-HSA-912291 (Reactome)
(un)folded

protein:(GlcNAc)2

(Man)9		ArrowR-HSA-915148 (Reactome)
(un)folded

protein:(GlcNAc)2

(Man)9		R-HSA-901024 (Reactome)
(un)folded

protein:(GlcNAc)2

(Man)9		R-HSA-901039 (Reactome)
(un)folded

protein:(GlcNAc)2

(Man)9		R-HSA-901074 (Reactome)
(un)folded

protein:(GlcNAc)2

(Man)9		R-HSA-912291 (Reactome)
(un)folded

protein:(GlcNAc)2

(Man)9		R-HSA-915148 (Reactome)
2xGNPNAT1mim-catalysisR-HSA-449734 (Reactome)
2xUAP1mim-catalysisR-HSA-446204 (Reactome)
ADPArrowR-HSA-191414 (Reactome)
ALG10 homologuemim-catalysisR-HSA-446194 (Reactome)
ALG11mim-catalysisR-HSA-446187 (Reactome)
ALG12mim-catalysisR-HSA-446198 (Reactome)
ALG13:ALG14mim-catalysisR-HSA-446207 (Reactome)
ALG1mim-catalysisR-HSA-446218 (Reactome)
ALG2mim-catalysisR-HSA-446208 (Reactome)
ALG2mim-catalysisR-HSA-449718 (Reactome)
ALG3mim-catalysisR-HSA-446188 (Reactome)
ALG5mim-catalysisR-HSA-446214 (Reactome)
ALG6mim-catalysisR-HSA-446202 (Reactome)
ALG8mim-catalysisR-HSA-446189 (Reactome)
ALG9mim-catalysisR-HSA-446215 (Reactome)
ALG9mim-catalysisR-HSA-446216 (Reactome)
ATPR-HSA-191414 (Reactome)
Ac-CoAR-HSA-449734 (Reactome)
AcGlcN1PArrowR-HSA-446185 (Reactome)
AcGlcN1PR-HSA-446204 (Reactome)
AcGlcN6PArrowR-HSA-449734 (Reactome)
AcGlcN6PR-HSA-446185 (Reactome)
B4GALT1-6 homodimersmim-catalysisR-HSA-975919 (Reactome)
CALR,CANXR-HSA-535717 (Reactome)
CALR:CANXArrowR-HSA-548890 (Reactome)
CDPArrowR-HSA-446195 (Reactome)
CO2ArrowR-HSA-191414 (Reactome)
CTPR-HSA-446195 (Reactome)
CoA-SHArrowR-HSA-449734 (Reactome)
DCHOLArrowR-HSA-4419979 (Reactome)
DCHOLR-HSA-446195 (Reactome)
DHDDSmim-catalysisR-HSA-4419978 (Reactome)
DOLDPR-HSA-446200 (Reactome)
DOLKmim-catalysisR-HSA-446195 (Reactome)
DOLP-ManArrowR-HSA-162715 (Reactome)
DOLP-ManArrowR-HSA-162721 (Reactome)
DOLP-ManR-HSA-162715 (Reactome)
DOLP-ManR-HSA-446188 (Reactome)
DOLP-ManR-HSA-446198 (Reactome)
DOLP-ManR-HSA-446215 (Reactome)
DOLP-ManR-HSA-446216 (Reactome)
DOLPArrowR-HSA-446188 (Reactome)
DOLPArrowR-HSA-446189 (Reactome)
DOLPArrowR-HSA-446194 (Reactome)
DOLPArrowR-HSA-446195 (Reactome)
DOLPArrowR-HSA-446198 (Reactome)
DOLPArrowR-HSA-446200 (Reactome)
DOLPArrowR-HSA-446202 (Reactome)
DOLPArrowR-HSA-446209 (Reactome)
DOLPArrowR-HSA-446215 (Reactome)
DOLPArrowR-HSA-446216 (Reactome)
DOLPArrowR-HSA-548884 (Reactome)
DOLPP1mim-catalysisR-HSA-446200 (Reactome)
DOLPR-HSA-162721 (Reactome)
DOLPR-HSA-446191 (Reactome)
DOLPR-HSA-446214 (Reactome)
DPAGT1mim-catalysisR-HSA-446191 (Reactome)
DPM1:DPM2:DPM3mim-catalysisR-HSA-162721 (Reactome)
DbGPArrowR-HSA-446211 (Reactome)
DbGPArrowR-HSA-446214 (Reactome)
DbGPR-HSA-446189 (Reactome)
DbGPR-HSA-446194 (Reactome)
DbGPR-HSA-446202 (Reactome)
DbGPR-HSA-446211 (Reactome)
DbGPR-HSA-548884 (Reactome)
E,E-FPPR-HSA-4419978 (Reactome)
EDEM1,3mim-catalysisR-HSA-6782685 (Reactome)
FUCA1 tetramermim-catalysisR-HSA-5693807 (Reactome)
FUT3mim-catalysisR-HSA-5693925 (Reactome)
FUT8mim-catalysisR-HSA-1028788 (Reactome)
Fru(6)PR-HSA-449715 (Reactome)
Fru(6)PR-HSA-532549 (Reactome)
GDP-FucArrowR-HSA-742345 (Reactome)
GDP-FucR-HSA-1028788 (Reactome)
GDP-FucR-HSA-5693925 (Reactome)
GDP-FucR-HSA-742345 (Reactome)
GDP-ManArrowR-HSA-446221 (Reactome)
GDP-ManR-HSA-162721 (Reactome)
GDP-ManR-HSA-446187 (Reactome)
GDP-ManR-HSA-446208 (Reactome)
GDP-ManR-HSA-446218 (Reactome)
GDP-ManR-HSA-449718 (Reactome)
GDPArrowR-HSA-1028788 (Reactome)
GDPArrowR-HSA-446187 (Reactome)
GDPArrowR-HSA-446208 (Reactome)
GDPArrowR-HSA-446218 (Reactome)
GDPArrowR-HSA-449718 (Reactome)
GDPArrowR-HSA-5693925 (Reactome)
GFPT1,2mim-catalysisR-HSA-449715 (Reactome)
GMPPA/Bmim-catalysisR-HSA-446221 (Reactome)
GTPR-HSA-446221 (Reactome)
Gal1,3Fuc1,4GlcNAc groupArrowR-HSA-5693925 (Reactome)
Gal1,3GlcNAc groupR-HSA-5693925 (Reactome)
GlcArrowR-HSA-532667 (Reactome)
GlcArrowR-HSA-532678 (Reactome)
GlcArrowR-HSA-548890 (Reactome)
GlcArrowR-HSA-964759 (Reactome)
GlcN6PArrowR-HSA-449715 (Reactome)
GlcN6PR-HSA-449734 (Reactome)
GlcNAcDOLDPArrowR-HSA-446191 (Reactome)
GlcNAcDOLDPR-HSA-446207 (Reactome)
Glycoprotein with

