NAGA encodes lysosomal alpha-N-acetylgalactosaminidase (alpha-NAGAL, EC 3.2.1.49), a soluble homodimeric glycoside hydrolase family 27 exoglycosidase that removes terminal alpha-linked N-acetylgalactosamine residues from glycopeptides (including mucin-type O-glycans and blood group A determinants) and glycolipids such as blood group A glycolipids in the lysosomal lumen. It is a paralog of alpha-galactosidase A (GLA) and retains only a weak side activity toward alpha-galactosides. Biallelic loss of NAGA causes NAGA deficiency (Schindler disease type I, Kanzaki disease and the intermediate type III), with lysosomal storage and urinary excretion of alpha-GalNAc-terminated glycopeptides and oligosaccharides.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004553 hydrolase activity, hydrolyzing O-glycosyl compounds | IEA GO_REF:0000120 | MODIFY | Summary: Generic O-glycosyl hydrolase activity is correct but uninformative; the specific activity is known. Reason: Replace with the specific EC 3.2.1.49 activity term, which is experimentally established. Proposed replacements: alpha-N-acetylgalactosaminidase activity Supporting Evidence: PMID:19683538 alpha-N-acetylgalactosaminidase (alpha-NAGAL; E.C. 3.2.1.49) is a lysosomal exoglycosidase that cleaves terminal alpha-N-acetylgalactosamine residues from glycopeptides and glycolipids |
| GO:0004557 alpha-galactosidase activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: NAGA has only a weak, promiscuous alpha-galactosidase activity inherited from the GH27 family. Reason: Kinetics show a ~20-fold higher KM for the alpha-galactoside than for the alpha-GalNAc substrate; the physiological alpha-galactosidase in lysosomes is GLA. The activity is real but not the core function. Supporting Evidence: PMID:19683538 The pNP-Ξ±-GalNAc substrate had a markedly lower KM (0.70 mM) compared to pNP-Ξ±-Gal (15.2 mM). |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | MODIFY | Summary: Cytoplasm is an uninformative location for a soluble lysosomal acid hydrolase. Reason: NAGA acts in the lysosomal lumen; lysosomal lumen is the appropriate specific location. Proposed replacements: lysosomal lumen Supporting Evidence: PMID:19683538 alpha-N-acetylgalactosaminidase (alpha-NAGAL; E.C. 3.2.1.49) is a lysosomal exoglycosidase that cleaves terminal alpha-N-acetylgalactosamine residues from glycopeptides and glycolipids file:human/NAGA/NAGA-uniprot.txt SUBCELLULAR LOCATION: Lysosome |
| GO:0005764 lysosome | EXP PMID:9741689 Degradation of blood group A glycolipid A-6-2 by normal and ... | ACCEPT | Summary: NAGA is a lysosomal enzyme. Reason: Lysosomal localisation is established by biochemical purification as a lysosomal hydrolase and by the lysosomal storage phenotype of NAGA deficiency. Supporting Evidence: PMID:19683538 alpha-N-acetylgalactosaminidase (alpha-NAGAL; E.C. 3.2.1.49) is a lysosomal exoglycosidase that cleaves terminal alpha-N-acetylgalactosamine residues from glycopeptides and glycolipids PMID:9741689 Skin fibroblasts from patients with alpha-N-acetylgalactosaminidase deficiency (Schindler disease) cannot degrade the major blood group A glycolipid. |
| GO:0005764 lysosome | IEA GO_REF:0000120 | ACCEPT | Summary: NAGA is a lysosomal enzyme. Reason: Lysosomal localisation is established by biochemical purification as a lysosomal hydrolase and by the lysosomal storage phenotype of NAGA deficiency. Supporting Evidence: PMID:19683538 alpha-N-acetylgalactosaminidase (alpha-NAGAL; E.C. 3.2.1.49) is a lysosomal exoglycosidase that cleaves terminal alpha-N-acetylgalactosamine residues from glycopeptides and glycolipids PMID:9741689 Skin fibroblasts from patients with alpha-N-acetylgalactosaminidase deficiency (Schindler disease) cannot degrade the major blood group A glycolipid. |
