Degradation pathway of sphingolipids, including diseases (Homo sapiens)

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521, 6SialidosisTay-SachsSandhoffGM1-gangliosidosisKrabbeFabrysialidase 4digalactosylceramide betaacrylsulfatase AGlobosideSap-BGloboside example 1alpha-galactosidase Aglobotriaosylceramidesphingomyelinasedigalactosylceramidebeta-hexosaminidase A, B:sialidase 3HEXAHEXAGM1-beta-galactosidase (GLB):sialidase 2digalactosylceramide alphasialidaseglucosylceramide-beta-glucosidaseHEXBGalCer-beta-galactosidasealpha-galactosidase Aacid ceramidasesialidase 1Globoside example 2GLB1GM2A 3GA2GM3CeramideSphingosinegalactosyl-ceramideSphingomyelinglucosylceramideSulfatidelactosylceramideGM2GM1GA1GM2-activator4Sap-BGM1-beta-galactosidease (GLB):GM2-activatorSap-BSap-BSap-CSap-CSap-Cglucosylceramide-beta-glucosidaseSap-ASap-BSap-BGLB1HEXAHEXBbeta-hexosaminidase A, B:HEXAGM1-beta-galactosidase (GLB):GLB1SandhoffGM1-gangliosidosisSandhoffGM2-gangliosidosis AB-variant16FabryFarberMetachromatic leukodystrophyGaucherNiemann-Pick ANiemann-Pick B


Description

The degradation of SphingoLipids (SLs) occurs through a series of specific hydrolases in the lysosome, after the compounds have been transported via the endosomal pathway. Disorders resulting from an enzyme defect are highlighted in pink. Hydrolase defects result in accumulation and lysosomal storage of substrates, leading to cell pathology.

This pathway was inspired by Chapter 25 ("Lysosomal Storage Disorders Including Neuronal Ceroid Lipofuscinoses") of the book of Blau (ISBN 3642403360 (978-3642403361)).

Proteins on this pathway have targeted assays available via the CPTAC Assay Portal

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Ontology Terms

 

