A4GALT (Gb3/CD77 synthase; EC 2.4.1.228) is a single-pass type II Golgi membrane glycosyltransferase with a lumenal catalytic domain. It transfers galactose from UDP-galactose in an alpha-1,4 linkage to lactosylceramide, producing globotriaosylceramide (Gb3, CD77 or P(k) antigen) and initiating globo-series glycosphingolipid biosynthesis. The wild-type enzyme also produces the P1 antigen by galactosylating paragloboside in the neolacto series. The enzyme can also cap complex N-glycans with the P1 glycotope. Its glycan products contribute to blood-group identity and can serve as receptors for Shiga toxins. Biallelic loss-of-function variants cause the p-null blood-group phenotype, classified as A4GALT-congenital disorder of glycosylation. The Q211E variant has a distinct effect: it broadens acceptor specificity to terminal GalNAc and produces NOR antigens associated with inherited polyagglutination.
Definition: Catalysis of the transfer of a galactosyl group from UDP-alpha-D-galactose to the terminal galactose of paragloboside (neolactotetraosylceramide) in an alpha-1,4 linkage, producing the P1 blood-group glycosphingolipid and UDP.
Justification: Wild-type A4GALT catalyzes both LacCer-to-Gb3/P(k) and paragloboside-to-P1 reactions. GO:0050512 specifies the former; complete inspection of the galactosyltransferase branch found no term for the latter. GO:0035250 specifies the donor but does not distinguish the acceptor. This proposed term fills that experimentally established acceptor-specific gap without inventing an identifier.
Parent term: UDP-galactosyltransferase activity
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0008378 galactosyltransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: The phylogenetic galactosyltransferase annotation agrees with the experimentally characterized human enzyme. Its established UDP-galactose donor is compatible with this broad galactosyltransferase term while retaining the P(k) and P1 acceptor breadth. Reason: Retain this biologically correct core activity at the existing level: galactosyltransferase activity covers both P(k) and P1 synthesis. GO:0035250 is a valid donor-specific child, but does not distinguish the missing P1 acceptor reaction. The overly general hexosyltransferase row is refined to that donor-specific term, and a separate ontology-term proposal expresses the actual P1 coverage gap. Supporting Evidence: PMID:10748143 showed alpha1, 4-galactosyltransferase activity only on lactosylceramide and galactosylceramide PMID:26773500 the consensus enzyme synthesizes both the P(k) and P1 antigens, while its p.Q211E variant additionally synthesizes the NOR antigen file:human/A4GALT/A4GALT-uniprot.txt from UDP-alpha-D-galactose in an alpha1,4 linkage to |
| GO:0006688 glycosphingolipid biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation to glycosphingolipid biosynthetic process. This is the correct core biological process: A4GALT initiates the globo-series branch of neutral glycosphingolipid biosynthesis by converting lactosylceramide to globotriaosylceramide (Gb3Cer), the root structure of the globo-series. Supporting Evidence: PMID:10748143 Since Gb3/CD77 synthase initiates the synthesis of globo series glycolipids |
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic annotation (UniProt Subcellular Location keyword mapping) to Golgi membrane. This is the correct, specific compartment for A4GALT, a single-pass type II Golgi membrane glycosyltransferase, and is consistent with the UniProt subcellular location and the Reactome TAS annotation. Supporting Evidence: file:human/A4GALT/A4GALT-uniprot.txt SUBCELLULAR LOCATION: Golgi apparatus membrane |
| GO:0016758 hexosyltransferase activity | IEA GO_REF:0000117 | MODIFY | Summary: A4GALT is a hexosyltransferase, but this high-level ARBA term does not identify the transferred sugar or donor. UDP-galactosyltransferase activity is the appropriate supported refinement across its P(k) and P1 acceptors. Reason: Use GO:0035250 to specify transfer of galactose from UDP-galactose while retaining the enzyme's experimentally demonstrated acceptor breadth. The lactosylceramide-specific reaction is already represented separately by GO:0050512. Proposed replacements: UDP-galactosyltransferase activity Supporting Evidence: PMID:26773500 the consensus enzyme synthesizes both the P(k) and P1 antigens, while its p.Q211E variant additionally synthesizes the NOR antigen |