GlcNAc in position

4		ArrowR-HSA-975903 (Reactome)
Glycoprotein with

GlcNAc in position

5		ArrowR-HSA-975916 (Reactome)
Glycoprotein with

bifurcating GlcNAc

in position 3		ArrowR-HSA-975926 (Reactome)
Glycoprotein with galactoseArrowR-HSA-975919 (Reactome)
Glycoprotein-Neu5AcArrowR-HSA-1022129 (Reactome)
Glycoprotein-Neu5AcArrowR-HSA-1022133 (Reactome)
Glycoprotein-Neu5AcArrowR-HSA-975902 (Reactome)
Glycoproteins with Man8 N-glycansArrowR-HSA-947991 (Reactome)
Glycoproteins with Man8 N-glycansR-HSA-947991 (Reactome)
H2OR-HSA-4419986 (Reactome)
H2OR-HSA-446200 (Reactome)
H2OR-HSA-5693807 (Reactome)
H2OR-HSA-6782685 (Reactome)
H2OR-HSA-901024 (Reactome)
H2OR-HSA-901036 (Reactome)
H2OR-HSA-901039 (Reactome)
H2OR-HSA-901074 (Reactome)
IPPPArrowR-HSA-191414 (Reactome)
IPPPR-HSA-4419978 (Reactome)
L-GlnR-HSA-449715 (Reactome)
L-GluArrowR-HSA-449715 (Reactome)
L-fucoseArrowR-HSA-5693807 (Reactome)
LMAN1:MCFD2mim-catalysisR-HSA-947991 (Reactome)
MAN1A1/A2/C1mim-catalysisR-HSA-964737 (Reactome)
MAN1A1/A2/C1mim-catalysisR-HSA-964825 (Reactome)
MAN1A1/A2/C1mim-catalysisR-HSA-964830 (Reactome)
MAN1B1,EDEM2mim-catalysisR-HSA-901024 (Reactome)
MAN1B1,EDEM2mim-catalysisR-HSA-901036 (Reactome)
MAN1B1,EDEM2mim-catalysisR-HSA-901039 (Reactome)
MAN1B1,EDEM2mim-catalysisR-HSA-901074 (Reactome)
MAN2:Zn2+mim-catalysisR-HSA-975814 (Reactome)
MANEAmim-catalysisR-HSA-964759 (Reactome)
MDCDDArrowR-HSA-446218 (Reactome)
MDCDDR-HSA-446208 (Reactome)
MGAT1mim-catalysisR-HSA-964768 (Reactome)
MGAT2mim-catalysisR-HSA-975829 (Reactome)
MGAT3mim-catalysisR-HSA-975926 (Reactome)
MGAT4smim-catalysisR-HSA-975903 (Reactome)
MGAT5mim-catalysisR-HSA-975916 (Reactome)
MLECArrowR-HSA-532667 (Reactome)
MLECR-HSA-901006 (Reactome)
MOGSmim-catalysisR-HSA-532678 (Reactome)
MPDU1ArrowR-HSA-446188 (Reactome)
MPDU1ArrowR-HSA-446198 (Reactome)
MPDU1ArrowR-HSA-446215 (Reactome)
MPDU1ArrowR-HSA-446216 (Reactome)
MPImim-catalysisR-HSA-532549 (Reactome)
MVA5PPR-HSA-191414 (Reactome)
MVD dimermim-catalysisR-HSA-191414 (Reactome)
Man1PArrowR-HSA-446201 (Reactome)
Man1PR-HSA-446221 (Reactome)
Man6PArrowR-HSA-532549 (Reactome)
Man6PR-HSA-446201 (Reactome)
ManArrowR-HSA-6782685 (Reactome)
ManArrowR-HSA-901024 (Reactome)
ManArrowR-HSA-901036 (Reactome)
ManArrowR-HSA-901039 (Reactome)
ManArrowR-HSA-901074 (Reactome)
ManArrowR-HSA-964737 (Reactome)
ManArrowR-HSA-964825 (Reactome)
ManArrowR-HSA-964830 (Reactome)
ManArrowR-HSA-975814 (Reactome)
N,N'-DCDOLDPArrowR-HSA-446207 (Reactome)
N,N'-DCDOLDPR-HSA-446218 (Reactome)
NADP+ArrowR-HSA-4419979 (Reactome)
NADPHR-HSA-4419979 (Reactome)
NGP:1,6-GlcNAcArrowR-HSA-1028788 (Reactome)
NGP:1,6-GlcNAcR-HSA-5693807 (Reactome)
NGPArrowR-HSA-5693807 (Reactome)
NGPR-HSA-1022129 (Reactome)
NGPR-HSA-1022133 (Reactome)
NGPR-HSA-1028788 (Reactome)
NGPR-HSA-975902 (Reactome)
NGPR-HSA-975903 (Reactome)
NGPR-HSA-975916 (Reactome)
NGPR-HSA-975919 (Reactome)
NGPR-HSA-975926 (Reactome)
Neu5AcR-HSA-1022129 (Reactome)
Neu5AcR-HSA-1022133 (Reactome)
Neu5AcR-HSA-975902 (Reactome)
OS9:SEL1:SYVN1 dimer:DERL2mim-catalysisR-HSA-1022127 (Reactome)
OST complexmim-catalysisR-HSA-446209 (Reactome)
PDIA3ArrowR-HSA-548890 (Reactome)
PDIA3R-HSA-901047 (Reactome)
PGM3mim-catalysisR-HSA-446185 (Reactome)
PMM1,2mim-catalysisR-HSA-446201 (Reactome)
PPiArrowR-HSA-4419986 (Reactome)
PPiArrowR-HSA-446204 (Reactome)
PPiArrowR-HSA-446221 (Reactome)
PiArrowR-HSA-191414 (Reactome)
PiArrowR-HSA-446200 (Reactome)
R-HSA-1017228 (Reactome) Glycoproteins with lesser folding defects get transported back to the ER and the CNX/CRT complex (Lederkremer, 2009).
R-HSA-1022127 (Reactome) Proteins with major folding defects are extracted from futile folding cycles in the calnexin chaperone system and the ER Quality Control Compartment, and are translocated back to the cytosol for ER-associated degradation (ERAD). The N-glycan is used as a signal to distinguish proteins to be degraded, by direct binding to a ubiquitin ligase complex composed of at least E3 ubiquitin-protein ligase synoviolin (SYVN1, HRD1), protein sel-1 homolog 1 (SEL1L), derlin-2 (DERL2) and protein OS-9 (OS9) (Christianson et al. 2008, Bernasconi et al. 2008, Alcock & Swanton 2009; review Olzmann et al. 2013).
R-HSA-1022129 (Reactome) Addition of sialic acid (Neu5Ac) to galactose-containing N-glycan. Neu5Ac is usually found at terminal positions of the N-glycan. This imparts a negative charge at neutral pH which affects the chemico-physical and biological properties of the N-glycans (for a review, see Schauer 2000); moreover, this modification can lead to the addition of extraordinarily long antennae such as polysialic acid (hundreds of sials) or polylactosamine repeats (dozens of disaccharide repeats) (Harduin-Lepers 2001), while the number of modifications on the antennae of N-glycans is usually lower.
There are over 20 sialyltransferases known in humans, 5 of which are known to act on N-glycans. Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1) is the only sialyltransferase known to transfer Neu5Ac to galactose (Gal) on N-Glycans (Dall'Olio 2000). A second beta-Galactoside alpha-2,6-sialyltransferase has been characterized, but this enzyme acts mainly on oligosaccharides (Krzewinski-Recchi et al. 2003). Neu5Ac can also be added via an alpha-2,3-linkage to Gal on N-glycans by CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 4 (ST3GAL4) (Ellies et al. 2002). ST8Sia II (ST8SIA2), ST8Sia III (ST8SIA3), and ST8Sia IV (ST8SIA6) have alpha-2,8-activity (Angata et al. 1997, Angata et al. 2000; Angata & Fuduka 2003).
R-HSA-1022133 (Reactome) Addition of sialic acid (Neu5Ac) to galactose-containing N-glycan. Sialic acid is usually found at terminal positions of the N-glycan. This imparts a negative charge at neutral pH which affects the chemico-physical and biological properties of the N-glycans (for a review, see Schauer 2000); moreover, this modification can lead to the addition of extraordinarily long antennae such as polysialic acid (hundreds of sials) or polylactosamine repeats (dozens of disaccharide repeats) (Harduin-Lepers 2001), while the number of modifications on the antennae of N-glycans is usually lower.
There are over 20 sialyltransferases known in humans, 5 of which are known to act on N-glycans. Beta-galactoside alpha-2,6-sialyltransferase 1
(ST6GAL1) is the only sialyltransferase known to transfer Neu5Ac to Gal on N-Glycans (Dall'Olio 2000). A second beta-galactoside alpha-2,6-sialyltransferase has been characterized, but this enzyme acts mainly on oligosaccharides (Krzewinski-Recchi et al. 2003). Neu5Ac can also be added via an alpha-2,3-linkage to Gal on N-glycans by CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 4 (ST3GAL4) (Ellies et al. 2002). ST8Sia II (ST8SIA2), ST8Sia III (ST8SIA3), and ST8Sia IV (ST8SIA6) have alpha-2,8-activity (Angata et al. 1997, Angata et al. 2000, Angata & Fuduka 2003).
R-HSA-1028788 (Reactome) Addition of a fucose moiety as an alpha 1-6 linkage to the first GlcNAc residue of the N-glycan (Clarke JL, Watkins WM 1999; Yamaguchi Y et al, 1999; Yamaguchi Y et al 2000).
R-HSA-162715 (Reactome) Dolichyl phosphate D-mannose (DOLPman) is flipped in the endoplasmic reticulum membrane so that its mannose moiety is oriented inwards, towards the endoplasmic reticulum lumen, where it is accessible to transferases catalyzing the synthesis of glycolipids and glycoproteins (Kinoshita & Inoue 2000).
R-HSA-162721 (Reactome) Cytosolic GDP-mannose reacts with dolichyl phosphate in the endoplasmic reticulum membrane to form dolichyl phosphate D-mannose (DOLPman). The reaction is catalysed by dolichyl-phosphate mannosyltransferase, a heterotrimeric protein embedded in the endoplasmic reticulum membrane. The first subunit of the heterotrimer (DPM1) appears to be the actual catalyst, and the other two subunits appear to stabilise it (Maeda et al. 2000).
R-HSA-191414 (Reactome) Mevalonate pyrophosphate decarboxylase (MPD) decarboxylates mevalonate-5-pyrophosphate (MVA5PP) into isopentenyl pyrophosphate (IPPP) while hydrolysing ATP to ADP and orthophosphate (Toth & Huwyler 1996).
R-HSA-4419978 (Reactome) The ER membrane-associated enzyme dehydrodolichyl diphosphate synthase (DHDDS) mediates the sequential head-to-tail cis addition of multiple isopentyl pyrophosphate (IPP) molecules to farnesyl pyrophosphate (E,E-FPP) to produce polyprenol pyrophosphate (pPPP) (Shridas et al. 2003). Dolichol in humans contain homologues ranging from 17-23 isoprene units, the most common homologues contain 19 or 20 isoprene units (Freeman et al. 1980).