Bibliography

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  1. Rafael J Tamargo, Arash Velayati, Ehud Goldin, Ellen Sidransky; ''The role of saposin C in Gaucher disease''; Mol Genet Metab., 2012 PubMed Europe PMC Scholia
  2. Novak A, Callahan JW, Lowden JA; ''Classification of disorders of GM2 ganglioside hydrolysis using 3H-GM2 as substrate.''; Biochim Biophys Acta, 1994 PubMed Europe PMC Scholia
  3. Knapp S, Vocadlo D, Gao Z, Kirk B, Lou J, Withers SG; ''NAG-thiazoline, an N-acetylbeta-hexosaminidase inhibitor that implicates acetamido participation''; J. Am. Chem. Soc.; doi:10.1021/ja960826u, 1996 DOI Scholia
  4. Hou Y, McInnes B, Hinek A, Karpati G, Mahuran D; ''A Pro504 --> Ser substitution in the beta-subunit of beta-hexosaminidase A inhibits alpha-subunit hydrolysis of GM2 ganglioside, resulting in chronic Sandhoff disease.''; J Biol Chem, 1998 PubMed Europe PMC Scholia
  5. Blau, Nenad, Duran, Marinus, Gibson, K. Michael, Dionisi-Vici, Carlo; ''Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases''; Springer, DOI: 10.1007/978-3-642-40337-8, 2014 (ed.1)
  6. Amado M, Almeida R, Carneiro F, Levery SB, Holmes EH, Nomoto M, Hollingsworth MA, Hassan H, Schwientek T, Nielsen PA, Bennett EP, Clausen H; ''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.''; J Biol Chem, 1998 PubMed Europe PMC Scholia
  7. Hou Y, Tse R, Mahuran DJ; ''Direct determination of the substrate specificity of the alpha-active site in heterodimeric beta-hexosaminidase A.''; Biochemistry, 1996 PubMed Europe PMC Scholia
  8. Thomas Kolter, Konrad Sandhoff; ''Sphingolipid metabolism diseases''; Biochim Biophys Acta . , 2006 PubMed Europe PMC Scholia
  9. Thomas Kolter, Richard L Proia, Konrad Sandhoff; ''Combinatorial ganglioside biosynthesis''; J Biol Chem . , 2002 PubMed Europe PMC Scholia
  10. Heike Schulze, Thomas Kolter, Konrad Sandhoff; ''Principles of lysosomal membrane degradation: Cellular topology and biochemistry of lysosomal lipid degradation''; Biochim Biophys Acta ., 2009 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
129325view14:03, 26 March 2024MkutmonOntology Term : 'disease pathway' added !
128224view13:17, 29 January 2024EweitzStandardize case
128223view13:09, 29 January 2024EweitzSoften disease color
124950view07:58, 7 January 2023EgonwFixed the OMIM link patterns
123688view11:30, 10 August 2022DeSlAdded last two missing protein annotations
123672view06:20, 9 August 2022EgonwRemoved the RHEA prefix
123669view15:03, 8 August 2022DeSlAdded disorders which were not connected to main pathway
123654view12:57, 8 August 2022DeSlAdded legend
123653view10:26, 8 August 2022DeSlFoudna nother ChEBI ID for digalactosylceramide
123652view10:24, 8 August 2022DeSlAnnotated galactosylceramide with new ID (since chebi was 'preliminary entry'.
123651view10:22, 8 August 2022DeSlUpdating GM2 and GM3 annotation to match up with Rhea0ID
123650view10:17, 8 August 2022DeSlAdded details on SapB and SapC, used similar annotation from UniProt (both encoded by same gene, no alternative annotation possible now).
123649view09:56, 8 August 2022DeSlModified description
123647view09:54, 8 August 2022DeSlAdded 3 principal refs for PW according to ed. 5 book chapter 60
123646view09:50, 8 August 2022DeSlConverted interactions to labels to grpahical interactions, added synonyms to metabolites from ed. 5 of book.
123645view09:38, 8 August 2022DeSlConverted interactions with disorders to graphical lines.
120394view08:51, 30 November 2021Fehrhartsmall graphical change
119291view11:05, 23 June 2021FinterlyAdded ISBN for book citation
115614view16:12, 1 March 2021DeSlOntology Term : 'Niemann-Pick disease type B' added !
115613view16:12, 1 March 2021DeSlOntology Term : 'Niemann-Pick disease type A' added !
111771view12:20, 7 September 2020DeSlFixed GalCer EC number ID (without space)
106375view00:57, 23 August 2019KhanspersModified description
105567view06:25, 9 August 2019KhanspersModified description
104405view15:06, 23 May 2019DeSlUpdated GM2A comment to remove weird signs.
104401view14:47, 23 May 2019DeSlUpdated comments for metabolites with weird signs.
104398view14:27, 23 May 2019DeSlUpdated ID of HEXB
104028view17:41, 25 April 2019IreneHemelModified description
104011view15:17, 25 April 2019DeSlAdded Rheas and lit refs
101823view15:44, 11 November 2018EgonwReplaced "Ensembl Human" with just "Ensembl", fixing links out.
98955view14:39, 17 October 2018DeSlConnected last unconnected interaction.
98950view12:21, 17 October 2018DeSlModified description
98249view09:31, 15 August 2018DeSlChanged layout of disease text-boxes, connected unconnected line.
98137view12:10, 25 July 2018DeSlChanged part of wrong symbols in globoside example 2
98136view12:01, 25 July 2018DeSlchanged weird symbols (again)
98135view11:12, 25 July 2018DeSlChanged two IDs from Ensembl Human to Ensembl, changed disease nodes to labels with linkouts to OMIM.
98134view10:03, 25 July 2018DeSlchanged weird symbols
98133view10:03, 25 July 2018DeSlchanged weird symbols
98132view09:55, 25 July 2018DeSlchanged weird symbols
98131view09:52, 25 July 2018DeSlReverted to version '08:44, 23 May 2018' by DeSl
97546view14:41, 24 May 2018AdoBioInfoNew mapping ID for lactase.
97518view13:50, 24 May 2018AdoBioInfoReplaced acid ceramidase ID for more Mappingz.
97516view13:46, 24 May 2018AdoBioInfoSike, another ID replaced.
97512view13:41, 24 May 2018AdoBioInfoReplaced database ID for more mapping.
97466view08:44, 23 May 2018DeSlChanged Swissprot IDs to TrEMBL
96376view06:39, 11 March 2018EgonwReplaced secondary ChEBI identifiers with primary identifiers.
94607view12:08, 30 September 2017EgonwModified title
94469view06:53, 12 September 2017Andrasome minor layout updates
94461view20:52, 9 September 2017DeSlChanged location of group GLB, GLB1 and Sap-B.
94460view20:51, 9 September 2017DeSlAdded annotaion for sialidase proteins; changed HEXA and GMSA group to complex (since GM2A is cofactor for HEXA).
94459view20:42, 9 September 2017DeSlAnnotated several protein nodes.

