Lysosomal glycoprotein (N-glycan) degradation; NEU1/GLB1/HEX/MAN2B1/MANBA/FUCA1/AGA/NAGA

Glycoproteins delivered to the lysosome are proteolysed to glycopeptides whose glycans are then dismantled by lumenal exoglycosidases working from both ends. From the non-reducing end, N-glycan antennae are trimmed residue by residue: capping sialic acid (NEU1), terminal galactose (GLB1), antennal N-acetylglucosamine (beta-hexosaminidase, HEXA/HEXB), alpha-linked mannoses (MAN2B1) and the core beta-mannose (MANBA); terminal alpha-N-acetylgalactosamine of blood group A and mucin-type determinants is removed by NAGA. From the reducing end, the core alpha1,6-fucose is removed by FUCA1, which is required because core fucosylation blocks aspartylglucosaminidase (AGA); AGA then cleaves the N-glycosidic GlcNAc-Asn bond, separating the glycan from the asparagine residue. Loss of any step causes a glycoproteinosis (oligosaccharidosis) with lysosomal storage and urinary excretion of the corresponding oligosaccharides or glycoasparagines: sialidosis, GM1 gangliosidosis, Sandhoff disease, alpha- and beta-mannosidosis, fucosidosis, aspartylglucosaminuria and NAGA deficiency.

MODULE:lysosomal_glycoprotein_degradationDRAFTMetabolic Pathwaymodules/lysosomal_glycoprotein_degradation.yaml
glycoprotein catabolic processGO:0006516
GO:0006516
The module is grounded in glycoprotein catabolic process (GO:0006516): lysosomal exoglycosidase degradation of glycoprotein-derived N-glycans.
PMID:27491075
A mouse model for fucosidosis recapitulates storage pathology and neurological features of the milder form of the human disease.
Core fucosylation sterically inhibits AGA, so FUCA1 action precedes AGA cleavage of the GlcNAc-Asn bond; Fuca1-null mice store core-fucosylated glycoasparagines.
file:human/FUCA1/FUCA1-ai-review.yaml
FUCA1 gene review (human)
The core-defucosylation step (UniProtKB:P04066, GO:0004560) matches the completed human FUCA1 review.
file:human/AGA/AGA-ai-review.yaml
AGA gene review (human)
The GlcNAc-Asn cleavage step (UniProtKB:P20933, GO:0003948) matches the completed human AGA review.
file:human/GLB1/GLB1-ai-review.yaml
GLB1 gene review (human)
The beta-galactosidase step (UniProtKB:P16278, GO:0004565) matches the completed human GLB1 review.
file:human/NAGA/NAGA-ai-review.yaml
NAGA gene review (human)
The alpha-N-acetylgalactosaminidase step (UniProtKB:P17050, GO:0008456) matches the completed human NAGA review.
9Nodes
8Parts
0Variant Sets
0Variants
8Annotons
5Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:lysosomal_glycoprotein_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.

Function consistency and core coverage

6 gene-function check(s) reflected in core functions · 0 conflict(s) · 10 evidence or coverage gap(s) (16 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
neu1_activity NEU1 (human)
UniProtKB:Q99519
Family Representative 		exo-alpha-sialidase activity
GO:0004308 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
glb1_activity GLB1 (human)
UniProtKB:P16278
Family Representative 		beta-galactosidase activity
GO:0004565 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hex_activity HEXB (human)
UniProtKB:P07686
Family Representative 		beta-N-acetylhexosaminidase activity
GO:0004563 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
man2b1_activity MAN2B1 (human)
UniProtKB:O00754
Family Representative 		alpha-mannosidase activity
GO:0004559 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
manba_activity MANBA (human)
UniProtKB:O00462
Family Representative 		beta-mannosidase activity
GO:0004567 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
fuca1_activity FUCA1 (human)
UniProtKB:P04066
Family Representative 		alpha-L-fucosidase activity
GO:0004560 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
aga_activity AGA (human)
UniProtKB:P20933
Family Representative 		N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity
GO:0003948 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
naga_activity NAGA (human)
UniProtKB:P17050
Family Representative 		alpha-N-acetylgalactosaminidase activity
GO:0008456 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
neu1_activity Sialidase family (NEU1)
PANTHER:PTHR10628
Family 		exo-alpha-sialidase activity
GO:0004308 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10628.
glb1_activity Glycosyl hydrolase 35 family (GLB1)
PANTHER:PTHR23421
Family 		beta-galactosidase activity
GO:0004565 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR23421.
hex_activity Glycosyl hydrolase 20 / beta-hexosaminidase family (HEX)
PANTHER:PTHR22600
Family 		beta-N-acetylhexosaminidase activity
GO:0004563 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR22600.
man2b1_activity Glycosyl hydrolase 38 / alpha-mannosidase family (MAN2B1)
PANTHER:PTHR11607
Family 		alpha-mannosidase activity
GO:0004559 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR11607.
manba_activity Glycosyl hydrolase 2 / beta-mannosidase family (MANBA)
PANTHER:PTHR43730
Family 		beta-mannosidase activity
GO:0004567 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR43730.
fuca1_activity Tissue alpha-L-fucosidase subfamily (FUCA1)
PANTHER:PTHR10030:SF2
Family 		alpha-L-fucosidase activity
GO:0004560 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10030:SF2.
aga_activity Glycosylasparaginase subfamily (AGA)
PANTHER:PTHR10188:SF6
Family 		N4-(beta-N-acetylglucosaminyl)-L-asparaginase activity
GO:0003948 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10188:SF6.
naga_activity Alpha-N-acetylgalactosaminidase subfamily (NAGA)
PANTHER:PTHR11452:SF25
Family 		alpha-N-acetylgalactosaminidase activity
GO:0008456 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR11452:SF25.

