ST6GAL1 (beta-galactoside alpha-2,6-sialyltransferase 1, ST6Gal-I; EC 2.4.3.1) is a Golgi-resident, single-pass type II membrane glycosyltransferase of the CAZy GT29 (sialyltransferase) family. It catalyzes transfer of N-acetylneuraminic acid (Neu5Ac) from the donor CMP-Neu5Ac in an alpha-2,6 linkage onto the terminal beta-linked galactose of complex-type N-glycans, generating the Sia-alpha-2,6-Gal (Neu5Ac-alpha-2,6-Gal-beta1,4-GlcNAc) epitope. It is the major enzyme producing alpha-2,6-sialylated N-glycans in vertebrates; this terminal cap is the recognition determinant of the SNA lectin and the ligand for the B-cell inhibitory receptor CD22/Siglec-2, and corresponds to the carbohydrate antigen formerly mislabeled CD75. The catalytic ectodomain (residues ~89-406) adopts a variant glycosyltransferase-A fold and uses an SN2 inversion, substrate-assisted charge-relay mechanism; the enzyme is inhibited by CTP. ST6GAL1 acts in the trans cisternae of the Golgi stack, where it forms disulfide-mediated and non-covalent homodimers and a trans-Golgi heterodimer with beta-1,4-galactosyltransferase 1. A catalytically active soluble ectodomain is released by proteolytic shedding and circulates in serum (secreted notably by liver during the acute-phase response and by activated platelets), where it can sialylate glycoproteins extrinsically. By modifying the N-glycans of secreted and cell-surface glycoproteins, ST6GAL1 influences immunoglobulin G Fc anti-inflammatory activity, B-cell and myeloid biology, and is frequently upregulated in carcinomas, but these roles all derive from the single alpha-2,6-sialyltransferase catalytic activity acting on diverse substrate glycoproteins.
Definition: Catalysis of the transfer of N-acetylneuraminate from CMP-N-acetyl-beta-neuraminate to the terminal beta-D-galactosyl residue of a complex-type N-linked oligosaccharide of a glycoprotein, forming an N-acetyl-alpha-neuraminyl-(2->6)-beta-D-galactosyl linkage (the Sia-alpha-2,6-Gal epitope). EC 2.4.3.1.
Justification: GO:0003835 (beta-galactoside alpha-2,6-sialyltransferase activity) is defined on a generic beta-galactoside acceptor, whereas the physiologically dominant ST6GAL1 reaction acts specifically on the terminal galactose of complex-type N-glycans on glycoproteins (the UniProt/Rhea protein-N-glycan acceptor reactions, e.g. RHEA:83927 and RHEA:82947). A child term grounded on the protein-N-glycan acceptor would let ST6GAL1 (and paralog ST6GAL2) be annotated to their exact physiological activity rather than the broader free-galactoside parent.
Parent term: beta-galactoside alpha-2,6-sialyltransferase activity
Mappings:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003835 beta-galactoside alpha-2,6-sialyltransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: This is the core molecular function of ST6GAL1 and is correct at the most specific level. Phylogenetic (IBA) inference here agrees with extensive direct experimental evidence (crystal structure, kinetics, and multiple in vitro activity assays) and with the UniProt/Rhea catalytic activity (RHEA:52104, EC 2.4.3.1). Supporting Evidence: PMID:23999306 Human beta-galactoside alpha-2,6-sialyltransferase I (ST6Gal-I) establishes the final glycosylation pattern of many glycoproteins by transferring a sialyl moiety to a terminal galactose. |
| GO:0006487 protein N-linked glycosylation | IBA GO_REF:0000033 | ACCEPT | Summary: Accurate and appropriately specific. ST6GAL1's principal biological role is the terminal alpha-2,6-sialylation (capping) step of complex-type N-glycan maturation. Supported independently by IDA (PMID:23999306) and consistent with the UniProt-annotated complex N-glycan acceptor reactions. |
| GO:0097503 sialylation | IBA GO_REF:0000033 | ACCEPT | Summary: Correct. Sialylation is the process directly performed by ST6GAL1. Also independently supported by IDA (PMID:23999306). A reasonable core process term, slightly broader than the specific alpha-2,6 linkage but accurate. |
| GO:0005794 Golgi apparatus | IBA GO_REF:0000033 | ACCEPT | Summary: Correct core localization. ST6GAL1 is a trans-Golgi resident enzyme; the IBA call agrees with direct evidence for Golgi membrane localization (PMID:20378551) and UniProt (Golgi stack membrane, trans cisternae). |