Defects in DHDDS cause retinitis pigmentosa 59 (RP59; MIM:613861), a pigment retinopathy, characterised by retinal pigment deposits (visible on fundus examination) and primary loss of rod photoreceptors followed by secondary loss of cone photoreceptors. Sufferers typically have night vision blindness and loss of mid to peripheral vision. As the condition progresses, they lose far peripheral vision and eventually central vision (Zuchner et al. 2011).
R-HSA-4419979 (Reactome) Polyprenol reductase (SRD5A3), resident on the endoplasmic reticulum membrane, mediates the reduction of the alpha-isoprene unit of polyprenol (pPNOL) to form dolichol (DCHOL) in a NADPH-dependent manner (Cantagrel et al. 2010). Defects in SRD5A3 cause congenital disorder of glycosylation 1q (SRD5A3-CDG, CDG1Q; MIM:612379), a neurodevelopmental disorder characterised by under-glycosylated serum glycoproteins resulting in nervous system development, psychomotor retardation, hypotonia, coagulation disorders and immunodeficiency (Cantagrel et al. 2010, Kasapkara et al. 2012). Defects in SRD5A3 can also cause Kahrizi syndrome (KHRZ; MIM:612713), a neurodevelopmental disorder characterised by mental retardation, cataracts, coloboma, kyphosis, and coarse facial features (Kahrizi et al. 2011).
R-HSA-4419986 (Reactome) In mammals, polyprenol pyrophosphate (pPPP) requires dephosphorylation to polyprenol (pPNOL), which can then be reduced. Although pPPP phosphatase activity has been reported (Wolf et al. 1991), no pPPP phosphatase enzyme has yet been identified (Schenk et al. 2001).
R-HSA-446185 (Reactome) Cytosolic PGM3 catalyzes the isomerization of N-acetyl-D-glucosamine 6-phosphate (GlcNAc6P) to form N-acetyl-D-glucosamine 1-phosphate (GlcNAc1P) (Pang H et al, 2002).
R-HSA-446187 (Reactome) A fourth mannose is added to the N-glycan precursor by ALG11. The addition of the fifth mannose, also by ALG11, is the last step occurring on the cytosolic side of the ER membrane (Cipollo JF et al, 2001). Both these reactions are alpha1,2 mannose additions.
R-HSA-446188 (Reactome) The sixth mannose is added to the N-glycan precursor. This reaction occurs in the ER lumen and uses a different mannose donor (dolichyl-phosphate-mannose) than the previous steps. It has been proposed that ALG3, along with all the mannosyl- and glucosyltransferases in the N-glycan biosynthesis pathway that use dolichyl-phosphate-mannose or dolichyl-phosphate-glucose as donor, derive from duplications of a common ancestral enzyme (Oriol et al. 2002). Defects in ALG3 are associated with Congenital Disorder of Glycosylation 1D (CDG1D) (Sun et al. 2005).
R-HSA-446189 (Reactome) The second glucose (supplied from the donor dolichol-phosphate-glucose) is added to the N-glycan precursor, mediated by ALG8 (Schollen E et al, 2004). Defects in ALG8 are the cause of congenital disorder of glycosylation type 1H (CDG1H) (Schollen E et al, 2004; Sun L et al, 2005).
R-HSA-446191 (Reactome) In the first step of N glycan precursor (LLO) synthesis, N acetylglucosamine is added, via an alpha 1,3 linkage, to a molecule of dolichyl phosphate, producing N acetyl D glucosaminyl diphosphodolichol (Eckert et al. 1998). This reaction is catalyzed by DPAGT1 (ALG7 in yeast), mutations in which are associated with CDG disorder type I J (Wu et al. 2003) and with congenital myasthenic syndrome with tubular aggregates type 2 (Belaya et al. 2012). The dolichyl phosphate acts as an anchor for the LLO, so that subsequent sugar addition reactions take place on a sugar anchored in the ER membrane.
R-HSA-446194 (Reactome) The last glucose is added to the N-glycan precursor. This reaction occurs inside the ER lumen and uses Dol-P-Glc as the glucose donor. In yeast, this reaction is catalyzed by ALG10 (Burda P and Aebi M,1998); however, this gene is duplicated in primates (Ciccarelli FD et al, 2005; Table 1), leading to two homologues, ALG10A and ALG10B, and to date there is no clear evidence to say which of these two paralogues (or both) is responsible for catalyzing this reaction in humans. No Congenital Disorders of Glycosylations are known to be associated with either gene.