Gene-review completeness (6/8 grounded genes reviewed)

5 complete review(s) · 4 with deep research · 2 missing review · 2 reviewed but lacking deep research

Gene Review Complete Deep research
AGA P20933 ✓ ✓ ✓
FUCA1 P04066 ✓ ✓ ✓
GLB1 P16278 ✓ 58/63 ✓
HEXB P07686 ✓ ✓ ✗
NAGA P17050 ✓ ✓ ✓
NEU1 Q99519 ✓ ✓ ✗
MANBA (human) O00462 ✗ — —
MAN2B1 (human) O00754 ✗ — —

Details

Context
lysosomal lumenGO:0043202
Lysosomal glycoprotein (N-glycan) degradationMetabolic Pathwaylysosomal_glycoprotein_degradation
glycoprotein catabolic processGO:0006516
Context
lysosomal lumenGO:0043202

Steps 6-7 (FUCA1, AGA) and the GLB1 and NAGA steps are grounded in completed human gene reviews; the NEU1, HEXA/HEXB, MAN2B1 and MANBA steps are grounded only in UniProt/EC and await gene reviews (NEU1, HEXA and HEXB reviews are INITIALIZED; MAN2B1 and MANBA have none). The reducing-end di-N-acetylchitobiase CTBS (UniProtKB:Q01459), which cleaves the chitobiose core after AGA in primates and rodents, is not modelled as a part because no GO molecular function term for its activity was identified. The cytosolic ENGASE/NGLY1 route for misfolded ER glycoproteins is a separate pathway. GLB1, NEU1 and the hexosaminidases are shared with the glycosphingolipid and keratan sulfate degradation modules; sialic acid released by NEU1 is exported by SLC17A5 (sialic_acid_metabolism module). The order of the non-reducing-end steps is the canonical order for complex N-glycans; for oligomannose glycans steps 1-3 do not apply.

Connections

neu1_step -> glb1_step Provides Input For
Desialylation exposes the penultimate beta-galactose.
glb1_step -> hex_step Provides Input For
Removal of galactose exposes antennal beta-GlcNAc.
hex_step -> man2b1_step Provides Input For
Removal of antennal GlcNAc exposes the alpha-mannose branches.
man2b1_step -> manba_step Provides Input For
Removal of alpha-mannoses leaves Man(beta1-4)GlcNAc for MANBA.
fuca1_step -> aga_step Provides Input For
Core defucosylation is required before AGA can cleave the GlcNAc-Asn bond.
Part 1: terminal sialic acid removal
hydrolysis of terminal alpha-linked sialic acid from N-glycan antennaeReactionneu1_step

Annotons

NEU1: lysosomal sialidase
neu1_activity
Participant: Family: Sialidase family (NEU1)
Family:
Sialidase family (NEU1)PANTHER:PTHR10628
Representative Members: NEU1 (human)UniProtKB:Q99519

Function

exo-alpha-sialidase activityGO:0004308
Substrates: sialylated glycoprotein-derived oligosaccharide
Products: N-acetylneuraminate desialylated oligosaccharide

Locations

lysosomal lumenGO:0043202

Deficiency = sialidosis; secondary NEU1 deficiency in galactosialidosis (CTSA).

Part 2: terminal galactose removal
hydrolysis of terminal beta-galactose from N-glycan antennaeReactionglb1_step

Annotons

GLB1: lysosomal acid beta-galactosidase
glb1_activity
Participant: Family: Glycosyl hydrolase 35 family (GLB1)
Family:
Glycosyl hydrolase 35 family (GLB1)PANTHER:PTHR23421
Representative Members: GLB1 (human)UniProtKB:P16278

Function

beta-galactosidase activityGO:0004565
Substrates: oligosaccharide with terminal beta-galactose
Products: D-galactose oligosaccharide with terminal GlcNAc

Locations

lysosomal lumenGO:0043202

Deficiency = GM1 gangliosidosis / MPS IVB, with oligosacchariduria.

