Glycosphingolipid / sphingolipid lysosomal degradation to ceramide and sphingosine (the sphingolipidoses); ARSA/GALC/GBA/SMPD1/ASAH1 + GM2A/PSAP

Complex sphingolipids are catabolised in the lysosome by a branched cascade of soluble acid hydrolases that strip the head group one residue at a time and converge on ceramide, which is finally hydrolysed to sphingosine. Sphingomyelin is cleaved by acid sphingomyelinase (SMPD1) directly to ceramide; glucosylceramide is cleaved by acid beta-glucocerebrosidase (GBA); galactosylceramide by galactocerebrosidase (GALC); and sulfatide is first desulfated by arylsulfatase A (ARSA) to galactosylceramide, which GALC then degrades. Gangliosides feed in from above (GM1 via GLB1, GM2 via beta-hexosaminidase A + the GM2-activator, globosides via GLA/HEXA-HEXB — reviewed in the ganglioside/GAG modules), ultimately yielding glucosylceramide. The convergent final step is acid ceramidase (ASAH1), which hydrolyses ceramide to sphingosine and a free fatty acid. Because the substrates are membrane-embedded lipids, most of these hydrolases require small non-enzymatic lipid-presenting cofactors: the four saposins (A, B, C, D) generated from prosaposin (PSAP) activate GALC, ARSA/GLB1, GBA and ASAH1 respectively, and the GM2-activator (GM2A) presents GM2 ganglioside to beta-hexosaminidase A. Each hydrolase and cofactor defines a sphingolipidosis: metachromatic leukodystrophy (ARSA), Krabbe disease (GALC), Gaucher disease (GBA), Niemann-Pick A/B (SMPD1), Farber disease / SMA-PME (ASAH1), the AB-variant GM2 gangliosidosis (GM2A) and combined saposin deficiency (PSAP).

MODULE:glycosphingolipid_lysosomal_degradationDRAFTMetabolic Pathwaymodules/glycosphingolipid_lysosomal_degradation.yaml
glycosphingolipid catabolic processGO:0046479 sphingolipid catabolic processGO:0030149
GO:0046479
glycosphingolipid catabolic process
The module is grounded in glycosphingolipid catabolic process (GO:0046479); it covers the lysosomal degradation of complex sphingolipids to ceramide and sphingosine.
GO:0030149
sphingolipid catabolic process
The pathway is lysosomal sphingolipid catabolism (GO:0030149) converging on ceramide/sphingosine.
Reactome:R-HSA-1660661
Sphingolipid metabolism
Step order and intermediates follow the human Reactome sphingolipid/glycosphingolipid degradation reactions R-HSA-1606807 (ARSA), R-HSA-1606564 (GALC), R-HSA-1605591 (GBA), R-HSA-9769742 (SMPD1) and R-HSA-1606602 (ASAH1).
file:human/ARSA/ARSA-ai-review.yaml
ARSA gene review (human)
The sulfatide desulfation step (UniProtKB:P15289, GO:0004098) matches the completed human ARSA review.
file:human/GALC/GALC-ai-review.yaml
GALC gene review (human)
The galactosylceramidase step (UniProtKB:P54803, GO:0004336) matches the completed human GALC review.
file:human/GBA/GBA-ai-review.yaml
GBA gene review (human)
The glucosylceramidase step (UniProtKB:P04062, GO:0004348) matches the completed human GBA review.
file:human/SMPD1/SMPD1-ai-review.yaml
SMPD1 gene review (human)
The sphingomyelin phosphodiesterase step (UniProtKB:P17405, GO:0004767) matches the completed human SMPD1 review.
file:human/ASAH1/ASAH1-ai-review.yaml
ASAH1 gene review (human)
The acid ceramidase (ceramide -> sphingosine) step (UniProtKB:Q13510, GO:0017040) matches the completed human ASAH1 review.
file:human/GM2A/GM2A-ai-review.yaml
GM2A gene review (human)
The GM2-activator lipid-presenting cofactor (UniProtKB:P17900, GO:7770043) matches the completed human GM2A review.
file:human/PSAP/PSAP-ai-review.yaml
PSAP gene review (human)
The saposin (A-D) activator precursor (UniProtKB:P07602, GO:0030290) matches the completed human PSAP review.
7Nodes
6Parts
0Variant Sets
0Variants
7Annotons
5Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:glycosphingolipid_lysosomal_degradation deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Gene-review completeness (7/7 grounded genes reviewed)

