ST3GAL5 (GM3 synthase; ST3 beta-galactoside alpha-2,3-sialyltransferase 5; SIAT9; lactosylceramide alpha-2,3-sialyltransferase, EC 2.4.3.9) is a Golgi membrane sialyltransferase of glycosyltransferase family 29 (GT29) that catalyzes the first committed step of ganglioside biosynthesis. It transfers sialic acid from CMP-N-acetylneuraminate onto the non-reducing terminal galactose of lactosylceramide (LacCer), producing GM3 (the simplest ganglioside) plus CMP. GM3 is the precursor of the a- and b-series gangliosides, so ST3GAL5 activity gates the entire complex ganglioside biosynthetic pathway. The enzyme can also sialylate other galactose-terminating glycosphingolipids (galactosylceramide, asialo-GM2/GA2, asialo-GM1/GA1), though LacCer is the preferred acceptor. It is a single-pass type II membrane protein anchored in the Golgi apparatus membrane with a large luminal catalytic domain, and is broadly expressed with high levels in brain, skeletal muscle, placenta and testis. Loss-of-function of ST3GAL5 abolishes GM3 and downstream ganglioside synthesis and causes salt-and-pepper developmental regression syndrome (GM3 synthase deficiency), an autosomal recessive infantile epileptic encephalopathy with developmental stagnation, cortical blindness and pigmentary skin changes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0009101 glycoprotein biosynthetic process | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Phylogenetic (IBA) propagation of a glycoprotein-biosynthesis term across the GT29 sialyltransferase family. ST3GAL5's demonstrated physiological substrate is a glycosphingolipid (lactosylceramide, giving GM3), not a glycoprotein; the glycoprotein term is pulled in because the GT29 family also contains protein sialyltransferases. This is an over-annotation for this gene, but as an experimental-tree-based inference it is retained rather than removed. Reason: ST3GAL5 acts on glycosphingolipid acceptors (LacCer -> GM3), not on glycoproteins; the family-level glycoprotein biosynthesis term does not reflect this gene's characterized function. Its true process role is captured by ganglioside/glycosphingolipid biosynthesis terms. |
| GO:0047291 lactosylceramide alpha-2,3-sialyltransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) support for the gene-specific GM3 synthase molecular function. This matches the experimentally demonstrated activity and the UniProt catalytic activity (LacCer + CMP-NeuAc -> GM3 + CMP; EC 2.4.3.9). Core molecular function. |
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to the Golgi membrane, consistent with the UniProt SUBCELLULAR LOCATION ("Golgi apparatus membrane"; single-pass type II membrane protein). Correct location for this Golgi-resident sialyltransferase. Supporting Evidence: file:human/ST3GAL5/ST3GAL5-uniprot.txt Golgi apparatus membrane |
| GO:0008373 sialyltransferase activity | IEA GO_REF:0000120 | MODIFY | Summary: Automated (ARBA/InterPro) assignment of the parent sialyltransferase activity term. Correct but non-specific; the gene-specific child term GO:0047291 (lactosylceramide alpha-2,3-sialyltransferase / GM3 synthase activity) is available and better captures the characterized function. Proposed replacements: lactosylceramide alpha-2,3-sialyltransferase activity |
| GO:0009101 glycoprotein biosynthetic process | IEA GO_REF:0000002 | REMOVE | Summary: InterPro2GO (IEA) mapping from the GT29/sialyltransferase domain to glycoprotein biosynthesis. ST3GAL5 is a glycosphingolipid sialyltransferase (LacCer -> GM3); it does not participate in glycoprotein biosynthesis. As a demonstrably mismatched electronic (IEA) inference it is removed. Reason: The domain-based glycoprotein term contradicts the characterized glycosphingolipid (ganglioside) function of ST3GAL5; substrates are lipids, not proteins. |
| GO:0047291 lactosylceramide alpha-2,3-sialyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (Rhea/EC 2.4.3.9) assignment of the gene-specific GM3 synthase molecular function, matching the UniProt catalytic activity and the experimental IDA. Core molecular function. |
| GO:0006688 glycosphingolipid biosynthetic process | TAS Reactome:R-HSA-9840309 | KEEP AS NON CORE | Summary: Reactome (TAS) annotation to glycosphingolipid biosynthesis. This is correct - GM3 is a glycosphingolipid and ganglioside biosynthesis is a subprocess of glycosphingolipid biosynthesis. It is a valid but broader parent of the more specific ganglioside biosynthetic process, so retained as non-core. |
