GLB1 (human) — curation notes

UniProtKB: P16278 (BGAL_HUMAN). HGNC:4298. EC 3.2.1.23. Glycosyl hydrolase family 35 (CAZy GH35).

Core biology (grounded in UniProt + cached publications; falcon deep research unavailable, HTTP 402)

GLB1 encodes lysosomal acid beta-galactosidase (β-Gal), an exoglycosidase that
hydrolyses terminal non-reducing β-D-galactose residues from a broad range of
substrates.

• UniProt CATALYTIC ACTIVITY: "Hydrolysis of terminal non-reducing beta-D-galactose
  residues in beta-D-galactosides.; EC=3.2.1.23" [file:human/GLB1/GLB1-uniprot.txt].
• UniProt FUNCTION [Isoform 1]: "Cleaves beta-linked terminal galactosyl residues from
  gangliosides, glycoproteins, and glycosaminoglycans." [file:human/GLB1/GLB1-uniprot.txt].
• pH optimum 4.5–5.5 (acid hydrolase) [file:human/GLB1/GLB1-uniprot.txt].

Two disease-relevant catabolic roles:
1. Ganglioside/glycosphingolipid catabolism — removes the terminal galactose of GM1
ganglioside (→ GM2) and of its asialo derivative GA1 (→ GA2). Deficiency → lysosomal
accumulation of GM1 and GA1 PMID:31720227. Also acts (with sap-B) on lactosylceramide/GM1 in vitro
PMID:8200356.
2. Keratan sulfate / glycosaminoglycan and glycoprotein catabolism — GM1
gangliosidosis / Morquio B accumulate keratan sulfate and β-galactose-terminated
N-/O-linked glycans. GLB1 deficiency is a "broad oligosaccharidosis" PMID:31720227.

Structure / mechanism

• Crystal structure (homodimer): catalytic TIM barrel + β-domain 1 + β-domain 2; "β-Gal
  is an exoglycosidase that catalyzes the hydrolysis of terminal β-linked galactose
  residues" PMID:22128166. Active site: proton donor Glu188, nucleophile Glu268
  (UniProt ACT_SITE). Binds galactose product; homodimer PMID:22128166.

Lysosomal multienzyme complex

• GLB1 forms a lysosomal complex with protective protein/cathepsin A (PPCA/CTSA),
  α-neuraminidase (NEU1) and GALNS; PPCA stabilises β-Gal multimers
  PMID:15714521.
  Loss of PPCA (galactosialidosis) → combined β-Gal/NEU1 deficiency; PPCA restores
  high-MW β-Gal multimers PMID:3084261.

Localisation

• Lysosome (isoform 1). Synthesised as precursor in RER → Golgi → mature high-MW multimer
  in lysosome PMID:3084261. UniProt SUBCELLULAR LOCATION [Isoform 1]: Lysosome
  [PMID:2511208, PMID:3084261].

Isoform 2 (EBP / elastin-binding protein / S-Gal)

• Alternatively spliced, catalytically inactive (~67 kDa); functions in elastic-fibre
  assembly (elastogenesis) as a recycling chaperone for tropoelastin; localises to
  perinuclear cytoplasm / cell surface, NOT lysosome [UniProt FUNCTION [Isoform 2],
  SUBCELLULAR LOCATION [Isoform 2]; PMID:2511208]. The perinuclear-region (GO:0048471) and
  cytoplasm (GO:0005737) CC annotations pertain to this non-catalytic isoform.

Disease

• Allelic disorders, all autosomal recessive lysosomal storage diseases:
  GM1-gangliosidosis types 1/2/3 (MIM 230500/230600/230650) and Mucopolysaccharidosis
  type IVB / Morquio B (MIM 253010) [UniProt DISEASE].

Annotation-review judgement calls

• PMID:11927518 (atherosclerosis / endothelial senescence): measures
  senescence-associated β-gal (SA-β-gal) histochemical staining, a phenotypic readout
  of lysosomal β-Gal activity at pH 6, not a biochemical characterisation of the GLB1
  enzyme's substrate specificity. The IDA "beta-galactosidase activity", "carbohydrate
  metabolic process", and "cytoplasm" annotations from this paper are over-annotations /
  peripheral (SA-β-gal signal is lysosomal, not cytoplasmic). Kept but marked
  over-annotated; not core.
• protein binding (GO:0005515) IPIs: PMID:32296183 (HuRI binary interactome — GOLM1,
  SLC10A6, SLC30A2, SLC7A1; membrane transporters, likely non-physiological Y2H hits);
  PMID:15498789 (NGX6 paper — GLB1 not the subject). Bare protein binding, uninformative.
  Per policy: MARK_AS_OVER_ANNOTATED, not REMOVE.
• GO:0042803 protein homodimerization activity IPI PMID:22128166: real — the crystal
  structure shows a homodimer. ACCEPT (non-core).
• Exosome / granule / extracellular-region CC terms (HDA proteomics + Reactome
  neutrophil-degranulation): GLB1 is a soluble lysosomal enzyme detected in these
  proteomic/secretory contexts but its site of action is the lysosome. Kept as non-core.
• IEA response to cortisone (GO:0051413) and response to Thyroglobulin triiodothyronine
  (GO:1904016): rat-ortholog electronic transfers (GO_REF:0000107), no human evidence,
  not molecular function of the enzyme. Marked over-annotated.