External references

DataNodes

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NameTypeDatabase referenceComment
CeramideMetaboliteCHEBI:17761 (ChEBI)
GA1MetaboliteCHEBI:27938 (ChEBI)
  • ganglioside GA1
  • AKA Gal-ß(1-3)-GalNAc-Gal-Glc-Cer
GA2MetaboliteCHEBI:27731 (ChEBI)
  • ganglioside GA2
  • AKA GalNAc-ß-(1-4)-Gal-Glc-Cer
GLB1GeneProductENSG00000170266 (Ensembl) GM1-beta-galactosidase 1
GM1-beta-galactosidase (GLB):Protein3.2.1.23 (Enzyme Nomenclature)
GM1-beta-galactosidease (GLB):Protein3.2.1.23 (Enzyme Nomenclature)
GM1MetaboliteCHEBI:18216 (ChEBI)
  • aka ganglioside GM1a, GM1a
  • AKA Gal-ß(1-3)-GalNAc-Gal[NeuAc]-Glc-Cer
GM2-activatorProtein2760 (Entrez Gene)
GM2A Protein2760 (Entrez Gene) GM2-Activator
GM2MetaboliteCHEBI:51013 (ChEBI)
  • ganglioside GM2
  • AKA GalNAc-ß(1-4)-Gal[NeuAc]-Glc-Cer
GM3MetaboliteCHEBI:15681 (ChEBI)
  • ganglioside GM3
  • AKA Α(2,3)NeuAc-Gal-ß(1-4)-Glc-Cer
GalCer-beta-galactosidaseProtein3.2.1.46 (Enzyme Nomenclature) GALCERase
Globoside example 1MetaboliteCHEBI:88167 (ChEBI) N-acetyl-beta-D-galactosaminyl-(1->3)-alpha-D-galactosyl-(1->4)-beta-D-galactosyl-(1->4)-beta-D-glucosyl-(1->1')-ceramide
Globoside example 2MetaboliteCHEBI:18259 (ChEBI) 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
GlobosideMetaboliteCHEBI:61360 (ChEBI) AKA GalNAc -ß(1-3)Gal-Glc-Cer
HEXAProteinENSG00000213614 (Ensembl)
HEXAProteinP06865 (Uniprot-TrEMBL) Hexosaminidase A; HEXA and the cofactor GM2 activator protein catalyze the degradation of the GM2 gangliosides
HEXBProteinP07686 (Uniprot-TrEMBL)
Sap-AProteinIPR003119 (InterPro)
Sap-BProteinIPR008139 (InterPro)
Sap-CProtein
SphingomyelinMetaboliteQ423143 (Wikidata)
SphingosineMetaboliteQ46298 (Wikidata)
SulfatideMetaboliteQ408584 (Wikidata) AKA O 3 S-3-Gal-Cer
acid ceramidaseProtein3.5.1.23 (Enzyme Nomenclature) Acid ceramidase (N-acylsphingosine deacylase, ASAH1)
acrylsulfatase AProteinENSG00000100299 (Ensembl) Arylsulfatase A (or cerebroside-sulfatase)
alpha-galactosidase AProtein2717 (Entrez Gene)
beta-hexosaminidase A, B:Protein3.2.1.52 (Enzyme Nomenclature)
digalactosylceramide alphaMetaboliteCHEBI:134506 (ChEBI) alpha-D-galactosyl-(1->4)-beta-D-galactosyl-N-(pentacosanoyl)sphingosine
digalactosylceramide betaMetaboliteCHEBI:134507 (ChEBI)
digalactosylceramideMetaboliteCHEBI:28811 (ChEBI) AKA Gal-α(1-4)-Gal-Cer
galactosyl-ceramideMetaboliteQ2756638 (Wikidata)
  • Galactocerebroside
  • AKA Gal-ß(1-1)-Cer
globotriaosylceramideMetabolite66616222 (PubChem-compound)
  • also known as CD77, Gb3, and ceramide trihexoside
  • AKA Gal-α(1-4)-Gal-Glc-Cer
glucosylceramide-beta-glucosidaseProtein
glucosylceramideMetaboliteQ35662896 (Wikidata) AKA Glc-ß(1-1)-Cer
lactosylceramideMetaboliteQ3215908 (Wikidata) AKA Gal-ß(1-4)-Glc-Cer
sialidase 1ProteinQ99519 (Uniprot-TrEMBL)
sialidase 2ProteinQ9Y3R4 (Uniprot-TrEMBL)
sialidase 3ProteinQ9UQ49 (Uniprot-TrEMBL)
sialidase 4ProteinQ8WWR8 (Uniprot-TrEMBL)
sialidaseProteinIPR004124 (InterPro)
sphingomyelinaseProtein3.1.4.12 (Enzyme Nomenclature) Sphingomyelin phosphodiesterase (also known as neutral sphingomyelinase, sphingomyelinase, or SMase)

Annotated Interactions

SourceTargetTypeDatabase referenceComment
GM1GM2mim-conversionRHEA:48282 (Rhea)
GM2GM3mim-conversionRHEA:47969 (Rhea)
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