| GO:0005975 carbohydrate metabolic process | IEA GO_REF:0000002 | MODIFY | Summary: Carbohydrate metabolic process is too general for NAGA. Reason: NAGA participates specifically in lysosomal catabolism of glycoproteins/glycopeptides and glycolipids. Proposed replacements: glycoprotein catabolic process Supporting Evidence: PMID:19683538 alpha-N-acetylgalactosaminidase (alpha-NAGAL; E.C. 3.2.1.49) is a lysosomal exoglycosidase that cleaves terminal alpha-N-acetylgalactosamine residues from glycopeptides and glycolipids |
| GO:0008456 alpha-N-acetylgalactosaminidase activity | IDA PMID:19683538 The 1.9 a structure of human alpha-N-acetylgalactosaminidase... | ACCEPT | Summary: Alpha-N-acetylgalactosaminidase activity is the defining core molecular function of NAGA. Reason: Purified recombinant human alpha-NAGAL hydrolyses terminal alpha-GalNAc residues (EC 3.2.1.49), and its loss causes Schindler/Kanzaki disease. Supporting Evidence: PMID:19683538 alpha-N-acetylgalactosaminidase (alpha-NAGAL; E.C. 3.2.1.49) is a lysosomal exoglycosidase that cleaves terminal alpha-N-acetylgalactosamine residues from glycopeptides and glycolipids PMID:2174888 the lysosomal glycohydrolase that cleaves alpha-N-acetylgalactosaminyl moieties from glycoconjugates |
| GO:0008456 alpha-N-acetylgalactosaminidase activity | IEA GO_REF:0000003 | ACCEPT | Summary: Alpha-N-acetylgalactosaminidase activity is the defining core molecular function of NAGA. Reason: Purified recombinant human alpha-NAGAL hydrolyses terminal alpha-GalNAc residues (EC 3.2.1.49), and its loss causes Schindler/Kanzaki disease. Supporting Evidence: PMID:19683538 alpha-N-acetylgalactosaminidase (alpha-NAGAL; E.C. 3.2.1.49) is a lysosomal exoglycosidase that cleaves terminal alpha-N-acetylgalactosamine residues from glycopeptides and glycolipids PMID:2174888 the lysosomal glycohydrolase that cleaves alpha-N-acetylgalactosaminyl moieties from glycoconjugates |
| GO:0008456 alpha-N-acetylgalactosaminidase activity | TAS PMID:2174888 Human alpha-N-acetylgalactosaminidase-molecular cloning, nuc... | ACCEPT | Summary: Alpha-N-acetylgalactosaminidase activity is the defining core molecular function of NAGA. Reason: Purified recombinant human alpha-NAGAL hydrolyses terminal alpha-GalNAc residues (EC 3.2.1.49), and its loss causes Schindler/Kanzaki disease. Supporting Evidence: PMID:19683538 alpha-N-acetylgalactosaminidase (alpha-NAGAL; E.C. 3.2.1.49) is a lysosomal exoglycosidase that cleaves terminal alpha-N-acetylgalactosamine residues from glycopeptides and glycolipids PMID:2174888 the lysosomal glycohydrolase that cleaves alpha-N-acetylgalactosaminyl moieties from glycoconjugates |
| GO:0009311 oligosaccharide metabolic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Oligosaccharide metabolic process is consistent with removal of terminal alpha-GalNAc from glycan chains but is broad. Reason: Phylogenetically inherited from the GH27 family; acceptable as a broad, non-core process. Supporting Evidence: PMID:19683538 alpha-N-acetylgalactosaminidase (alpha-NAGAL; E.C. 3.2.1.49) is a lysosomal exoglycosidase that cleaves terminal alpha-N-acetylgalactosamine residues from glycopeptides and glycolipids |
| GO:0016052 carbohydrate catabolic process | IDA PMID:19683538 The 1.9 a structure of human alpha-N-acetylgalactosaminidase... | KEEP AS NON CORE | Summary: Carbohydrate catabolic process is correct but general. Reason: The structural/enzymological study shows hydrolysis of carbohydrate substrates; more specific glycoprotein and glycolipid catabolic terms capture the core role. Supporting Evidence: PMID:19683538 alpha-N-acetylgalactosaminidase (alpha-NAGAL; E.C. 3.2.1.49) is a lysosomal exoglycosidase that cleaves terminal alpha-N-acetylgalactosamine residues from glycopeptides and glycolipids |