| GO:0003835 beta-galactoside alpha-2,6-sialyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate of the core catalytic MF from an automated (multi-method IEA) source mapped to EC 2.4.3.1 / RHEA. Correct; redundant with the IBA, EXP, IDA and TAS annotations to the same term. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Reflects the soluble form of ST6GAL1, which is shed from the Golgi/membrane and circulates in serum, where it can sialylate glycoproteins extrinsically. This is a genuine secondary localization (UniProt: Secreted, by similarity to rat P13721) but is secondary to the Golgi-resident catalytic site of action; kept as non-core. Supporting Evidence: file:human/ST6GAL1/ST6GAL1-deep-research-falcon.md BACE1 (Ξ²-site amyloid precursor protein-cleaving enzyme 1) cleaves ST6GAL1 to release a soluble, catalytically active form lacking the transmembrane domain, enabling secretion and extracellular sialylation activity |
| GO:0008373 sialyltransferase activity | IEA GO_REF:0000120 | MODIFY | Summary: Correct but over-general parent term. The specific activity beta-galactoside alpha-2,6-sialyltransferase activity (GO:0003835) is experimentally established and should be used instead. Proposed replacements: beta-galactoside alpha-2,6-sialyltransferase activity |
| GO:0009101 glycoprotein biosynthetic process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Not wrong but a broad parent of the more informative N-linked glycosylation / sialylation process annotations already present. Retained as a non-core, higher-level descriptor (InterPro2GO electronic inference). |
| GO:0032580 Golgi cisterna membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Correct and appropriately specific localization (UniProt subcellular-location mapping). ST6GAL1 is a single-pass type II membrane protein of the Golgi stack cisternae (trans cisternae), consistent with PMID:20378551 and UniProt. |
| GO:0006487 protein N-linked glycosylation | IEA GO_REF:0000107 | ACCEPT | Summary: Duplicate of the core N-linked glycosylation process annotation, transferred electronically from the mouse ortholog (Q64685). Correct. |
| GO:0016266 protein O-linked glycosylation via N-acetylgalactosamine | TAS Reactome:R-HSA-977068 | KEEP AS NON CORE | Summary: ST6GAL1 is predominantly an N-glycan alpha-2,6-sialyltransferase, but Reactome documents a minor activity terminating O-GalNAc (mucin-type) glycans, including conversion of Tn to sialyl-Tn antigen. This O-glycan role is real but minor and context-specific relative to the dominant N-glycan function; kept as non-core. |
| GO:0003835 beta-galactoside alpha-2,6-sialyltransferase activity | TAS Reactome:R-HSA-4085033 | ACCEPT | Summary: Core catalytic MF (Reactome reaction "ST6GAL1,2 transfer Neu5Ac to terminal Gal (alpha-2,6 link)"). Correct; redundant with the experimentally supported annotations to the same term. |
| GO:0003835 beta-galactoside alpha-2,6-sialyltransferase activity | TAS Reactome:R-HSA-975902 | ACCEPT | Summary: Core catalytic MF (Reactome "ST6GAL1 transfers Neu5Ac to terminal Gal of N-glycans"). Correct; redundant duplicate. |
| GO:0003835 beta-galactoside alpha-2,6-sialyltransferase activity | TAS Reactome:R-HSA-977071 | ACCEPT | Summary: Core catalytic MF; this Reactome reaction concerns transfer of sialic acid to Tn antigens to form sialyl-Tn. The activity is correct (same enzyme), though the O-GalNAc/sTn acceptor is a minor context relative to the N-glycan role. |
| GO:0003835 beta-galactoside alpha-2,6-sialyltransferase activity | EXP PMID:25733881 Controlled tetra-Fc sialylation of IVIg results in a drug ca... | ACCEPT | Summary: Strong experimental support for the core catalytic activity: controlled alpha-2,6-sialylation of IgG Fc N-glycans by ST6GAL1 to generate tetra-Fc-sialylated IVIg with enhanced anti-inflammatory activity. Supporting Evidence: PMID:25733881 Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity. |
| GO:0003835 beta-galactoside alpha-2,6-sialyltransferase activity | EXP PMID:36280670 A universal glycoenzyme biosynthesis pipeline that enables e... | ACCEPT | Summary: Strong experimental support for the core catalytic activity (cell-free glycoenzyme remodeling pipeline using recombinant ST6GAL1 to install alpha-2,6 sialic acid; UniProt-cited EC 2.4.3.1 evidence). Supporting Evidence: PMID:36280670 A universal glycoenzyme biosynthesis pipeline that enables efficient cell-free remodeling of glycans. |
