GALT (galactose-1-phosphate uridylyltransferase; EC 2.7.7.12) is a cytosolic enzyme that catalyzes the third, central step of the Leloir pathway of galactose metabolism: it reversibly transfers a uridylyl (UMP) group from UDP-alpha-D-glucose to alpha-D-galactose 1-phosphate, producing alpha-D-glucose 1-phosphate and UDP-alpha-D-galactose. Catalysis proceeds by a double-displacement (ping-pong) mechanism in which the transferred UMP is held as a covalent phospho-histidine intermediate on active-site His186 (within the His-Pro-His motif) before it is passed to the incoming hexose-1-phosphate. The enzyme is an obligate homodimer, with each active site built from residues contributed by both subunits, and binds zinc at a site distinct from the active site that stabilizes the fold and suppresses aggregation. By regenerating UDP-glucose and interconverting UDP-hexoses, GALT couples dietary and endogenous galactose to glycolysis and to the pool of nucleotide sugars used for glycoconjugate synthesis. Loss of GALT activity causes classic (type I) galactosemia, the most severe galactosemia, an autosomal recessive disorder in which galactose-1-phosphate and galactitol accumulate on milk feeding, producing neonatal hepatic and renal failure, cataracts, bleeding diathesis and E. coli sepsis, and, despite dietary galactose restriction, long-term cognitive, speech, motor, and (in females) ovarian complications.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0008108 UDP-glucose:hexose-1-phosphate uridylyltransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function. GALT is the Leloir-pathway uridylyltransferase (EC 2.7.7.12) transferring UMP from UDP-glucose to galactose-1-phosphate. The IBA call across the GALT/PANTHER family is the correct, appropriately specific molecular function. Reason: Directly supported by the human enzyme structure and kinetics, and consistent with the phylogenetically conserved family function. Supporting Evidence: PMID:27005423 revealing a homodimer arrangement that contains a covalent uridylylated intermediate and glucose-1-phosphate in the active site, as well as a structural zinc-binding site, per monomer |
| GO:0033499 beta-D-galactose catabolic process via UDP-galactose, Leloir pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Core biological process. GALT performs the committed third step of the Leloir pathway that catabolizes galactose via UDP-galactose. This is the most precise BP term for GALT's role. Reason: Phylogenetically conserved pathway role, corroborated by the biochemical reaction and by disease biology in which loss of GALT blocks this step. Supporting Evidence: PMID:27005423 The Leloir pathway consists of four enzymes, namely galactose mutarotase (GALM), galactokinase 1, (GALK1), galactose 1-phosphate uridylyltransferase (GALT) and UDP-galactose 4 |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | MODIFY | Summary: GALT is a soluble cytosolic metabolic enzyme. The IBA cytoplasm call is correct but less specific than the cytosol term (GO:0005829, part_of cytoplasm) that GALT already carries from Reactome. Reason: Correct but general. GALT has no signal peptide, transmembrane segment or organelle-targeting sequence, the human enzyme is purified and crystallised as a soluble homodimer, and Reactome places both the normal and the defective GALT reactions in the cytosol. Cytosol is a part_of descendant of cytoplasm already carried by the gene, so the row is refined to it rather than kept at cytoplasm. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000235304 SUPPORTS TRANSFER Human GALT lies inside this galactose-1-phosphate uridylyltransferase clade (seeded by yeast GAL7, E. coli GalT and human GALT) with no sign of relocalisation; the node-level cytoplasm term is sound but coarser than the cytosol location of the human enzyme. Proposed replacements: cytosol Supporting Evidence: PMID:27005423 revealing a homodimer arrangement that contains a covalent uridylylated intermediate and glucose-1-phosphate in the active site |
| GO:0006012 galactose metabolic process | IEA GO_REF:0000120 | MODIFY | Summary: Correct but general parent process. GALT's role in galactose metabolism is specifically the uridylyltransfer step of the Leloir pathway, captured by GO:0033499, which the gene already carries (IBA, TAS). Reason: Correct but general: GO:0033499 is_a galactose catabolic process is_a galactose metabolic process, and the human enzyme's reaction places it in the Leloir pathway. Refined to the specific descendant already on the gene. Proposed replacements: beta-D-galactose catabolic process via UDP-galactose, Leloir pathway Supporting Evidence: PMID:27005423 The Leloir pathway consists of four enzymes, namely galactose mutarotase (GALM), galactokinase 1, (GALK1), galactose 1-phosphate uridylyltransferase (GALT) and UDP-galactose 4 |
| GO:0008108 UDP-glucose:hexose-1-phosphate uridylyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Same core molecular function as the IBA/IDA/EXP calls, here derived from InterPro/EC/RHEA mappings (EC 2.7.7.12; RHEA:13989). Correct and specific. Reason: The EC/RHEA-based electronic mapping matches the experimentally established reaction of the human enzyme. Supporting Evidence: PMID:27005423 GALT (EC 2.7.7.12) reversibly converts galactose 1-phosphate (Gal-1-P) and UDP glucose (UDP-Glc) into glucose 1-phosphate (Glc-1-P) and UDP galactose (UDP-Gal) |