| GO:0050512 lactosylceramide 4-alpha-galactosyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation (RHEA:11924 / EC:2.4.1.228 mapping) to the specific molecular function lactosylceramide 4-alpha-galactosyltransferase activity. This precisely captures the Gb3/CD77 synthase reaction and is corroborated by direct experimental evidence (PMID:10748143) and by Reactome. Core function. Supporting Evidence: PMID:10748143 showed alpha1, 4-galactosyltransferase activity only on lactosylceramide and galactosylceramide |
| GO:0006688 glycosphingolipid biosynthetic process | TAS Reactome:R-HSA-9840309 | ACCEPT | Summary: Reactome TAS annotation to glycosphingolipid biosynthetic process, via the "Glycosphingolipid biosynthesis" pathway. Correct core biological process; A4GALT catalyzes the LacCer-to-Gb3Cer step that initiates the globo-series of glycosphingolipids. Supporting Evidence: PMID:10748143 Since Gb3/CD77 synthase initiates the synthesis of globo series glycolipids |
| GO:0050512 lactosylceramide 4-alpha-galactosyltransferase activity | TAS Reactome:R-HSA-9846477 | ACCEPT | Summary: Reactome TAS annotation (reaction "A4GALT transfers galactose to LacCer") to the specific molecular function lactosylceramide 4-alpha-galactosyltransferase activity. This is the enzyme's core catalytic function and matches the experimental evidence. Supporting Evidence: PMID:10748143 showed alpha1, 4-galactosyltransferase activity only on lactosylceramide and galactosylceramide |
| GO:0050512 lactosylceramide 4-alpha-galactosyltransferase activity | EXP PMID:10748143 Molecular cloning of globotriaosylceramide/CD77 synthase, a ... | ACCEPT | Summary: Direct experimental (EXP) annotation to lactosylceramide 4-alpha-galactosyltransferase activity. In the expression-cloning study, extracts of cells transfected with the A4GALT cDNA showed alpha-1,4-galactosyltransferase activity on lactosylceramide, producing Gb3/CD77. This is the definitive experimental support for the core molecular function. Supporting Evidence: PMID:10748143 showed alpha1, 4-galactosyltransferase activity only on lactosylceramide and galactosylceramide |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-9846477 | ACCEPT | Summary: Reactome TAS annotation to Golgi membrane. This is the correct specific compartment where A4GALT acts as a type II Golgi glycosyltransferase, consistent with the UniProt subcellular location. Supporting Evidence: file:human/A4GALT/A4GALT-uniprot.txt SUBCELLULAR LOCATION: Golgi apparatus membrane |
| GO:0016020 membrane | IDA PMID:10748143 Molecular cloning of globotriaosylceramide/CD77 synthase, a ... | MODIFY | Summary: The original cloning study predicts a type II membrane protein. The reviewed UniProt record and the Reactome reaction locate A4GALT specifically in the Golgi membrane. Reason: Refine the broad membrane annotation to Golgi membrane using the combined localization evidence. This does not imply that the original paper directly imaged Golgi localization. Proposed replacements: Golgi membrane Supporting Evidence: PMID:10748143 predicted a type II membrane protein file:human/A4GALT/A4GALT-uniprot.txt SUBCELLULAR LOCATION: Golgi apparatus membrane |
| GO:0007009 plasma membrane organization | IDA PMID:10747952 Cloning and expression of the histo-blood group Pk UDP-galac... | UNDECIDED | Summary: The accessible abstract of PMID:10747952 demonstrates P(k) synthase activity and cell-surface antigen expression, but does not establish the assembly, arrangement or disassembly of the plasma membrane required by GO:0007009. Reason: The publication cache is abstract-only, and attempts to retrieve the full article did not yield usable full text. It is therefore not possible to adjudicate the experimental plasma-membrane-organization annotation. Glycolipid synthesis alone does not identify the membrane-organization experiment, but absence of that experiment from the abstract is insufficient to reject the curator's assertion. Supporting Evidence: PMID:10747952 Transfection of P(k)-negative Namalwa cells with alpha4Gal-T1 resulted in strong P(k) expression. |