R-HSA-446195 (Reactome) Dolichol kinase (DOLK, TMEM15) mediates the phosphorylation of dolichol (DCHOL) to form dolichyl phosphate (DOLP) in the ER membrane (Fernandez et al. 2002). Defects in DOLK cause congenital disorder of glycosylation type 1M (CDG1M aka dolichol kinase deficiency; MIM:610768), a severe multisystem disorder characterised by under-glycosylated serum glycoproteins which results in nervous system under-development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. Death occurs in early life (Kranz et al. 2007).
R-HSA-446198 (Reactome) The eighth mannose is added to the N-glycan precursor. This reaction occurs in the ER lumen and uses dolichyl phosphate D-mannose as a mannose donor. Defects in ALG12 are the cause of congenital disorder of glycosylation type 1G (CDG1G) (Chantret I et al, 2002).
R-HSA-446200 (Reactome) In the last step of the N-glycan precursor biosynthesis pathway, the mature N-glycan (Glc3Man9GlcNAc2) is removed from the dolichyl diphosphate (DOLDP) molecule upon which it has been synthesized and attached to a nascent protein. The released DOLDP molecule is de-phosphorylated by dolichyl diphosphatase 1 (DOLPP1) to dolichyl phosphate (DOLP). DOLP is thus salvaged and be used as substrate for the synthesis of another N-glycan oligosaccharide (Wedgwood & Strominger 1980).
R-HSA-446201 (Reactome) Phosphomannomutases 1 and 2 (PMM1 and PMM2) catalyse the isomerisation of mannose 6-phosphate (Man6P) to mannose 1-phosphate (Man1P) in the cytosol of cells (Wada & Sakamoto 1997, Matthijs et al. 1997). Mutations in the PMM2 gene are one of the causes of Jaeken syndrome. a disease of glycosylation, type CDGIa. (Matthijs et al. 1997b).
R-HSA-446202 (Reactome) The first glucose is added to the N-glycan precursor, mediated by ALG6. Defects in ALG6 are associated with CDG-Ic disorder (Imbach T et al, 1999; Sun L et al, 2005). The donor is a dolichol-phosphate-glucose (synthesized by ALG5).
R-HSA-446204 (Reactome) Cytosolic UAP1 catalyzes the reaction of N-acetyl-D-glucosamine 1-phosphate (GlcNAc1P) and UTP to UDP-N-acetyl-D-glucosamine and pyrophosphate. Structural studies indicate that the active form of the enzyme is a dimer (Peneff C et al, 2001).
R-HSA-446207 (Reactome) A second N-acetylglucosamine is added to the N-glycan precursor via a beta-1,4 linkage. This reaction is catalyzed by the ALG13:ALG14 complex, in which ALG13 functions as the catalyst and ALG14 functions as a membrane anchor which recruits ALG13 to the cytosolic face of ER (Gao XD et al, 2005).
R-HSA-446208 (Reactome) A second mannose is added to the N-glycan precursor via an alpha-1,3 linkage. The reaction is catalyzed by the mannosyltransferase ALG2. This is a bifunctional enzyme with both alpha 1,3- and alpha 1,6-mannosyltransferase activities. In humans, only the alpha 1,3 activity used in this reaction has been elucidated (Thiel et al. 2003). Defects in ALG2 are the cause of ALG2-CDG (CDG-1i; MIM:607906) (Thiel et al. 2003).
R-HSA-446209 (Reactome) The 14-sugar N-glycan precursor (aka lipid-linked oligosaccharide, LLO), synthesized in the previous reactions, is attached in a single step to a nascent protein, releasing the dolichyl phosphate anchor and the as-yet unfolded glycoprotein. The reaction occurs cotranslationally as the growing peptide chain leaves a ribosome associated with the ER membrane and enters the ER lumen. This reaction is catalyzed by the oligosaccharyltransferase (OST) complex, comprising at least seven proteins; DAD1 (Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit DAD1), DDOST (OST48 in yeast), RPN1 (ribophorin 1), RPN2 (ribophorin 2), OST4, TUSC3 (N33), MAGT1 (magnesium transporter protein 1) and either STT3A or STT3B (Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit STT3A and B), which contain the catalytic domain (Kelleher & Gilmore 2006). A mutation in RPN2 is associated with CDG-Ix (Vleugels et al. 2009). The signal for glycosylation is the consensus sequence Asn - X - Thr/Ser, where the first amino acid is always Asn, the second can be any amino acid except for Pro, and the third position may be Thr, Ser or Cys, with a preference for the first (Breuer et al. 2001). Not all Asn - X - Thr/Ser sites are modified in vivo (Petrescu et al. 2004).
R-HSA-446211 (Reactome) Dolichyl-phosphate-glucose is flipped toward the luminal side of the ER membrane (Imbach T et al, 1999). The exact mechanism and proteins involved in this step are not clear yet, but it is known that it must be carried out by a different flippase than the one that catalyzes the flipping of the N-glycan precursor (Sanyal S et al, 2008).
R-HSA-446212 (Reactome) The precursor of the N-glycan sugar, now in the form of (GlcNAc)2 (Man)5 (PP-Dol), is flipped across the ER membrane, moving it from the cytosolic side into the ER lumen. The exact mechanism of this translocation is not well understood: the protein RFT1 is known to be involved (Helenius et al. 2002), along with an unknown flippase, which is distinct from the one that flips the Dol-P linked precursors (Dol-P-Mannose and Dol-P-glucose) (Sanyal et al. 2008). Defects in RFT1 are associated with Congenital Disorder of Glycosylation 1N (CDG1N) (Haeuptle et al. 2008).
R-HSA-446214 (Reactome) Dolichyl-phosphate beta-glucosyltransferase (ALG5) associated with the endoplasmic reticulum (ER) membrane catalyzes the reaction of cytosolic UDP-glucose with dolichyl phosphate exposed on the cytosolic face of the ER membrane to form Dolichyl-P-glucose with its glucose moiety oriented toward the cytosol (Imbach T et al, 1999).
R-HSA-446215 (Reactome) The seventh mannose is added to the N-glycan precursor. This reaction occurs in the ER lumen and uses dolichyl phosphate D-mannose as the mannose donor with ALG9 mediating the reaction. Defects in ALG9 are the cause of congenital disorder of glycosylation type 1L (CDG1L) (Frank CG et al, 2004; Weinstein M et al, 2005). For many years ALG9 has been thought to be involved in bipolar affective disorder (Baysal BE et al, 2002), but this hypothesis has been proven wrong (Baysal BE et al, 2006).
