B4GALT6 (Q9UBX8) — gene review notes

Identity

• Gene: B4GALT6 (HGNC:929), human, chromosome 18. UniProt Q9UBX8 (B4GT6_HUMAN), 382 aa.
• Names: Beta-1,4-galactosyltransferase 6 / Beta4Gal-T6 / b4Gal-T6; Lactosylceramide synthase (LacCer synthase); Glucosylceramide beta-1,4-galactosyltransferase; UDP-Gal:glucosylceramide beta-1,4-galactosyltransferase.
• EC 2.4.1.274 [file:human/B4GALT6/B4GALT6-uniprot.txt "EC=2.4.1.274 {ECO:0000269|PubMed:1551920, ECO:0000269|PubMed:3099851}"].
• Family: glycosyltransferase 7 family (CAZy GT7; PANTHER PTHR19300:SF47) [file:human/B4GALT6/B4GALT6-uniprot.txt "Belongs to the glycosyltransferase 7 family."]. Paralog of B4GALT5 (68% aa identity, the closest of the six B4GALT family members) PMID:9597550.

Core molecular function

• Lactosylceramide synthase: transfers galactose from UDP-galactose to glucosylceramide (GlcCer) to make lactosylceramide (LacCer) + UDP.
• UniProt FUNCTION [file:human/B4GALT6/B4GALT6-uniprot.txt "Catalyzes the synthesis of lactosylceramide (LacCer) via the"] ... [file:human/B4GALT6/B4GALT6-uniprot.txt "transfer of galactose from UDP-galactose to glucosylceramide (GlcCer)"].
• Reaction (RHEA:31495, EC 2.4.1.274): beta-D-glucosyl-(1<->1')-N-acylsphing-4-enine + UDP-alpha-D-galactose = LacCer + UDP + H+ [file:human/B4GALT6/B4GALT6-uniprot.txt].
• GO term: GO:0008489 "UDP-galactose:glucosylceramide beta-1,4-galactosyltransferase activity" (verified current label via OLS; catalysis of GlcCer + UDP-Gal -> LacCer).

Biochemical characterization (experimental, human)

• PMID:3099851 (Chatterjee & Castiglione 1987, abstract-only in cache): characterized GalT-2 activity transferring galactose from UDP-galactose to glucosylceramide in cultured human proximal-tubular cells; product comigrated with authentic lactosylceramide on TLC/HPLC; terminal beta-galactosyl confirmed by beta-galactosidase cleavage. Cofactor Mn2+/Mg2+; Km(GlcCer) 3 uM, Km(UDP-Gal) 0.5 uM [PMID:3099851 "The purified 14C-labelled product comigrated with authentic lactosylceramide"; "optimum activity was obtained in the presence of 1.0 mM Mn2+/Mg2+"]. UniProt uses this ref for EC 2.4.1.274, cofactor, and kinetic parameters.
• PMID:1551920 (Chatterjee et al. 1992, abstract-only): purified UDP-galactose:GlcCer beta-1,4-galactosyltransferase (GalT-2) 440-fold to homogeneity from human kidney; major product Cer1-1betaGlc4-1Gal (= LacCer), preferred substrate GlcCer PMID:1551920. NOTE: this is a biochemically purified enzyme, before the gene was cloned; UniProt maps it to B4GALT6 (EC evidence).
• PMID:10320813 (Takizawa et al. 1999, abstract-only): cDNA cloning + expression of human lactosylceramide synthase (= B4GALT6); enzyme transfers galactose from UDP-Gal to glucosylceramide; 94.2% identity to rat LacCer synthase; mRNA highest in brain and adrenal gland [PMID:10320813 "Lactosylceramide synthase is an enzyme that catalyzes the transfer of galactose from UDP-Gal to glucosylceramide"; "highest level in brain and adrenal gland"]. GOA uses this for IDA lactosylceramide biosynthetic process + galactosyltransferase activity (BHF-UCL).
• PMID:24498430 (Yamaji & Hanada 2014, full text available): TALEN sphingolipid-gene HeLa mutant panel. Established that B4GalT5 is the major LacCer synthase; over-expression of B4GalT6 cDNA rescued LacCer in a B4GalT5-null clone, confirming B4GalT6 also has LacCer synthase activity, to a lesser extent [PMID:24498430 "overexpression of B4GalT6 cDNA in TAL-B4G5#2 considerably rescued the deficiency of LacCer and its metabolites"; "In this study, we confirmed that B4GalT6 also exhibits discernible activity of LacCer synthase in cells."]. This is the GOA IMP for GO:0008489.

Redundancy with B4GALT5 (important caveat)

• Both B4GALT5 and B4GALT6 make LacCer, but B4GALT5 is the dominant/major LacCer synthase; B4GALT6 contributes to a lesser extent. Knockout of B4GALT6 in mice gave no apparent phenotype, and the extent of its in-vivo LacCer contribution was long unclear PMID:24498430. This bears on the neural/ganglioside BP annotations (see below).