| GO:0008270 zinc ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Structural zinc binding. The human GALT crystal structure shows a divalent metal site per monomer that prefers zinc and confers stability; this InterPro-based IEA is consistent with the experimental (IDA) zinc annotation. The site is distinct from the active site, so this is a structural rather than catalytic function. Reason: Zinc binding is experimentally confirmed for human GALT and corroborated by the structure, but serves a structural/stability role separate from the core catalytic uridylyltransferase activity. Supporting Evidence: PMID:27005423 Altogether our findings suggest hGALT contains one Zn2+ binding site, which confers stability to the protein |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | REMOVE | Summary: Bare protein-binding annotation from a high-throughput interactome screen (PMID:16189514; partner(s) UniProtKB:Q15645). No partner of these is linked to a defined GALT activity, complex or pathway role. Reason: Under the protein-binding policy, generic GO:0005515 carries no functional information. The screen supports no more informative molecular function for GALT (none of the partners is a Leloir-pathway enzyme or a known regulator of GALT, and GALT's established self-association is as an obligate catalytic homodimer, not captured by this term). Removal records that the term is uninformative; it does not mean the reported binary interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Bare protein-binding annotation from a high-throughput interactome screen (PMID:25416956; partner(s) UniProtKB:Q07912). No partner of these is linked to a defined GALT activity, complex or pathway role. Reason: Under the protein-binding policy, generic GO:0005515 carries no functional information. The screen supports no more informative molecular function for GALT (none of the partners is a Leloir-pathway enzyme or a known regulator of GALT, and GALT's established self-association is as an obligate catalytic homodimer, not captured by this term). Removal records that the term is uninformative; it does not mean the reported binary interaction is false. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | REMOVE | Summary: Bare protein-binding annotation from a high-throughput interactome screen (PMID:25910212; partner(s) UniProtKB:Q07912-2). No partner of these is linked to a defined GALT activity, complex or pathway role. Reason: Under the protein-binding policy, generic GO:0005515 carries no functional information. The screen supports no more informative molecular function for GALT (none of the partners is a Leloir-pathway enzyme or a known regulator of GALT, and GALT's established self-association is as an obligate catalytic homodimer, not captured by this term). Removal records that the term is uninformative; it does not mean the reported binary interaction is false. |
| GO:0005515 protein binding | IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ... | REMOVE | Summary: Bare protein-binding annotation from a high-throughput interactome screen (PMID:26871637; partner(s) UniProtKB:Q15645). No partner of these is linked to a defined GALT activity, complex or pathway role. Reason: Under the protein-binding policy, generic GO:0005515 carries no functional information. The screen supports no more informative molecular function for GALT (none of the partners is a Leloir-pathway enzyme or a known regulator of GALT, and GALT's established self-association is as an obligate catalytic homodimer, not captured by this term). Removal records that the term is uninformative; it does not mean the reported binary interaction is false. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: Bare protein-binding annotation from a high-throughput interactome screen (PMID:28514442; partner(s) UniProtKB:Q8WUN7). No partner of these is linked to a defined GALT activity, complex or pathway role. Reason: Under the protein-binding policy, generic GO:0005515 carries no functional information. The screen supports no more informative molecular function for GALT (none of the partners is a Leloir-pathway enzyme or a known regulator of GALT, and GALT's established self-association is as an obligate catalytic homodimer, not captured by this term). Removal records that the term is uninformative; it does not mean the reported binary interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Bare protein-binding annotation from a high-throughput interactome screen (PMID:32296183; partner(s) UniProtKB:P15559, UniProtKB:Q3LI66, UniProtKB:Q8WUN7 and UniProtKB:Q9HAV7). No partner of these is linked to a defined GALT activity, complex or pathway role. Reason: Under the protein-binding policy, generic GO:0005515 carries no functional information. The screen supports no more informative molecular function for GALT (none of the partners is a Leloir-pathway enzyme or a known regulator of GALT, and GALT's established self-association is as an obligate catalytic homodimer, not captured by this term). Removal records that the term is uninformative; it does not mean the reported binary interaction is false. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Bare protein-binding annotation from a high-throughput interactome screen (PMID:33961781; partner(s) UniProtKB:Q8WUN7). No partner of these is linked to a defined GALT activity, complex or pathway role. Reason: Under the protein-binding policy, generic GO:0005515 carries no functional information. The screen supports no more informative molecular function for GALT (none of the partners is a Leloir-pathway enzyme or a known regulator of GALT, and GALT's established self-association is as an obligate catalytic homodimer, not captured by this term). Removal records that the term is uninformative; it does not mean the reported binary interaction is false. |
| GO:0033499 beta-D-galactose catabolic process via UDP-galactose, Leloir pathway | TAS Reactome:R-HSA-70370 | ACCEPT | Summary: Core biological process, curated by Reactome as part of galactose catabolism. Duplicates the IBA call for the same specific Leloir-pathway term. Reason: Authoritative pathway annotation matching GALT's committed step in the Leloir pathway. |
| GO:0008108 UDP-glucose:hexose-1-phosphate uridylyltransferase activity | EXP PMID:1897530 Molecular characterization of two galactosemia mutations: co... | ACCEPT | Summary: Experimental support for the core uridylyltransferase function: this study characterized galactosemia missense variants (including the common Q188R, near the active-site His-Pro-His triad) by their effect on GALT enzymatic activity, confirming that GALT catalyzes the uridylyltransferase reaction. Reason: Variant activity measurements directly probe and confirm GALT's uridylyltransferase activity. Supporting Evidence: PMID:1897530 two amino acid residues downstream from the active site histidine-proline-histidine triad and results in about 10% of normal enzymatic activity |
| GO:0008108 UDP-glucose:hexose-1-phosphate uridylyltransferase activity | TAS Reactome:R-HSA-5610038 | ACCEPT | Summary: Reactome curation of the (defective) GALT uridylyl-transfer reaction; supports the same core molecular function. Reason: Authoritative curated annotation of GALT's catalytic activity. |
| GO:0008108 UDP-glucose:hexose-1-phosphate uridylyltransferase activity | EXP PMID:22461411 Correlation assessment among clinical phenotypes, expression... | ACCEPT | Summary: Experimental support for the core function: recombinant wild-type and variant human GALT enzymes were assayed for uridylyltransferase activity (Vmax/KM for gal-1-P and UDP-glucose), directly measuring the EC 2.7.7.12 reaction. Reason: In vitro kinetic characterization of the human enzyme confirms the uridylyltransferase activity. Supporting Evidence: PMID:22461411 Galactose-1-phosphate uridylyltransferase (GALT) catalyzes the conversion of galactose-1-phosphate to UDP-galactose, a key step in the galactose metabolism |
| GO:0006011 UDP-alpha-D-glucose metabolic process | IDA PMID:27005423 Molecular basis of classic galactosemia from the structure o... | KEEP AS NON CORE | Summary: GALT consumes UDP-alpha-D-glucose as the uridylyl donor and regenerates it as part of the Leloir cycle, so it participates in UDP-glucose metabolism. Supported by the structure showing the UDP-glucose-derived covalent UMP intermediate and glucose-1-phosphate product in the active site. Reason: Accurate: GALT catalyses a reaction of UDP-glucose (its uridylyl donor, converted to UDP-galactose), so it takes part in UDP-glucose metabolism. This is a consequence of the core Leloir step rather than a separate core role, so it is kept as non-core. Supporting Evidence: PMID:27005423 GALT (EC 2.7.7.12) reversibly converts galactose 1-phosphate (Gal-1-P) and UDP glucose (UDP-Glc) into glucose 1-phosphate (Glc-1-P) and UDP galactose (UDP-Gal) |
| GO:0006012 galactose metabolic process | IDA PMID:27005423 Molecular basis of classic galactosemia from the structure o... | MODIFY | Summary: Experimental (structure-based) support that GALT acts in galactose metabolism. Correct but broader than the specific Leloir catabolic term (GO:0033499) that the same paper places GALT in. Reason: Correct but general. The paper explicitly places GALT as one of the four Leloir-pathway enzymes, so the specific descendant GO:0033499 (already on the gene) is supported. Proposed replacements: beta-D-galactose catabolic process via UDP-galactose, Leloir pathway Supporting Evidence: PMID:27005423 Galactose (Gal) is an essential monosaccharide within the human body, with the Leloir pathway being its principal metabolic route |
| GO:0008108 UDP-glucose:hexose-1-phosphate uridylyltransferase activity | IDA PMID:27005423 Molecular basis of classic galactosemia from the structure o... | ACCEPT | Summary: Direct structural/biochemical evidence for the core uridylyltransferase function: the 1.9 A human GALT structure captured the covalent uridylyl-His186 intermediate plus glucose-1-phosphate, and mutation of His186 abolished uridylylation, confirming the catalytic mechanism. Reason: Definitive experimental evidence for GALT's molecular function in the human enzyme. Supporting Evidence: PMID:27005423 confirming that His186 is the site of uridylylation |