R-HSA-446216 (Reactome) The last mannose is added to the N-glycan precursor. This reaction occurs in the ER lumen, uses Dolichyl phosphate D-mannose as the mannose donor, and is catalyzed by ALG9. Defects in ALG9 are the cause of congenital disorder of glycosylation type 1L (CDG1L) (Frank CG et al, 2004; Weinstein M et al, 2005). For many years ALG9 was thought to be involved in bipolar affective disorder (Baysal BE et al, 2002), but this hypothesis has been proven wrong (Baysal BE et al, 2006).
R-HSA-446218 (Reactome) A mannose is added to the N-glycan precursor via a beta-1,4 linkage. The reaction is catalyzed by ALG1 (Takahashi T et al, 2000). Defects in ALG1 lead to congenital disorder of glycosylation type 1K (CDG1K) (Schwarz et al. 2004; Kranz et al. 2004; Grubenmann et al. 2004).
R-HSA-446221 (Reactome) Mannose 1-phosphate is converted to GDP-Mannose by mannose-1-phosphate guanyltransferase alpha and beta forms (GMPPA/B). This enzyme had originally been characterized from rat and bovine sources (Verachtert H et al, 1966) and more recently from pig (Ning B and Elbein AD, 2000).
R-HSA-449715 (Reactome) Glucosamine-fructose 6-phosphate aminotransferases 1 and 2 (GFPT1,2) are the first and rate-limiting enzymes in the hexosamine synthesis pathway, and thus formation of hexosamines like N-acetylglucosamine (GlcNAc). These enzymes probably play a role in limiting the availability of substrates for the N- and O- linked glycosylation of proteins (McKnight et al. 1992, Oki et al. 1999). GFPT1 and 2 are required for normal functioning of neuromuscular synaptic transmission. Defects in GFPT1 lead to altered muscle fibre morphology and impaired neuromuscular junction development (Senderek et al. 2011).
R-HSA-449718 (Reactome) A third mannose is added to the N-glycan precursor by ALG2 using its alpha1,6-mannosyltransferase activity. This has been demonstrated experimentally in yeast (O'Reilly MK et al, 2006; Kämpf M et al, 2009); the human reaction is inferred by homology. Defects in ALG2 are the cause for CDG1I (Thiel C et al, 2003).
R-HSA-449734 (Reactome) Cytosolic GNPNAT1 catalyzes the reaction of glucosamine 6-phosphate and acetyl-CoA to form N-acetyl-glucosamine 6-phosphate (GlcNAc6P) and CoA-SH. Structural studies indicate that the active form of the enzyme is a dimer (Wang J et al, 2008).
R-HSA-532549 (Reactome) Mannose-6-phosphate isomerase (MPI) isomerises fructose 6-phosphate (Fru6P) to mannose 6-phosphate (Man6P) (Proudfoot et al. 1994). Defects in this gene are associated with congenital disorder of glycosylation type 1B (CDG1B). Oral administration of mannose is an efficient therapy against this defect (Schollen et al. 2000).
R-HSA-532667 (Reactome) A second glucose is removed from the N-linked glycan. The removal of an alpha1,3 glucose moiety is catalyzed by glucosidase II, a complex composed of an alpha subunit (GANAB) with catalytic activity and a beta subunit (GLU2B; PRKCSH), probably with regulatory and recruitment function (Pelletier MF et al, 2000). GANAB can exist in two different isoforms, but both are able to catalyze both of the reactions catalyzed by glucosidase II (Pelletier MF et al, 2000). Defects in PRKCSH are a cause of polycystic liver disease (PCLD).
R-HSA-532678 (Reactome) After the glycosylated precursor is attached to the protein, the outer alpha-1,2-linked glucose is removed by by mannosyl-oligosaccharide glucosidase (MOGS, GCS1 in yeast). This is a mandatory step for the protein folding control and glycan extension, and defects in MOGS are associated with congenital disorder of glycosylation type IIb (CDGIIb) (De Praeter et al. 2000, Völker et al. 2002).
R-HSA-535717 (Reactome) Calnexin (membrane protein) and calreticulin (soluble in ER) are two lectins (proteins that can bind a glycan) which recognize the mono-glucosylated form of the N-glycan and mediate the folding of the glycoproteins to which they are attached to (Ou WJ et al, 1993; Nauseef Wm et al, 1995). Calmegin is another chaperone with the same role expressed only in testis (van Lith M et al, 2007). These lectins act as chaperons, providing a protected environment where the unfolded glycoprotein can fold without forming interactions with other proteins or components in the ER. The unfolded protein can loop between these two steps multiple time, therefore this process is called the 'calnexin/calreticulin cycle'. If the protein achieves correct folding, it is modified by Mannosidase I and then moved to the cis-Golgi where the glycan is further processed.
R-HSA-548884 (Reactome) The UDP-glucose:glycoprotein glucosyltransferases 1 and 2 (UGGT1 and 2) are able to distinguish proteins with minor folding defects in the ERQC and reglucosylate them, by transferring a glucose (from dolichyl beta-D-glucosyl phosphate, DbGP) onto the alpha 1,3 mannose of the b (or c, not shown here) branch (Arnold et al. 2000, Arnold et al. 2003). The major affinity of these enzymes for proteins with minor folding defects has been demonstrated, but the exact mechanism that enable them to distinguish proteins with major and minor defects is still unknown (Pearse et al. 2008).
R-HSA-548890 (Reactome) While the protein is bound to the chaperone complex, the glycan is still accessible to glucosidase II, which eventually removes the last remaining glucose residue. This also results in breaking the interaction between the chaperone and the glycoprotein, independently of whether the latter has achieved proper folding (Pelletier MF et al, 2000). This has been interpreted as a 'timing mechanism', in which a protein has only a limited period of time to achieve correct folding when bound to the chaperone, to avoid the scenario where proteins that take too long to fold would block the availability of CNX or CRT. Proteins with folding defects get transported to the Endoplasmic Reticulum Quality Control Compartment, while proteins with correct folding are transported to the cis-Golgi where the glycan is further modified.
R-HSA-5693807 (Reactome) Tissue alpha-L-fucosidase (FUCA1) is a lysosomal enzyme that removes terminal L-fucose residues from the oligosaccharide chains of N-glycoproteins (NGPs). In humans, FUCA1 encodes the tissue enzyme, whilst FUCA2 encodes plasma alpha-L-fucosidase (Intra et al. 2007). Defects in FUCA1 can cause fucosidosis (FUCA1D; MIM:230000), a rare lysosomal storage disorder characterised by progressive psychomotor deterioration, angiokeratoma and growth retardation (Willems et al. 1999).