Part 3: terminal N-acetylglucosamine removal
hydrolysis of antennal terminal beta-N-acetylglucosamineReactionhex_step

Annotons

HEXA/HEXB: lysosomal beta-hexosaminidase
hex_activity
Participant: Family: Glycosyl hydrolase 20 / beta-hexosaminidase family (HEX)
Family:
Glycosyl hydrolase 20 / beta-hexosaminidase family (HEX)PANTHER:PTHR22600
Representative Members: HEXB (human)UniProtKB:P07686

Function

beta-N-acetylhexosaminidase activityGO:0004563
Substrates: oligosaccharide with terminal beta-GlcNAc
Products: N-acetyl-D-glucosamine oligomannoside

Locations

lysosomal lumenGO:0043202

Deficiency of HEXB = Sandhoff disease (also GM2 gangliosidosis).

Part 4: alpha-mannose removal
hydrolysis of alpha1,2/1,3/1,6-linked mannose of the oligomannose coreReactionman2b1_step

Annotons

MAN2B1: lysosomal alpha-mannosidase
man2b1_activity
Participant: Family: Glycosyl hydrolase 38 / alpha-mannosidase family (MAN2B1)
Family:
Glycosyl hydrolase 38 / alpha-mannosidase family (MAN2B1)PANTHER:PTHR11607
Representative Members: MAN2B1 (human)UniProtKB:O00754

Function

alpha-mannosidase activityGO:0004559
Substrates: oligomannoside
Products: D-mannose Man(beta1-4)GlcNAc

Locations

lysosomal lumenGO:0043202

Deficiency = alpha-mannosidosis.

Part 5: beta-mannose removal
hydrolysis of the core beta1,4-linked mannoseReactionmanba_step

Annotons

MANBA: lysosomal beta-mannosidase
manba_activity
Participant: Family: Glycosyl hydrolase 2 / beta-mannosidase family (MANBA)
Family:
Glycosyl hydrolase 2 / beta-mannosidase family (MANBA)PANTHER:PTHR43730
Representative Members: MANBA (human)UniProtKB:O00462

Function

beta-mannosidase activityGO:0004567
Substrates: Man(beta1-4)GlcNAc
Products: D-mannose N-acetyl-D-glucosamine

Locations

lysosomal lumenGO:0043202

Deficiency = beta-mannosidosis.

Part 6: core fucose removal
hydrolysis of core alpha1,6-fucose (and antennal alpha-fucose)Reactionfuca1_step

Annotons

FUCA1: tissue alpha-L-fucosidase
fuca1_activity
Participant: Family: Tissue alpha-L-fucosidase subfamily (FUCA1)
Family:
Tissue alpha-L-fucosidase subfamily (FUCA1)PANTHER:PTHR10030:SF2
Representative Members: FUCA1 (human)UniProtKB:P04066

Function

alpha-L-fucosidase activityGO:0004560
Substrates: core-fucosylated glycoasparagine (Fuc(alpha1-6)GlcNAc-Asn) fucosylated oligosaccharide
Products: L-fucose non-fucosylated glycoasparagine

Locations

lysosomal lumenGO:0043202

Deficiency = fucosidosis.

Part 7: GlcNAc-Asn bond cleavage
hydrolysis of the N-glycosidic GlcNAc-Asn linkageReactionaga_step

Annotons

AGA: aspartylglucosaminidase (glycosylasparaginase)
aga_activity
Participant: Family: Glycosylasparaginase subfamily (AGA)
Family:
Glycosylasparaginase subfamily (AGA)PANTHER:PTHR10188:SF6
Representative Members: AGA (human)UniProtKB:P20933

Function

N4-(beta-N-acetylglucosaminyl)-L-asparaginase activityGO:0003948
Substrates: glycoasparagine (GlcNAc-Asn-linked oligosaccharide)
Products: L-aspartate N-glycan with free reducing-end GlcNAc (glycosylamine, hydrolysed to free oligosaccharide)

Locations

lysosomal lumenGO:0043202

Deficiency = aspartylglucosaminuria.

Part 8: terminal alpha-GalNAc removal
hydrolysis of terminal alpha-N-acetylgalactosamine (blood group A and mucin-type determinants)Reactionnaga_step

Annotons

NAGA: alpha-N-acetylgalactosaminidase
naga_activity
Participant: Family: Alpha-N-acetylgalactosaminidase subfamily (NAGA)
Family:
Alpha-N-acetylgalactosaminidase subfamily (NAGA)PANTHER:PTHR11452:SF25
Representative Members: NAGA (human)UniProtKB:P17050

Function

alpha-N-acetylgalactosaminidase activityGO:0008456
Substrates: glycopeptide or glycolipid with terminal alpha-GalNAc
Products: N-acetyl-D-galactosamine de-capped glycoconjugate

Locations

lysosomal lumenGO:0043202

Deficiency = Schindler/Kanzaki disease (NAGA deficiency).