7 complete review(s) · 0 with deep research · 0 missing review · 7 reviewed but lacking deep research

Gene Review Complete Deep research
ARSA P15289 ✓ ✓ ✗
ASAH1 Q13510 ✓ ✓ ✗
GALC P54803 ✓ ✓ ✗
GBA P04062 ✓ ✓ ✗
GM2A P17900 ✓ ✓ ✗
PSAP P07602 ✓ ✓ ✗
SMPD1 P17405 ✓ ✓ ✗

Details

Context
lysosomal lumenGO:0043202
Glycosphingolipid / sphingolipid lysosomal degradationMetabolic Pathwayglycosphingolipid_lysosomal_degradation
glycosphingolipid catabolic processGO:0046479 sphingolipid catabolic processGO:0030149
Context
lysosomal lumenGO:0043202

Lysosomal glycosphingolipid/sphingolipid degradation, grounded to the human enzymes ARSA (UniProtKB:P15289, GO:0004098, EC 3.1.6.8), GALC (P54803, GO:0004336, EC 3.2.1.46), GBA (P04062, GO:0004348, EC 3.2.1.45), SMPD1 (P17405, GO:0004767, EC 3.1.4.12) and ASAH1 (Q13510, GO:0017040, EC 3.5.1.23), plus the non-catalytic lipid-presenting cofactors PSAP (P07602, GO:0030290 sphingolipid activator protein activity; precursor of saposins A-D) and GM2A (P17900, GO:7770043 lipid chaperone activity; GM2 activator). GO molecular-function/BP/location terms were taken from the completed human gene reviews and verified against the local go.db; Reactome reaction ids/titles were verified against the local reactome cache. Each step uses a PANTHER family selector; the cofactor node groups PSAP and GM2A. The pathway is a convergent tree: sphingomyelin (SMPD1), glucosylceramide (GBA) and galactosylceramide (GALC; fed by ARSA desulfation of sulfatide) all yield ceramide, which ASAH1 hydrolyses to sphingosine — the exit point recycled by the salvage pathway. Gangliosides enter from above via GLB1 (GM1), HEXA/HEXB + GM2A (GM2) and GLA (globosides) — reviewed in the ganglioside/GAG modules (GLA/HEXA/HEXB/GLB1 already on main). Because the substrates are membrane lipids, the hydrolases depend on the saposins (SapA->GALC, SapB->ARSA/GLB1, SapC->GBA, SapD->ASAH1) and GM2A (->HexA), modelled here as an activator node that positively regulates the hydrolases. Disorders (the sphingolipidoses): metachromatic leukodystrophy (ARSA), Krabbe (GALC), Gaucher (GBA), Niemann-Pick A/B (SMPD1), Farber / SMA-PME (ASAH1), AB-variant GM2 gangliosidosis (GM2A) and combined saposin deficiency (PSAP).

Connections

arsa_step -> galc_step Provides Input For
ARSA desulfation of sulfatide yields galactosylceramide, the GALC substrate.
galc_step -> asah1_step Provides Input For
GALC produces ceramide, hydrolysed by ASAH1 to sphingosine.
gba_step -> asah1_step Provides Input For
GBA produces ceramide, hydrolysed by ASAH1 to sphingosine.
smpd1_step -> asah1_step Provides Input For
SMPD1 produces ceramide, hydrolysed by ASAH1 to sphingosine.
activator_step -> gba_step Positively Regulates
Saposins/GM2-activator present membrane glycosphingolipids to their degrading hydrolases.
Part 1: sulfatide desulfation
sulfatide to galactosylceramide (3-O-desulfation)Reactionarsa_step

Annotons

ARSA: arylsulfatase A / cerebroside-3-sulfatase
arsa_activity
Participant: Family: Sulfatase family (ARSA)
Family:
Sulfatase family (ARSA)PANTHER:PTHR42693
Representative Members: ARSA (human)UniProtKB:P15289

Function

cerebroside-sulfatase activityGO:0004098
Substrates: sulfatide (3-O-sulfogalactosylceramide)
Products: galactosylceramide sulfate

Locations

lysosomal lumenGO:0043202

Deficiency = metachromatic leukodystrophy (MLD).