R-HSA-5693925 (Reactome) Human galactoside 3(4)-L-fucosyltransferase (FUT3) may be involved in Lewis blood group (Le) determination. Le+ individuals have an active enzyme while Le- individuals have an inactive enzyme. FUT3 catalyses alpha-1,3 and alpha-1,4 glycosidic linkages involved in the expression of Le blood groups. The 1,3-galactosyl derivative is shown here (Cameron et al. 1995).
R-HSA-6782685 (Reactome) Proteins with major folding defects are extracted from futile folding cycles in the calnexin chaperone system and the ER Quality Control Compartment, and are translocated back to the cytosol for degradation. The ER degradation-enhancing alpha-mannosidase-like proteins 1 and 3 (EDEM1 and 3) can catalyse the sequential hydrolysis of (GlcNAc)2 (Man)8 to (GlcNAc)2 (Man)7-5. The products are recognised by quality control proteins and become targets for ER-associated degradation (ERAD) (Ninagawa et al. 2014, Hirao et al. 2006).
R-HSA-742345 (Reactome) The human gene SLC35C1 encodes the GDP-fucose transporter FUCT1. It resides on the Golgi membrane and mediates the transport of GDP-fucose (GDP-Fuc) formed from a de novo pathway and/or a salvage pathway into the Golgi lumen. Defects in SLC35C1 causes the congenital disorder of glycosylation type 2C, also known as leukocyte adhesion deficiency type II (LAD2) (Lubke et al. 2001).
R-HSA-901006 (Reactome) A recently discovered protein called malectin is known to recognize the Glc(2)Man(9)GlcNAc(2) glycan (Schallus T et al, 2008). The exact role of this interaction is not clear but malectin is thought to regulate the availability of this substrate to glucosidase II, or to act as a chaperone to stabilize the unfolded protein.
R-HSA-901024 (Reactome) The enzyme ER Man I can slowly trim up to four of the mannoses on the N-glycan on unfolded proteins accumulated in the ER. This step describes the removal of the mannose in the A position (Hirao et al, 2006; Frenkel et al, 2003).
R-HSA-901036 (Reactome) Removal of the second mannose on the alpha 1,3 branch (Frenzel Z et al, 2003).
R-HSA-901039 (Reactome) The enzyme ER Man I can slowly trim up to four of the mannoses on the N-glycan on unfolded proteins accumulated in the ER. This step describes the removal of the mannose in the C position (Gonzalez et al. 1999, Karaveg et al. 2005, Avezov et al. 2008).
R-HSA-901047 (Reactome) ERp57/ERp27 is a thiol-oxidoreductase that interacts with calnexin and mediates the formation of disulfide bonds in the unfolded glycoprotein (Alanen HI et al, 2006).
R-HSA-901074 (Reactome) The enzyme ER Man I can slowly trim up to four of the mannoses on the N-glycan on unfolded proteins accumulated in the ER. This step describes the removal of the mannose in the B position (Gonzalez et al. 1999, Karaveg et al. 2005, Avezov et al. 2008). The ER degradation-enhancing alpha-mannosidase-like protein 2 (EDEM2) is also able to hydrolyse the alpha-1,2-mannose from (GlcNAc)2 (Man)9 to form (GlcNAc)2 (Man)8b (Ninagawa et al. 2014).
R-HSA-912291 (Reactome) Proteins with folding defects get transported to the Endoplasmic Reticulum Quality Control Compartment (Molinari, 2007).
R-HSA-915148 (Reactome) Correctly folded proteins, after being released from the Calnexin/Calreticulin cycle, are translocated to the Golgi (Hauri H et al, 2000; Hauri HP et al, 2002; Molinari, 2007).
R-HSA-947991 (Reactome) The LMAN1(also known as ERGIC-53)/MCFD2 complex recognizes Man8 and Man9 N-glycans released by the Calnexin/Calreticulin cycle and mediate their transport to the Golgi (Nyefeler B et al, 2003; Zhang B et al, 2003). Man8 glycan transfer is shown here.
R-HSA-964737 (Reactome) In the cis-Golgi, Man7, Man8 or Man9 N-glycans are progressively trimmed to Man5 N-glycans. The reaction can be catalyzed by one of three known mannosidases, expressed in different tissues and with slightly different affinity. These enzymes trim the mannoses in a different order (Tremblay and Herscovics, 2000), but produce the same output with 5 mannoses.
A small confusion on the nomenclature of these genes coding for these enzymes is present in the literature: the standard HGNC symbols are MAN1A1, MAN1A2, MAN1C1, but MAN1A2 is also referred to as MAN1B in certain publications, while MAN1B1 is the enzyme acting in the ERQC compartment on unfolded glycoproteins. Moreover, the names do not correspond to a preference of these enzymes for which of the three mannose branches these trim first.
R-HSA-964759 (Reactome) Cells exposed to castanospermine or 1-deoxynojirimycin (inhibitors of the glucosidase enzymes GCS1 and GANAB), are still able to carry out glycosylation and produce complex glycans. This is due to the existence of an alternative route catalyzed by the enzyme endomannosidase (Moore and Spiro, 1990).
Glycoproteins that pass through this route probably skip or have a reduced interaction with the Calnexin/Calreticulin cycle, and are transported to the cis-golgi through a route that has not been described yet (probably through the general ER to Golgi flow). Here, the Endomannosidase enzyme, which resides on the Golgi membrane (Hardt et al 2005; Hamilton et al 2005) is able to remove the tri-, di-, or mono-glucose substituted mannose on branch A, leading to a deglucosylated N-glycan structure (Lubas and Spiro, 1988).
R-HSA-964768 (Reactome) This is the first committed step in the synthesis of complex and hybrid N-glycans and is specific to multicellular organisms (Kumar et al, 1990; Hull et al, 1991). Hybri N-glycans are important for inter-cellular interactions and therefore during embryonic development of multicellular organisms, and it is probable that these pathways have evolved just before the emergence of multicellular organisms. Support for this hypothesis is provided by the phenomena of CDG and by the effects of null mutations in C.elegans.
R-HSA-964825 (Reactome) In the cis-Golgi, Man7, Man8 or Man9 N-glycans are progressively trimmed to Man5 N-glycans. The reaction can be catalyzed by one of three known mannosidases, expressed in different tissues and with slightly different affinity. These enzymes trim the mannoses in a different order (Tremblay and Herscovics, 2000), but produce the same output with 5 mannoses.
