Degradation pathway of sphingolipids, including diseases (WP4153)

Homo sapiens

Test pathway to include dieases in pathways, in order to deduce biomarkers.

Authors

Denise Slenter , Andra Waagmeester , Egon Willighagen , Ado , Irene Hemel , Kristina Hanspers , Finterly Hu , Friederike Ehrhart , and Eric Weitz

Activity

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Organisms

Homo sapiens

Communities

Inherited Metabolic Disorders (IMD) Pathways Rare Diseases

Annotations

Pathway Ontology

altered sphingolipid metabolic pathway glycosphingolipid metabolic pathway lacto-series glycosphingolipid metabolic pathway sphingolipid biosynthetic pathway sphingolipid metabolic pathway sphingolipid degradation pathway

Disease Ontology

Krabbe disease Niemann-Pick disease GM1 gangliosidosis GM2 gangliosidosis, AB variant gangliosidosis metachromatic leukodystrophy Niemann-Pick disease type B GM2 gangliosidosis disease Sandhoff disease Fabry disease Farber lipogranulomatosis Tay-Sachs disease Gaucher's disease Niemann-Pick disease type A

Participants

Label Type Compact URI Comment
Digalactosylceramide Metabolite chebi:134506 AKA Gal-α(1-4)-Gal-Cer
Digalactosylceramide beta Metabolite chebi:134507
Globoside Metabolite chebi:61360 AKA GalNAc -ß(1-3)Gal-Glc-Cer
Globoside example 1 Metabolite chebi:88167 N-acetyl-beta-D-galactosaminyl-(1->3)-alpha-D-galactosyl-(1->4)-beta-D-galactosyl-(1->4)-beta-D-glucosyl-(1->1')-ceramide
globotriaosylceramide Metabolite pubchem.compound:66616222 also known as CD77, Gb3, and ceramide trihexoside
AKA Gal-α(1-4)-Gal-Glc-Cer
Globoside example 2 Metabolite chebi:18259 N-acetyl-beta-D-galactosaminyl-(1->3)-alpha-D-galactosyl-(1->4)-beta-D-galactosyl-(1->4)-beta-D-glucosyl-(1->1')-N-acylsphing-4-enine
Digalactosylceramide alpha Metabolite chebi:134506 alpha-D-galactosyl-(1->4)-beta-D-galactosyl-N-(pentacosanoyl)sphingosine
GA2 Metabolite chebi:27731 ganglioside GA2
AKA GalNAc-ß-(1-4)-Gal-Glc-Cer
GM3 Metabolite chebi:79210 ganglioside GM3
AKA Α(2,3)NeuAc-Gal-ß(1-4)-Glc-Cer
Ceramide Metabolite chebi:17761
Sphingosine Metabolite wikidata:Q46298
galactosyl-ceramide Metabolite wikidata:Q2756638 Galactocerebroside
AKA Gal-ß(1-1)-Cer
Sphingomyelin Metabolite wikidata:Q423143
Glucosylceramide Metabolite wikidata:Q35662896 AKA Glc-ß(1-1)-Cer
Sulfatide Metabolite wikidata:Q408584 AKA O 3 S-3-Gal-Cer
lactosylceramide Metabolite wikidata:Q3215908 AKA Gal-ß(1-4)-Glc-Cer
GM2 Metabolite chebi:79218 ganglioside GM2
AKA GalNAc-ß(1-4)-Gal[NeuAc]-Glc-Cer
GM1 Metabolite chebi:18216 aka ganglioside GM1a, GM1a
AKA Gal-ß(1-3)-GalNAc-Gal[NeuAc]-Glc-Cer
GA1 Metabolite chebi:27938 ganglioside GA1
AKA Gal-ß(1-3)-GalNAc-Gal-Glc-Cer
SCARB2 GeneProduct ncbigene:950 AKA scavenger receptor class B, member 2/ lysosomal intergral membrane protein 2
PSAP GeneProduct ncbigene:5660
GLB1 GeneProduct ensembl:ENSG00000170266 GM1-beta-galactosidase 1
GLB1 GeneProduct ensembl:ENSG00000170266 GM1-beta-galactosidase 1
GLB1 GeneProduct ensembl:ENSG00000170266 GM1-beta-galactosidase 1
NPC1 GeneProduct ncbigene:4864 AKA scavenger receptor class B, member 2/ lysosomal intergral membrane protein 2
NPC2 GeneProduct ncbigene:10577 AKA scavenger receptor class B, member 2/ lysosomal intergral membrane protein 2
LIPA GeneProduct ensembl:ENSG00000107798 AKA scavenger receptor class B, member 2/ lysosomal intergral membrane protein 2
HEXB Protein uniprot:P07686
GM1-beta-galactosidase (GLB): Protein eccode:3.2.1.23
Sap-B Protein interpro:IPR008139 SaposinB
HEXA Protein uniprot:P06865 Hexosaminidase A; HEXA and the cofactor GM2 activator protein catalyze the degradation of the GM2 gangliosides
Sialidase 2 Protein uniprot:Q9Y3R4
Acrylsulfatase A Protein ensembl:ENSG00000100299 Arylsulfatase A (or cerebroside-sulfatase)
Sialidase 1 Protein uniprot:Q99519
Sphingomyelinase Protein eccode:3.1.4.12 Sphingomyelin phosphodiesterase (also known as neutral sphingomyelinase, sphingomyelinase, or SMase)
Sialidase Protein interpro:IPR004124
Glucosylceramide-beta-glucosidase Protein uniprot:P04062 Based on disorder (Goucher), this enzyme is assumed to be GBA)
GM2A Protein ncbigene:2760 GM2-Activator
Beta-hexosaminidase A, B: Protein eccode:3.2.1.52
Alpha-galactosidase A Protein ncbigene:2717
Sialidase 3 Protein uniprot:Q9UQ49
Alpha-galactosidase A Protein ncbigene:2717
Acid ceramidase Protein eccode:3.5.1.23 Acid ceramidase (N-acylsphingosine deacylase, ASAH1)
GalCer-beta-galactosidase Protein eccode:3.2.1.46 GALCERase
Sialidase 4 Protein uniprot:Q8WWR8
HEXA Protein ensembl:ENSG00000213614
GM2-activator Protein ncbigene:2760