| GO:0008378 galactosyltransferase activity | IDA PMID:10747952 Cloning and expression of the histo-blood group Pk UDP-galac... | ACCEPT | Summary: The original expression study established P(k) synthase activity in insect cells and restored P(k) expression in Namalwa cells. The combined biochemical evidence establishes transfer from UDP-galactose, corroborating this galactosyltransferase annotation. Reason: Retain this biologically correct core activity at the existing level: galactosyltransferase activity covers both P(k) and P1 synthesis. GO:0035250 is a valid donor-specific child, but does not distinguish the missing P1 acceptor reaction. The overly general hexosyltransferase row is refined to that donor-specific term, and a separate ontology-term proposal expresses the actual P1 coverage gap. Supporting Evidence: PMID:10748143 showed alpha1, 4-galactosyltransferase activity only on lactosylceramide and galactosylceramide PMID:26773500 the consensus enzyme synthesizes both the P(k) and P1 antigens, while its p.Q211E variant additionally synthesizes the NOR antigen PMID:10747952 Transfection of P(k)-negative Namalwa cells with alpha4Gal-T1 resulted in strong P(k) expression. file:human/A4GALT/A4GALT-uniprot.txt from UDP-alpha-D-galactose in an alpha1,4 linkage to |
| GO:0008378 galactosyltransferase activity | IDA PMID:10748143 Molecular cloning of globotriaosylceramide/CD77 synthase, a ... | ACCEPT | Summary: Expression cloning demonstrated alpha-1,4-galactosyltransferase activity on lactosylceramide and galactosylceramide. The established UDP-galactose donor corroborates galactosyltransferase activity across these acceptors and the subsequently established P1 reaction. Reason: Retain this biologically correct core activity at the existing level: galactosyltransferase activity covers both P(k) and P1 synthesis. GO:0035250 is a valid donor-specific child, but does not distinguish the missing P1 acceptor reaction. The overly general hexosyltransferase row is refined to that donor-specific term, and a separate ontology-term proposal expresses the actual P1 coverage gap. Supporting Evidence: PMID:10748143 showed alpha1, 4-galactosyltransferase activity only on lactosylceramide and galactosylceramide PMID:26773500 the consensus enzyme synthesizes both the P(k) and P1 antigens, while its p.Q211E variant additionally synthesizes the NOR antigen file:human/A4GALT/A4GALT-uniprot.txt from UDP-alpha-D-galactose in an alpha1,4 linkage to |
| GO:0000139 Golgi membrane | NAS PMID:10748143 Molecular cloning of globotriaosylceramide/CD77 synthase, a ... | ACCEPT | Summary: Golgi membrane is the established location of A4GALT. The original publication predicts type II membrane topology; the more specific Golgi assignment is retained with its original NAS evidence and is corroborated by UniProt and the Reactome reaction. Reason: The Golgi assignment is consistent with the biosynthetic reaction and independent curated localization. A prediction of membrane topology alone is not direct experimental localization. Supporting Evidence: file:human/A4GALT/A4GALT-uniprot.txt SUBCELLULAR LOCATION: Golgi apparatus membrane |
| GO:0006688 glycosphingolipid biosynthetic process | NAS PMID:10748143 Molecular cloning of globotriaosylceramide/CD77 synthase, a ... | ACCEPT | Summary: NAS annotation to glycosphingolipid biosynthetic process. Correct core biological process; A4GALT initiates globo-series glycosphingolipid synthesis by converting lactosylceramide to Gb3Cer. Independently supported by IBA and Reactome TAS. Supporting Evidence: PMID:10748143 Since Gb3/CD77 synthase initiates the synthesis of globo series glycolipids |
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Q: What fraction of endogenous human P1 is carried on N-glycoproteins in normal tissues, and how does it depend on A4GALT expression and competing sialylation?
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