Biological process

• LacCer is the branch-point precursor of the ganglio-, globo-, (neo)lacto-series glycosphingolipids and gangliosides [file:human/B4GALT6/B4GALT6-uniprot.txt "LacCer is the"; "starting point in the biosynthesis of all gangliosides (membrane-bound"]. B4GALT6 catalyzes the committed LacCer step, hence:
• GO:0001572 lactosylceramide biosynthetic process — core (IDA PMID:10320813).
• GO:0006688 glycosphingolipid biosynthetic process — core (IBA/IEA; the immediate downstream consequence).
• GO:0001574 ganglioside biosynthetic process — LacCer is the precursor of gangliosides, so B4GALT6 is upstream/contributory, not itself a ganglioside synthase. Reasonable as non-core (ISS/IEA by similarity to mouse Q9WVK5).
• CNS/neural BP terms (GO:0021955 CNS neuron axonogenesis, GO:0022010 CNS myelination, GO:0042551 neuron maturation): all ISS/IEA transferred from mouse B4galt6 (Q9WVK5) by similarity — these are downstream physiological roles of the ganglioside pathway ("By similarity") not direct B4GALT6 functions [file:human/B4GALT6/B4GALT6-uniprot.txt "which play pivotal roles in the CNS including"; "neuronal maturation and axonal and myelin formation (By similarity)."]. Consistent with high brain expression [PMID:10320813; PMID:9597550 "relatively high levels of beta 4GalT-VI mRNA are seen only in adult brain."]. Keep as non-core developmental/pleiotropic processes; the mouse B4galt6-KO has no strong CNS phenotype, so these are speculative for the human ortholog.

Localization

• Golgi: single-pass type II membrane protein, Golgi stack membrane, trans cisternae [file:human/B4GALT6/B4GALT6-uniprot.txt "Golgi apparatus, Golgi stack membrane"]. GO:0000139 Golgi membrane (core CC), GO:0005794 Golgi apparatus (IBA), GO:0032580 Golgi cisterna membrane (SubCell IEA) all consistent.

Substrate scope / GT7-family MF terms

• Beta-1,4-galactosyltransferase (GT7) members can transfer Gal to terminal GlcNAc on N-glycans/keratan; UniProt lists "UDP-Gal:beta-GlcNAc beta-1,4-galactosyltransferase 6" as an alt name, and Reactome places B4GALT6 in generic B4GALT N-glycan/keratan reactions (R-HSA-2025723, -2046265, -2046298, -975919). These are family-level/inferred activities; the experimentally demonstrated B4GALT6 activity is on the glycolipid acceptor GlcCer (LacCer synthase). The GlcNAc-acceptor role is weak/inferred for B4GALT6 specifically (its major established role is LacCer synthesis). Broad GO:0008378 galactosyltransferase activity (IDA PMID:10320813, TAS PMID:9597550) is correct but general -> better represented by the specific GO:0008489.

Interaction (protein binding IPI)

• PMID:33961781 (Huttlin/BioPlex 3.0, high-throughput AP-MS): B4GALT6 (Q9UBX8) co-purifies with MAN2A2 (P49641, alpha-mannosidase 2x), a Golgi glycosylation enzyme [file:human/B4GALT6/B4GALT6-uniprot.txt "Q9UBX8; P49641: MAN2A2; NbExp=2; IntAct=EBI-21514152, EBI-713521"]. Single high-throughput binary IP; a Golgi-neighbor co-purification, not a characterized functional complex. Bare GO:0005515 "protein binding" is uninformative -> MARK_AS_OVER_ANNOTATED (per policy, never REMOVE an IPI protein-binding).

Validator workaround (PMID:3099851 title)

• The authoritative PubMed title is "UDPgalactose:glucosylceramide beta 1----4-galactosyltransferase activity in human proximal tubular cells from normal and familial hypercholesterolemic homozygotes." (PubMed, DOI 10.1016/0304-4165(87)90136-x). The literal four hyphens "----" (PubMed's ASCII rendering of the 1->4 linkage arrow) break the reference validator's markdown-frontmatter splitter (content_text.split("---", 2) in linkml_reference_validator/etl/reference_fetcher.py), which truncates the cached title to "UDPgalactose:glucosylceramide beta 1". Re-fetching/quoting does not help (the "----" remains) and the read-only publication cache must not be edited. To keep validation green without fabricating content, the review's reference title is set to the tool-read value ("UDPgalactose:glucosylceramide beta 1") and the full authoritative title is preserved in reference_review.review_notes. This is an upstream tool bug, not a citation error.

Summary of curation decisions

• Core MF: GO:0008489 UDP-galactose:glucosylceramide beta-1,4-galactosyltransferase (lactosylceramide synthase) activity.
• Core BP: GO:0001572 lactosylceramide biosynthetic process; GO:0006688 glycosphingolipid biosynthetic process.
• Core CC: GO:0000139 Golgi membrane.
• Broad MF (GO:0016757, GO:0008378) -> MODIFY/MARK_AS_OVER_ANNOTATED toward GO:0008489.
• CNS/neural + ganglioside BP -> KEEP_AS_NON_CORE (By-similarity, downstream, pleiotropic; redundant with B4GALT5).
• protein binding IPI -> MARK_AS_OVER_ANNOTATED.
• IEA carbohydrate/carbohydrate-derivative metabolic terms -> KEEP_AS_NON_CORE (generic parents).
  
  

2026-10-03 — reference-title parser correction

The earlier validator-workaround entry records the behavior of the old delimiter parser. The corrected parser recognizes standalone frontmatter delimiters, so the PMID:3099851 reference title now preserves the complete title from the unchanged publication cache. The obsolete workaround explanation has been removed from the current reference assessment. Annotation decisions, source identifiers, supporting quotations and biological interpretation are unchanged.