Part 2: galactosylceramide hydrolysis
galactosylceramide to ceramideReactiongalc_step

Annotons

GALC: galactosylceramidase
galc_activity
Participant: Family: Glycosyl hydrolase 59 family (GALC)
Family:
Glycosyl hydrolase 59 family (GALC)PANTHER:PTHR15172
Representative Members: GALC (human)UniProtKB:P54803

Function

galactosylceramidase activityGO:0004336
Substrates: galactosylceramide (galactocerebroside)
Products: ceramide galactose

Locations

lysosomal lumenGO:0043202

Deficiency = Krabbe disease (globoid cell leukodystrophy).

Part 3: glucosylceramide hydrolysis
glucosylceramide to ceramideReactiongba_step

Annotons

GBA: acid beta-glucocerebrosidase
gba_activity
Participant: Family: Glycosyl hydrolase 30 family (GBA)
Family:
Glycosyl hydrolase 30 family (GBA)PANTHER:PTHR11069
Representative Members: GBA (human)UniProtKB:P04062

Function

glucosylceramidase activityGO:0004348
Substrates: glucosylceramide (glucocerebroside)
Products: ceramide glucose

Locations

lysosomal lumenGO:0043202

Deficiency = Gaucher disease.

Part 4: sphingomyelin hydrolysis
sphingomyelin to ceramideReactionsmpd1_step

Annotons

SMPD1: acid sphingomyelinase
smpd1_activity
Participant: Family: Acid sphingomyelinase family (SMPD1)
Family:
Acid sphingomyelinase family (SMPD1)PANTHER:PTHR10340
Representative Members: SMPD1 (human)UniProtKB:P17405

Function

sphingomyelin phosphodiesterase activityGO:0004767
Substrates: sphingomyelin
Products: ceramide phosphocholine

Locations

lysosomal lumenGO:0043202

Deficiency = Niemann-Pick disease types A and B.

Part 5: convergent final step (ceramide to sphingosine)
ceramide to sphingosine + fatty acidReactionasah1_step

Annotons

ASAH1: acid ceramidase
asah1_activity
Participant: Family: Acid ceramidase / N-acylethanolamine-hydrolase family (ASAH1)
Family:
Acid ceramidase / N-acylethanolamine-hydrolase family (ASAH1)PANTHER:PTHR28583
Representative Members: ASAH1 (human)UniProtKB:Q13510

Function

N-acylsphingosine amidohydrolase activityGO:0017040
Substrates: ceramide
Products: sphingosine free fatty acid

Locations

lysosomal lumenGO:0043202

Convergent final step of glycosphingolipid degradation. Deficiency = Farber disease / SMA-PME.

Part 6: lipid-presenting activator cofactors
saposin (A-D) and GM2-activator lipid presentationReactionactivator_step

Annotons

PSAP: prosaposin (saposins A-D)
psap_activity
Participant: Family: Saposin / prosaposin family (PSAP)
Family:
Saposin / prosaposin family (PSAP)PANTHER:PTHR11480
Representative Members: PSAP (human)UniProtKB:P07602

Function

sphingolipid activator protein activityGO:0030290
Substrates: membrane glycosphingolipids (sulfatide, GalCer, GlcCer, ceramide)
Products: enzyme-accessible lipid substrate (presented to ARSA/GALC/GBA/ASAH1)

Locations

lysosomal lumenGO:0043202

Non-catalytic saposin cofactors; deficiency phenocopies the cognate enzyme diseases.

GM2A: GM2 activator protein
gm2a_activity
Participant: Family: GM2 activator protein family (GM2A)
Family:
GM2 activator protein family (GM2A)PANTHER:PTHR17357
Representative Members: GM2A (human)UniProtKB:P17900

Function

lipid chaperone activityGO:7770043
Substrates: GM2 ganglioside
Products: GM2 presented to beta-hexosaminidase A

Locations

lysosomal lumenGO:0043202

Non-catalytic GM2-presenting cofactor for beta-hexosaminidase A.