| GO:0003835 beta-galactoside alpha-2,6-sialyltransferase activity | EXP PMID:37632720 Divergent Enzymatic Assembly of a Comprehensive 64-Membered ... | ACCEPT | Summary: Strong experimental support for the core catalytic activity (divergent enzymatic assembly of a 64-membered IgG N-glycan library using ST6GAL1 for alpha-2,6 sialylation; UniProt-cited EC 2.4.3.1 evidence). Supporting Evidence: PMID:37632720 Divergent Enzymatic Assembly of a Comprehensive 64-Membered IgG N-Glycan Library for Functional Glycomics. |
| GO:0005576 extracellular region | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer (from rat ortholog P13721) of the secreted/soluble localization. Same biological content as the IEA extracellular-region annotation; the soluble serum form is genuine but secondary to the Golgi catalytic site. Kept as non-core. |
| GO:0019082 viral protein processing | TAS Reactome:R-HSA-9683673 | MARK AS OVER ANNOTATED | Summary: This annotation comes from Reactome SARS-CoV-2 pathways in which cellular sialyltransferases glycosylate viral proteins (here ORF3a). The underlying molecular event is ST6GAL1's ordinary host-glycosylation activity; framing a housekeeping glycosylation step as a dedicated "viral protein processing" function over-extends the gene's role. The enzyme is not virus-specific. |
| GO:0019082 viral protein processing | TAS Reactome:R-HSA-9694548 | MARK AS OVER ANNOTATED | Summary: Same as above (Reactome SARS-CoV-2 spike maturation). The molecular event is generic host sialylation of viral glycoproteins; "viral protein processing" over-extends ST6GAL1's role. The Reactome curation even states the spike sialic acids are added "presumably by the cell's sialyltransferases". |
| GO:0008373 sialyltransferase activity | TAS Reactome:R-HSA-9683769 | MODIFY | Summary: Over-general parent MF asserted within a SARS-CoV-2 O-glycosylation Reactome reaction. The specific activity GO:0003835 is established for ST6GAL1 and should be used instead of the parent sialyltransferase activity term. Proposed replacements: beta-galactoside alpha-2,6-sialyltransferase activity |
| GO:0008373 sialyltransferase activity | TAS Reactome:R-HSA-9697018 | MODIFY | Summary: Over-general parent MF asserted within a SARS-CoV-2 spike sialylation Reactome reaction. Replace with the specific GO:0003835 established for ST6GAL1. Proposed replacements: beta-galactoside alpha-2,6-sialyltransferase activity |
| GO:0000139 Golgi membrane | IDA PMID:20378551 Golgi N-glycosyltransferases form both homo- and heterodimer... | ACCEPT | Summary: Direct, live-cell evidence (BiFC and immunofluorescence with a Golgi marker) that ST6GAL1 localizes to Golgi membranes. This is the core localization and the site of catalytic action. Supporting Evidence: PMID:20378551 BiFC signal was detected almost exclusively in the Golgi membranes of the cells. |
| GO:0042803 protein homodimerization activity | IDA PMID:20378551 Golgi N-glycosyltransferases form both homo- and heterodimer... | ACCEPT | Summary: Well supported by direct evidence: ST6GAL1 forms disulfide-mediated and non-covalent homodimers in live Golgi membranes (BiFC; >90% of molecules homodimeric), independent of the TM cysteine (C24G). A genuine molecular function that organizes the enzyme in the Golgi, though distinct from its core catalytic activity. Supporting Evidence: PMID:20378551 over 90% of the SiaT molecules appear to be homodimeric in the Golgi membranes of live cells |
| GO:0005515 protein binding | IPI PMID:16237761 Screening of hepatocyte proteins binding to F protein of hep... | REMOVE | Summary: Uninformative generic protein-binding annotation derived from a yeast two-hybrid screen for hepatocyte proteins binding the hepatitis C virus F protein, in which "1 colony was sialyltransferase" among 36 colonies, with no follow-up validation specific to ST6GAL1. Per curation guidance, generic "protein binding" with weak, non-physiological Y2H evidence and no informative partner-specific function should not be retained. |
| GO:0003835 beta-galactoside alpha-2,6-sialyltransferase activity | IDA PMID:23999306 The structure of human Ξ±-2,6-sialyltransferase reveals the b... | ACCEPT | Summary: Direct experimental support for the core catalytic activity from the human ST6Gal-I crystal structure paper (mechanism, CMP product/inhibitor complexes, glycan binding mode). Strongest single-paper evidence for GO:0003835. Supporting Evidence: PMID:23999306 ST6Gal-I establishes the final glycosylation pattern of many glycoproteins by transferring a sialyl moiety to a terminal galactose. |