| GO:0003836 beta-galactoside (CMP) alpha-2,3-sialyltransferase activity | TAS Reactome:R-HSA-4084984 | MODIFY | Summary: Reactome (TAS) family-level annotation from the reaction "ST3GAL1-6 transfer Neu5Ac to terminal Gal (alpha-2,3 link)". GO:0003836 is defined for the beta-D-galactosyl-(1->3)-GalNAc-R (O-glycan) acceptor reaction shared by the ST3GAL family, not for the LacCer -> GM3 reaction that defines ST3GAL5. The gene-specific term GO:0047291 better represents this enzyme's characterized activity. Proposed replacements: lactosylceramide alpha-2,3-sialyltransferase activity |
| GO:0003836 beta-galactoside (CMP) alpha-2,3-sialyltransferase activity | TAS Reactome:R-HSA-9844860 | MODIFY | Summary: Reactome (TAS) annotation from "ST3GAL5 transfers NeuNAc to ceramides". Although the Reactome reaction is ST3GAL5-specific, the mapped GO term GO:0003836 is the generic beta-galactoside (O-glycan Gal-1,3-GalNAc-R) sialyltransferase term rather than the glycosphingolipid GM3 synthase term. The gene-specific GO:0047291 more precisely captures the LacCer -> GM3 activity described by this Reactome event. Proposed replacements: lactosylceramide alpha-2,3-sialyltransferase activity |
| GO:0001574 ganglioside biosynthetic process | IC PMID:9822625 Expression cloning and functional characterization of human ... | ACCEPT | Summary: Curator inference (IC) from the GM3 synthase molecular function (GO:0047291) to ganglioside biosynthesis. ST3GAL5 catalyzes the first committed step of ganglioside synthesis (LacCer -> GM3, the precursor of a- and b-series gangliosides), so this is the core biological process. |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-4084984 | ACCEPT | Summary: Reactome (TAS) annotation placing the ST3GAL1-6 alpha-2,3- sialyltransferase reaction in the Golgi membrane, consistent with the UniProt subcellular location. Correct location. |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-9844860 | ACCEPT | Summary: Reactome (TAS) annotation localizing the ST3GAL5 ceramide sialylation reaction to the Golgi membrane, consistent with UniProt. Correct location. |
| GO:0006688 glycosphingolipid biosynthetic process | TAS PMID:10092602 Expression cloning of mouse cDNA of CMP-NeuAc:Lactosylcerami... | KEEP AS NON CORE | Summary: Author-statement (TAS) annotation to glycosphingolipid biosynthesis, supported by the mouse GM3-synthase cloning paper describing an enzyme that "initiates the synthesis of gangliosides". Correct but a broader parent of the more specific ganglioside biosynthetic process, so retained as non-core. Supporting Evidence: PMID:10092602 an enzyme that initiates the synthesis of |
| GO:0008373 sialyltransferase activity | TAS PMID:10092602 Expression cloning of mouse cDNA of CMP-NeuAc:Lactosylcerami... | MODIFY | Summary: Author-statement (TAS) annotation to the parent sialyltransferase activity term, from the mouse GM3-synthase paper. Correct but non-specific; the gene-specific GO:0047291 (GM3 synthase activity) better captures the LacCer-specific function reported ("only lactosylceramide showed significant activity as an acceptor"). Proposed replacements: lactosylceramide alpha-2,3-sialyltransferase activity Supporting Evidence: PMID:10092602 only lactosylceramide showed significant activity as an acceptor |
| GO:0016020 membrane | TAS PMID:10092602 Expression cloning of mouse cDNA of CMP-NeuAc:Lactosylcerami... | MODIFY | Summary: Author-statement (TAS) annotation to the generic "membrane" term, consistent with the type II membrane topology reported, but uninformative. ST3GAL5 is specifically a Golgi membrane protein, so GO:0000139 (Golgi membrane) is the appropriate replacement. Proposed replacements: Golgi membrane Supporting Evidence: PMID:10092602 predicted a type II membrane protein |
| GO:0047291 lactosylceramide alpha-2,3-sialyltransferase activity | IDA PMID:9822625 Expression cloning and functional characterization of human ... | ACCEPT | Summary: Direct experimental (IDA) demonstration of GM3 synthase activity - cells transfected with the cloned human cDNA synthesized GM3 de novo, with lactosylceramide as the best acceptor. This is the defining, gene-specific core molecular function of ST3GAL5. Supporting Evidence: PMID:9822625 The best acceptor substrate for the gene product was lactosylceramide |
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Download this section (compressed HTML)Q: To what extent does the broader acceptor specificity (GalCer -> GM4; GA2 -> GM2; GA1 -> GM1) reflect a physiologically relevant in vivo activity versus an in vitro capability, and is it isoform-3-specific?
Experiment: Quantitative glycosphingolipid profiling (mass spectrometry) of cells and tissues with defined ST3GAL5 loss-of-function to confirm GM3 depletion and downstream ganglioside collapse, and to test whether residual GM4/GM1/GM2 arises from the minor acceptor activities.
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