A small confusion on the nomenclature of these genes coding for these enzymes is present in the literature: the standard HGNC symbols are MAN1A1, MAN1A2, MAN1C1, but MAN1A2 is also referred to as MAN1B in certain publications, while MAN1B1 is the enzyme acting in the ERQC compartment on unfolded glycoproteins. Moreover, the names do not correspond to a preference of these enzymes for which of the three mannose branches these trim first.
R-HSA-964830 (Reactome) In the cis-Golgi, Man7, Man8 or Man9 N-glycans are progressively trimmed to Man5 N-glycans. The reaction can be catalyzed by one of three known mannosidases, expressed in different tissues and with slightly different affinity. These enzymes trim the mannoses in a different order (Tremblay and Herscovics, 2000), but produce the same output with 5 mannoses.
A small confusion on the nomenclature of these genes coding for these enzymes is present in the literature: the standard HGNC symbols are MAN1A1, MAN1A2, MAN1C1, but MAN1A2 is also referred to as MAN1B in certain publications, while MAN1B1 is the enzyme acting in the ERQC compartment on unfolded glycoproteins. Moreover, the names do not correspond to a preference of these enzymes for which of the three mannose branches these trim first.
R-HSA-975814 (Reactome) The removal of mannoses on the alpha,1,6 arm by MAN2A1 or MAN2A2 is required for efficient formation of complex-type N-glycans (Misago M et al, 1995; Crispin M et al, 2007). These two enzymes carry out the same function and the disruption of both inhibits the formation of complex N-glycans in vivo (Akama TO et al, 2006).
R-HSA-975829 (Reactome) The addition of a GlcNAc on the alpha-1,6 mannose on the alpha-1,4 branch is required for the synthesis of complex N-glycans (Tan et al. 1995). Defects in this gene are associated with Congenital Disorder of Glycosylation type IIa (Tan et al. 1996, Wang et al. 2002).
R-HSA-975902 (Reactome) Addition of sialic acid to galactose-containing N-glycan. Sialic acid is usually found at terminal positions of the N-glycan. This imparts a negative charge at neutral pH which affects the chemico-physical and biological properties of the N-glycans (for review, see Schauer 2000); moreover, this modification can lead to the addition of extraordinarily long antennae such as polysialic acid (hundreds of sials) or polylactosamine repeats (dozens of disaccharide repeats) (Harduin-Lepers 2001), while the number of modifications on the antennae of N-glycans is usually lower.
There are over 20 sialyltransferases known in humans, 5 of which are known to act on N-glycans. Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1) is the only sialyltransferase known to transfer sialic acid to galactose on N-Glycans (Dall'Olio 2000). A second beta-galactoside alpha-2,6-sialyltransferase has been characterized, but this enzyme acts mainly on oligosaccharides (Krzewinski-Recchi et al. 2003). Neu5Ac can also be added via an alpha-2,3-linkage to galactose on N-glycans by CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 4 (ST3GAL4) (Ellies et al. 2002). ST8Sia II (ST8SIA2), ST8Sia III (ST8SIA3), and ST8Sia IV (ST8SIA6) have alpha-2,8-activity (Angata et al. 1997, Angata et al. 2000, Angata & Fuduka 2003).
R-HSA-975903 (Reactome) N-acetylglucosaminyltransferase (GnT)-IV catalyzes the addition of GlcNAc beta,1,4 on the GlcNAc beta1,2 Man,alpha1,3 arm of both complex and hybrid N-glycans (Oguri S et al, 2006). Two human GnT-IV isozymes have been characterized (MGAT4A, MGAT4B) , plus a putative MGAT4C on chromosome 2 (Furukawa T et al, 1999). Aberrant expression of MGAT4A or MGAT4B is associated with pancreatic cancer (Ide Y et al, 2006; Kudo T et al , 2007)
R-HSA-975916 (Reactome) N-acetylglucosaminyltransferase (GnT)-V catalyzes the addition of GlcNAc beta 1,4 on the GlcNAc beta1,2 Man,alpha1,6 arm of complex type N-Glycans (Park C et al, 1999; Granowski M et al, 2000; Wang L et al, 2007). The activity of MGAT5 competes with MGAT3 (Pinho SS et al, 2009) and is associated with gastric cancer (Tian H et al, 2008) and multiple sclerosis (Brynedal B et al, 2010).
R-HSA-975919 (Reactome) Addition of a galactose residue on N-acetylglucosamine. The family of beta 4-galactosyltransferases is composed by at least six known members with different K(m) and acceptor specifities (Guo S et al, 2001) and probably originated by duplication (Lo NW et al, 1998). B4GALT1 is associated with Congenital Disorder of Glycosylation of type IId (Hansske B et al, 2002), and is expressed as two splicing isoforms of which only one is localizated in the Golgi system (Lopez LC et al, 1991; Schaub BE et al, 2006). B4GALT2 is key in the regulation of proteins involved in neuronal development (Sasaki N et
al, 2005).
R-HSA-975926 (Reactome) The addition of a bisecting GlcNAc to a complex N-glycan by MGAT3 is one of the most important regulatory steps in N-glycosylation, directing the pathway toward the synthesis of complex and hybrid N-glycans. This addition changes the structure of the N-glycan and inhibits further modification by MGAT2, MGAT4, MGAT5A/B and FUT8. Defects in MGAT3 have been shown to be associated with predisposition to cancer and several developmental defects (Song et al 2010; Stanley 2002).
RFT1mim-catalysisR-HSA-446212 (Reactome)
SLC35C1mim-catalysisR-HSA-742345 (Reactome)
SRD5A3mim-catalysisR-HSA-4419979 (Reactome)
ST3GAL4mim-catalysisR-HSA-1022129 (Reactome)
ST6GAL1mim-catalysisR-HSA-975902 (Reactome)
ST8SIA2,3,6mim-catalysisR-HSA-1022133 (Reactome)
UDP-GalR-HSA-975919 (Reactome)
UDP-GlcNAcArrowR-HSA-446204 (Reactome)
UDP-GlcNAcR-HSA-446191 (Reactome)
UDP-GlcNAcR-HSA-446207 (Reactome)
UDP-GlcNAcR-HSA-964768 (Reactome)
UDP-GlcNAcR-HSA-975829 (Reactome)
UDP-GlcNAcR-HSA-975903 (Reactome)
UDP-GlcNAcR-HSA-975916 (Reactome)
UDP-GlcNAcR-HSA-975926 (Reactome)
UDP-GlcR-HSA-446214 (Reactome)
UDPArrowR-HSA-446207 (Reactome)
UDPArrowR-HSA-964768 (Reactome)
UGGT1,2mim-catalysisR-HSA-548884 (Reactome)
UMPArrowR-HSA-446191 (Reactome)
UTPR-HSA-446204 (Reactome)
glucosidase IImim-catalysisR-HSA-532667 (Reactome)
glucosidase IImim-catalysisR-HSA-548890 (Reactome)
pPNOLArrowR-HSA-4419986 (Reactome)
pPNOLR-HSA-4419979 (Reactome)
pPPP phosphatasemim-catalysisR-HSA-4419986 (Reactome)
pPPPArrowR-HSA-4419978 (Reactome)
pPPPR-HSA-4419986 (Reactome)
unfolded