Sap-B Protein uniprot:P07602 Sap-B is assumed to represent Saposin-B, which 'stimulates the hydrolysis of galacto-cerebroside sulfate by arylsulfatase A (EC 3.1.6.8), GM1 gangliosides by beta-galactosidase (EC 3.2.1.23) and globotriaosylceramide by alpha-galactosidase A (EC 3.2.1.22). Saposin-B forms a solubilizing complex with the substrates of the sphingolipid hydrolases.' Source: https://www.uniprot.org/uniprotkb/P07602/entry
Alternative names: Cerebroside sulfate activator (CSAct) DispersinSphingolipid activator protein 1 (SAP-1) Sulfatide/GM1 activator
GM1-beta-galactosidease (GLB): Protein eccode:3.2.1.23
GM2-activator Protein ncbigene:2760
Sap-B Protein interpro:IPR008139
Sap-B Protein uniprot:P07602 Sap-B is assumed to represent Saposin-B, which 'stimulates the hydrolysis of galacto-cerebroside sulfate by arylsulfatase A (EC 3.1.6.8), GM1 gangliosides by beta-galactosidase (EC 3.2.1.23) and globotriaosylceramide by alpha-galactosidase A (EC 3.2.1.22). Saposin-B forms a solubilizing complex with the substrates of the sphingolipid hydrolases.' Source: https://www.uniprot.org/uniprotkb/P07602/entry
Alternative names: Cerebroside sulfate activator (CSAct) DispersinSphingolipid activator protein 1 (SAP-1) Sulfatide/GM1 activator
Sap-C Protein uniprot:P07602 Sap-C is assumed to represent Saposin-C, which ' stimulates the hydrolysis of glucosylceramide by beta-glucosylceramidase (EC 3.2.1.45) and galactosylceramide by beta-galactosylceramidase (EC 3.2.1.46). Saposin-C apparently acts by combining with the enzyme and acidic lipid to form an activated complex, rather than by solubilizing the substrate.' Source:[https://www.uniprot.org/uniprotkb/P07602/entry]
'Saposin C is one of four homologous proteins derived from sequential cleavage of the saposin precursor protein, prosaposin.' [PMID:22652185]
Alternative names: A1 activatorCo-beta-glucosidaseGlucosylceramidase activatorSphingolipid activator protein 2 (SAP-2)
Amino acid sequence of saposin C: C'-SDVYCEVCEFLVKEVTKLIDNNKTEKEILDAFDKMCSKLPKSLSEECQEVVDTYGSSILSILLEEVSPELVCSMLHLCSG-N' [PMID:22652185]
Sap-C Protein uniprot:P07602 Sap-C is assumed to represent Saposin-C, which ' stimulates the hydrolysis of glucosylceramide by beta-glucosylceramidase (EC 3.2.1.45) and galactosylceramide by beta-galactosylceramidase (EC 3.2.1.46). Saposin-C apparently acts by combining with the enzyme and acidic lipid to form an activated complex, rather than by solubilizing the substrate.' Source:[https://www.uniprot.org/uniprotkb/P07602/entry]
Alternative names: A1 activatorCo-beta-glucosidaseGlucosylceramidase activatorSphingolipid activator protein 2 (SAP-2)
Sap-C Protein uniprot:P07602 Sap-C is assumed to represent Saposin-C, which ' stimulates the hydrolysis of glucosylceramide by beta-glucosylceramidase (EC 3.2.1.45) and galactosylceramide by beta-galactosylceramidase (EC 3.2.1.46). Saposin-C apparently acts by combining with the enzyme and acidic lipid to form an activated complex, rather than by solubilizing the substrate.' Source:[https://www.uniprot.org/uniprotkb/P07602/entry]
Alternative names: A1 activatorCo-beta-glucosidase Glucosylceramidase activator Sphingolipid activator protein 2 (SAP-2)
Glucosylceramide-beta-glucosidase Protein uniprot:P54803 Based on disorder (Krabbe), this enzyme is assumed to be GALC)
Sap-A Protein interpro:IPR003119
Sap-B Protein uniprot:P07602 Sap-B is assumed to represent Saposin-B, which 'stimulates the hydrolysis of galacto-cerebroside sulfate by arylsulfatase A (EC 3.1.6.8), GM1 gangliosides by beta-galactosidase (EC 3.2.1.23) and globotriaosylceramide by alpha-galactosidase A (EC 3.2.1.22). Saposin-B forms a solubilizing complex with the substrates of the sphingolipid hydrolases.' Source: https://www.uniprot.org/uniprotkb/P07602/entry
Alternative names: Cerebroside sulfate activator (CSAct) DispersinSphingolipid activator protein 1 (SAP-1) Sulfatide/GM1 activator
Sap-B Protein uniprot:P07602 Sap-B is assumed to represent Saposin-B, which 'stimulates the hydrolysis of galacto-cerebroside sulfate by arylsulfatase A (EC 3.1.6.8), GM1 gangliosides by beta-galactosidase (EC 3.2.1.23) and globotriaosylceramide by alpha-galactosidase A (EC 3.2.1.22). Saposin-B forms a solubilizing complex with the substrates of the sphingolipid hydrolases.' Source: https://www.uniprot.org/uniprotkb/P07602/entry
Alternative names: Cerebroside sulfate activator (CSAct) DispersinSphingolipid activator protein 1 (SAP-1) Sulfatide/GM1 activator
HEXA Protein ensembl:ENSG00000213614
HEXB Protein uniprot:P07686
Beta-hexosaminidase A, B: Protein eccode:3.2.1.52
HEXA Protein ensembl:ENSG00000213614
GM1-beta-galactosidase (GLB): Protein eccode:3.2.1.23