| GO:0008270 zinc ion binding | IDA PMID:27005423 Molecular basis of classic galactosemia from the structure o... | KEEP AS NON CORE | Summary: Direct evidence that human GALT binds zinc. The crystal structure and biophysical assays (DSF, ITC) identify a divalent metal site per monomer that preferentially binds Zn2+ and stabilizes the protein. The site lies away from the active site, indicating a structural rather than catalytic role. Reason: Zinc binding is experimentally confirmed but serves a structural/stability role distinct from the catalytic uridylyltransferase activity, so it is retained as a non-core function. Supporting Evidence: PMID:27005423 Altogether our findings suggest hGALT contains one Zn2+ binding site, which confers stability to the protein |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5610038 | ACCEPT | Summary: Correct subcellular localization. GALT is a soluble cytosolic Leloir enzyme; Reactome curates it in the cytosol. Reason: Consistent with GALT's function as a soluble cytoplasmic metabolic enzyme. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-70361 | ACCEPT | Summary: Correct cytosolic localization (duplicate Reactome curation for the forward GALT reaction). Reason: Consistent with GALT's soluble cytosolic role in the Leloir pathway. |
| GO:0005794 Golgi apparatus | IDA PMID:20605918 The Lyn kinase C-lobe mediates Golgi export of Lyn through c... | REMOVE | Summary: Isolated Golgi apparatus IDA from a paper on Golgi export of the Src-family kinase Lyn via ACSL3. The paper's "GalT" is the trans-Golgi marker beta-1,4-galactosyltransferase (B4GALT1), not galactose-1-phosphate uridylyltransferase, so the row is attached to the wrong gene product. Reason: The cached record is abstract-only, but the publisher full text (https://journals.biologists.com/jcs/article/123/15/2649/31141/The-Lyn-kinase-C-lobe-mediates-Golgi-export-of-Lyn) was checked. GalT is defined there as the Golgi marker beta-1,4-galactosyltransferase ("ACSL3 was seen with the Golgi caveolin and beta-1,4-galactosyltransferase (GalT) where Lyn accumulated") and is used with GM130 as a Golgi-resident reference ("knockdown of ACSL3 did not affect Golgi localization of GalT and GM130"). Galactose-1-phosphate uridylyltransferase is not studied. The GALT annotation is therefore a symbol collision with B4GALT1 (UniProtKB:P15291), recorded below as a source defect. Nothing else places GALT in the Golgi: the human enzyme is a soluble cytosolic homodimer. These quotations are not in the cached abstract, so they are given here rather than as supporting_text. Supporting Evidence: PMID:20605918 After synthesis in the cytoplasm, Lyn accumulates on the Golgi and is subsequently transported to the plasma membrane. |
| GO:0006012 galactose metabolic process | TAS PMID:1427861 The human galactose-1-phosphate uridyltransferase gene. | MODIFY | Summary: Traceable author statement that GALT functions in galactose metabolism, from the paper cloning the human GALT gene and linking its deficiency to classic galactosemia. Correct but general parent process. Reason: Well-supported involvement in galactose metabolism, but broader than the specific Leloir catabolic term GO:0033499 (a descendant already on the gene), which describes GALT's step. Proposed replacements: beta-D-galactose catabolic process via UDP-galactose, Leloir pathway Supporting Evidence: PMID:1427861 Classical galactosemia is an inborn error of metabolism caused by a deficiency of galactose-1-phosphate uridyltransferase (GALT) |
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Download this section (compressed HTML)Q: Beyond the canonical Leloir catabolic direction, how quantitatively important is GALT's contribution to interconverting UDP-hexoses that feed glycoconjugate/glycan synthesis, and does impaired glycosylation contribute independently to the long-term complications of classic galactosemia?
Q: What is the physiological stoichiometry and role of zinc binding in human GALT in vivo, and does metal occupancy modulate the folding and aggregation of common misfolding variants such as Q188R?
Experiment: Structure-guided pharmacological-chaperone/stabilizer screening for common misfolding GALT variants (e.g. Q188R, K285N), measuring rescue of uridylyltransferase activity, thermal stability, and aggregation in cellular models.
Hypothesis: Small-molecule stabilizers can rescue the activity and reduce aggregation of common misfolding GALT variants.
Type: biochemical/cell-based screen
Experiment: Quantitative flux and metabolomic profiling in GALT-deficient versus gene-corrected human cells and organoids to dissect the relative contributions of galactose-1-phosphate accumulation, UDP-hexose depletion, and altered glycosylation to cellular toxicity.
Hypothesis: Toxicity in classic galactosemia arises from distinguishable contributions of galactose-1-phosphate accumulation, UDP-hexose depletion, and altered glycosylation.
Type: metabolomics/isotope flux
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