protein:(Glc)1 (GlcNAc)2 (Man)9

(Asn)1:chaperone:ERp57		ArrowR-HSA-901047 (Reactome)
unfolded

protein:(Glc)1

(GlcNAc)2 (Man)8b		ArrowR-HSA-548884 (Reactome)
unfolded

protein:(Glc)1 (GlcNAc)2 (Man)9

(Asn)1:chaperone		ArrowR-HSA-535717 (Reactome)
unfolded

protein:(Glc)1 (GlcNAc)2 (Man)9

(Asn)1:chaperone		R-HSA-901047 (Reactome)
unfolded

protein:(Glc)1 (GlcNAc)2 (Man)9

(Asn)1		ArrowR-HSA-1017228 (Reactome)
unfolded

protein:(Glc)1 (GlcNAc)2 (Man)9

(Asn)1		ArrowR-HSA-532667 (Reactome)
unfolded

protein:(Glc)1 (GlcNAc)2 (Man)9

(Asn)1		R-HSA-535717 (Reactome)
unfolded

protein:(Glc)1

(GlcNAc)2 (Man)9		R-HSA-1017228 (Reactome)
unfolded

protein:(Glc)2 (GlcNAc)2 (Man)9

(Asn)1:malectin		ArrowR-HSA-901006 (Reactome)
unfolded

protein:(Glc)2 (GlcNAc)2 (Man)9

(Asn)1:malectin		R-HSA-532667 (Reactome)
unfolded

protein:(Glc)2 (GlcNAc)2 (Man)9

(Asn)1		ArrowR-HSA-532678 (Reactome)
unfolded

protein:(Glc)2 (GlcNAc)2 (Man)9

(Asn)1		R-HSA-901006 (Reactome)
unfolded

protein:(Glc)3 (GlcNAc)2 (Man)9

(Asn)1		ArrowR-HSA-446209 (Reactome)
unfolded

protein:(Glc)3 (GlcNAc)2 (Man)9

(Asn)1		R-HSA-532678 (Reactome)
unfolded

protein:(GlcNAc)2

(Man)5		ArrowR-HSA-1022127 (Reactome)
unfolded

protein:(GlcNAc)2

(Man)5		ArrowR-HSA-6782685 (Reactome)
unfolded

protein:(GlcNAc)2

(Man)5		R-HSA-1022127 (Reactome)
unfolded

protein:(GlcNAc)2

(Man)7aa		ArrowR-HSA-901036 (Reactome)
unfolded

protein:(GlcNAc)2

(Man)8a		ArrowR-HSA-901024 (Reactome)
unfolded

protein:(GlcNAc)2

(Man)8a		R-HSA-901036 (Reactome)
unfolded

protein:(GlcNAc)2

(Man)8b		ArrowR-HSA-901074 (Reactome)
unfolded

protein:(GlcNAc)2

(Man)8b		R-HSA-548884 (Reactome)
unfolded

protein:(GlcNAc)2

(Man)8b		R-HSA-6782685 (Reactome)
unfolded

protein:(GlcNAc)2

(Man)8c		ArrowR-HSA-901039 (Reactome)
unfolded

protein:glycan (no

glucose)		ArrowR-HSA-548890 (Reactome)
unfolded protein:glycan:chaperone:ERp57R-HSA-548890 (Reactome)
unfolded proteinR-HSA-446209 (Reactome)
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