| GO:0006054 N-acetylneuraminate metabolic process | IDA PMID:23999306 The structure of human Ξ±-2,6-sialyltransferase reveals the b... | KEEP AS NON CORE | Summary: Correct: by consuming CMP-Neu5Ac and transferring Neu5Ac onto acceptors, ST6GAL1 participates in sialic-acid (N-acetylneuraminate) metabolism. Slightly broad but accurate; retained as a non-core process descriptor alongside the more specific sialylation term. |
| GO:0006487 protein N-linked glycosylation | IDA PMID:23999306 The structure of human Ξ±-2,6-sialyltransferase reveals the b... | ACCEPT | Summary: Direct support for the core process: the structure paper characterizes ST6Gal-I acting on complex N-glycan acceptors. Correct and specific. Supporting Evidence: PMID:23999306 the binding mode of complex glycans |
| GO:0097503 sialylation | IDA PMID:23999306 The structure of human Ξ±-2,6-sialyltransferase reveals the b... | ACCEPT | Summary: Direct support for the core sialylation process. Correct; consistent with the IBA annotation to the same term. Supporting Evidence: PMID:23999306 transferring a sialyl moiety to a terminal galactose |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-4085033 | ACCEPT | Summary: Core Golgi-membrane localization (Reactome). Correct; redundant with the IDA Golgi membrane annotation. |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-9683769 | ACCEPT | Summary: Core Golgi-membrane localization asserted in a SARS-CoV-2 O-glycosylation Reactome reaction. The localization itself is correct (redundant duplicate). |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-9697018 | ACCEPT | Summary: Core Golgi-membrane localization asserted in a SARS-CoV-2 spike sialylation Reactome reaction. Correct; redundant duplicate. |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-975902 | ACCEPT | Summary: Core Golgi-membrane localization (Reactome N-glycan sialylation reaction). Correct; redundant duplicate. |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-977071 | ACCEPT | Summary: Core Golgi-membrane localization (Reactome sialyl-Tn reaction). Correct; redundant duplicate. |
| GO:0008373 sialyltransferase activity | IDA PMID:21081508 Universal phosphatase-coupled glycosyltransferase assay. | MODIFY | Summary: Direct biochemical measurement of ST6GAL1 kinetics (phosphatase-coupled assay; KM ~530 uM for CMP-NeuAc) demonstrates sialyltransferase activity, but the term is the over-general parent. Modify to the specific beta-galactoside alpha-2,6-sialyltransferase activity (GO:0003835). Proposed replacements: beta-galactoside alpha-2,6-sialyltransferase activity |
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Download this section (compressed HTML)Q: What protease(s) shed the catalytically active soluble ST6GAL1 ectodomain into serum in humans, and is BACE1 the principal sheddase as suggested in the secondary literature? A GO localization/process annotation for the soluble form awaits this.
Q: To what extent does ST6GAL1 act physiologically on O-GalNAc (mucin-type) glycans and sialyl-Tn formation versus the dominant N-glycan acceptor, in normal tissues versus carcinoma?
Q: Are the homodimer and the B4GALT1 heterodimer functionally required for full catalytic efficiency or fidelity of N-glycan sialylation in vivo, or do they primarily serve Golgi retention?
Experiment: Acceptor-substrate profiling of recombinant human ST6GAL1 against defined N-glycan, O-GalNAc (Tn/Core1/Core2), and free-galactoside acceptors to quantify the relative physiological preference and refine the activity annotation.
Experiment: Tissue-specific (B-cell, myeloid, hepatocyte) conditional St6gal1 knockouts with serum and cell-surface glycomics to dissociate intrinsic (Golgi) from extrinsic (soluble serum enzyme) alpha-2,6-sialylation contributions.
Experiment: Structure-guided disruption of the disulfide/non-covalent homodimer and the B4GALT1 heterodimer interfaces, followed by live-cell Golgi-retention and N-glycan-sialylation efficiency assays, to test the functional role of oligomerization.
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