| GO:0016139 glycoside catabolic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Glycoside catabolic process is a broad parent of NAGA's glycoconjugate catabolism. Reason: Correct in the general sense (hydrolysis of alpha-GalNAc glycosides) but less informative than glycoprotein/glycolipid catabolic process. Supporting Evidence: PMID:19683538 alpha-N-acetylgalactosaminidase (alpha-NAGAL; E.C. 3.2.1.49) is a lysosomal exoglycosidase that cleaves terminal alpha-N-acetylgalactosamine residues from glycopeptides and glycolipids |
| GO:0019377 glycolipid catabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: NAGA is required for lysosomal degradation of blood group A glycolipids. Reason: NAGA-deficient fibroblasts virtually fail to degrade blood group A glycolipid A-6-2; glycolipid catabolism is a core process. Supporting Evidence: PMID:9741689 Skin fibroblasts from patients with alpha-N-acetylgalactosaminidase deficiency (Schindler disease) cannot degrade the major blood group A glycolipid. PMID:19683538 alpha-N-acetylgalactosaminidase (alpha-NAGAL; E.C. 3.2.1.49) is a lysosomal exoglycosidase that cleaves terminal alpha-N-acetylgalactosamine residues from glycopeptides and glycolipids |
| GO:0019377 glycolipid catabolic process | IMP PMID:9741689 Degradation of blood group A glycolipid A-6-2 by normal and ... | ACCEPT | Summary: NAGA is required for lysosomal degradation of blood group A glycolipids. Reason: NAGA-deficient fibroblasts virtually fail to degrade blood group A glycolipid A-6-2; glycolipid catabolism is a core process. Supporting Evidence: PMID:9741689 Skin fibroblasts from patients with alpha-N-acetylgalactosaminidase deficiency (Schindler disease) cannot degrade the major blood group A glycolipid. PMID:19683538 alpha-N-acetylgalactosaminidase (alpha-NAGAL; E.C. 3.2.1.49) is a lysosomal exoglycosidase that cleaves terminal alpha-N-acetylgalactosamine residues from glycopeptides and glycolipids |
| GO:0042803 protein homodimerization activity | IPI PMID:19683538 The 1.9 a structure of human alpha-N-acetylgalactosaminidase... | KEEP AS NON CORE | Summary: NAGA is a homodimer in its crystal structure. Reason: Homodimerization is a structural property of the active enzyme rather than its biological function. Supporting Evidence: PMID:19683538 Human Ξ±-NAGAL is a homodimer with each monomer containing 394 residues |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: Detection in urinary/prostatic exosome proteomes is a high-throughput observation. Reason: Lysosomal hydrolases are frequently detected in exosome proteomes; this does not reflect a site of NAGA function. Supporting Evidence: PMID:23533145 In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine |
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Download this section (compressed HTML)Q: Which glycoconjugates are the quantitatively dominant in vivo substrates of NAGA in neurons versus skin endothelium, and does this explain the divergent Schindler type I and Kanzaki phenotypes?
Suggested experts: lysosomal glycobiology experts
Experiment: Glycomic profiling of lysosome-enriched fractions from NAGA-null human iPSC-derived neurons and endothelial cells.
Hypothesis: Different cell types accumulate different alpha-GalNAc-terminated glycoconjugates, accounting for tissue-specific disease.
Type: glycomics
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