References

  1. NAG-thiazoline, An N-Acetyl-β-hexosaminidase Inhibitor That Implicates Acetamido Participation. Knapp S, Vocadlo D, Gao Z, Kirk B, Lou J, Withers SG. J Am Chem Soc [Internet]. 1996 Jan 1;118(28):6804–5. Available from: http://dx.doi.org/10.1021/ja960826u DOI Scholia
  2. Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases [Internet]. Blau N, Duran M, Gibson KM, Dionisi-Vici C. Springer; 2014. 0 p. Available from: https://books.google.com/books/about/Physician_s_Guide_to_the_Diagnosis_Treat.html?hl=&id=wJRBnwEACAAJ OpenLibrary Worldcat
  3. Classification of disorders of GM2 ganglioside hydrolysis using 3H-GM2 as substrate. Novak A, Callahan JW, Lowden JA. Biochim Biophys Acta. 1994 Mar 2;1199(2):215–23. PubMed Europe PMC Scholia
  4. Direct determination of the substrate specificity of the alpha-active site in heterodimeric beta-hexosaminidase A. Hou Y, Tse R, Mahuran DJ. Biochemistry. 1996 Apr 2;35(13):3963–9. PubMed Europe PMC Scholia
  5. A family of human beta3-galactosyltransferases. Characterization of four members of a UDP-galactose:beta-N-acetyl-glucosamine/beta-nacetyl-galactosamine beta-1,3-galactosyltransferase family. Amado M, Almeida R, Carneiro F, Levery SB, Holmes EH, Nomoto M, et al. J Biol Chem. 1998 May 22;273(21):12770–8. PubMed Europe PMC Scholia
  6. A Pro504 --> Ser substitution in the beta-subunit of beta-hexosaminidase A inhibits alpha-subunit hydrolysis of GM2 ganglioside, resulting in chronic Sandhoff disease. Hou Y, McInnes B, Hinek A, Karpati G, Mahuran D. J Biol Chem. 1998 Aug 14;273(33):21386–92. PubMed Europe PMC Scholia
  7. Combinatorial ganglioside biosynthesis. Kolter T, Proia RL, Sandhoff K. J Biol Chem. 2002 Jul 19;277(29):25859–62. PubMed Europe PMC Scholia
  8. Sphingolipid metabolism diseases. Kolter T, Sandhoff K. Biochim Biophys Acta. 2006 Dec;1758(12):2057–79. PubMed Europe PMC Scholia
  9. Principles of lysosomal membrane degradation: Cellular topology and biochemistry of lysosomal lipid degradation. Schulze H, Kolter T, Sandhoff K. Biochim Biophys Acta. 2009 Apr;1793(4):674–83. PubMed Europe PMC Scholia
  10. The role of saposin C in Gaucher disease. Tamargo RJ, Velayati A, Goldin E, Sidransky E. Mol Genet Metab. 2012 Jul;106(3):257–63. PubMed Europe PMC Scholia