GALM is the cytosolic aldose 1-epimerase (galactose mutarotase; EC 5.1.3.3) that catalyzes the first step of the Leloir pathway of galactose metabolism. It interconverts the beta- and alpha-anomers of D-galactose (beta-D-galactose <=> alpha-D-galactose), maintaining the anomeric equilibrium and ensuring a sufficient supply of the alpha-anomer, which galactokinase (GALK1) requires as its substrate; the downstream Leloir enzymes GALK1, GALT, and GALE then convert galactose into glucose 1-phosphate. GALM also mutarotates D-glucose (alpha-D-glucose <=> beta-D-glucose), though it prefers galactose over glucose. The enzyme is a monomer with a single-domain beta-sandwich fold typical of the aldose epimerase family; catalysis uses His-176 as the proton donor and Glu-307 as the proton acceptor, with His-107 also contributing. Biallelic loss-of-function GALM variants cause galactose mutarotase deficiency (galactosemia type IV, GALAC4), an autosomal recessive inborn error of galactose metabolism.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0033499 beta-D-galactose catabolic process via UDP-galactose, Leloir pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) inference that GALM participates in the Leloir pathway of galactose catabolism. This is the core biological process of GALM: it catalyzes the first (mutarotase) step supplying alpha-D-galactose to GALK1. Reason: Consistent with the experimentally established Leloir-pathway role and the PANTHER aldose-1-epimerase family. Represents a core function. Human GALM is one of the experimentally grounded seeds of node PTN000009552, so its presence in WITH/FROM is expected, not circular. Supporting Evidence: file:human/GALM/GALM-uniprot.txt Involved in the maintenance of the equilibrium between the beta- and alpha-anomers of galactose, therefore ensuring a sufficient supply of the alpha-anomer for GALK1 (PubMed:12753898). PMID:30451973 GALM encoding galactose mutarotase, which catalyzes epimerization between Ξ²- and Ξ±-D-galactose in the first step of the Leloir pathway |
| GO:0004034 aldose 1-epimerase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) inference of aldose 1-epimerase activity, the core molecular function of GALM, matching the family-level assignment for PTN000009552. Reason: The defining catalytic activity of GALM, independently supported by direct experimental characterization (PMID:12753898). Core molecular function. Supporting Evidence: PMID:12753898 Enzyme assays show that the protein has aldose 1-epimerase activity |
| GO:0006006 glucose metabolic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference that GALM participates in glucose metabolism, reflecting the family's ability to mutarotate glucose in addition to galactose. Reason: GALM does mutarotate D-glucose in vitro, but with lower affinity/turnover than galactose (KM 54 mM vs 37 mM; kcat 4900 vs 12000 s-1), and the enzyme "exhibits a preference for galactose over glucose" (PMID:12753898). Glucose mutarotation is a genuine but secondary activity, not the core physiological role. Supporting Evidence: PMID:12753898 the protein has aldose 1-epimerase activity and exhibits a preference for galactose over glucose |
| GO:0004034 aldose 1-epimerase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (RHEA/EC 5.1.3.3) assignment of aldose 1-epimerase activity, the core molecular function. Reason: Correctly mapped from EC 5.1.3.3 / RHEA:10264,RHEA:28675 to the specific MF term; matches experimental evidence. Supporting Evidence: file:human/GALM/GALM-uniprot.txt Reaction=alpha-D-galactose = beta-D-galactose; Xref=Rhea:RHEA:28675, ChEBI:CHEBI:27667, ChEBI:CHEBI:28061; EC=5.1.3.3; Evidence={ECO:0000269|PubMed:12753898}; |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | MODIFY | Summary: Subcellular-location mapping (UniProt SL-0086) placing GALM in the cytoplasm. Reason: Correct but general. GALM is a soluble enzyme without signal peptide or transmembrane segment that acts with the cytosolic Leloir enzymes, and the gene already carries the more specific GO:0005829 cytosol (Reactome TAS rows, accepted here), an is_a descendant of cytoplasm. Refine to cytosol. Proposed replacements: cytosol Supporting Evidence: file:human/GALM/GALM-uniprot.txt Involved in the maintenance of the equilibrium between the beta- and alpha-anomers of galactose, therefore ensuring a sufficient supply of the alpha-anomer for GALK1 (PubMed:12753898). |
| GO:0005975 carbohydrate metabolic process | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO mapping to the high-level carbohydrate metabolic process, from the aldose epimerase domains. Reason: True but a very general grouping term. The specific process GALM serves is the Leloir pathway (GO:0033499, accepted in this review), an is_a descendant of carbohydrate metabolic process. Refine to that term. Proposed replacements: beta-D-galactose catabolic process via UDP-galactose, Leloir pathway Supporting Evidence: PMID:30451973 GALM encoding galactose mutarotase, which catalyzes epimerization between Ξ²- and Ξ±-D-galactose in the first step of the Leloir pathway |
| GO:0016853 isomerase activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO mapping to the generic parent term isomerase activity. Reason: Correct but overly general: GALM's activity is specifically aldose 1-epimerase activity (GO:0004034), which is a descendant of isomerase activity and is already annotated with strong experimental support. Replace the generic parent with the specific MF. Proposed replacements: aldose 1-epimerase activity Supporting Evidence: PMID:12753898 Enzyme assays show that the protein has aldose 1-epimerase activity |
| GO:0019318 hexose metabolic process | IEA GO_REF:0000120 | MODIFY | Summary: Automated mapping (UniPathway/InterPro) to hexose metabolic process, consistent with GALM acting on the hexoses galactose and glucose. Reason: Accurate but general. The specific hexose process supported for GALM is the Leloir pathway (GO:0033499), an is_a descendant of hexose metabolic process via galactose metabolic process. Glucose mutarotation is covered separately by the non-core glucose metabolic process rows. Proposed replacements: beta-D-galactose catabolic process via UDP-galactose, Leloir pathway Supporting Evidence: file:human/GALM/GALM-uniprot.txt Mutarotase that catalyzes the interconversion of beta-D-galactose and alpha-D-galactose during galactose metabolism (PubMed:12753898). |
| GO:0030246 carbohydrate binding | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO mapping to carbohydrate binding, derived from the sugar-binding beta-sandwich (GH-type carbohydrate-binding) domain signatures. Reason: GALM binds galactose/glucose only transiently as catalytic substrates in its active site, not as a lectin-type carbohydrate-binding module. GO:0030246 (carbohydrate binding) implies a dedicated binding function distinct from catalysis; this is an over-annotation propagated from the structural fold signature. The catalytic substrate interaction is already captured by the aldose 1-epimerase activity annotation. Supporting Evidence: file:human/GALM/GALM-uniprot.txt IPR014718; GH-type_carb-bd. |
| GO:0033499 beta-D-galactose catabolic process via UDP-galactose, Leloir pathway | TAS Reactome:R-HSA-70370 | ACCEPT | Summary: Reactome-curated (TAS) assignment of GALM to the Leloir pathway of galactose catabolism. Reason: Curator-asserted pathway membership matching the established biology; core biological process. Supporting Evidence: PMID:30451973 GALM encoding galactose mutarotase, which catalyzes epimerization between Ξ²- and Ξ±-D-galactose in the first step of the Leloir pathway |
| GO:0006012 galactose metabolic process | IEA GO_REF:0000041 | MODIFY | Summary: UniPathway-based (UPA00214) mapping to galactose metabolic process. Reason: Correct but less specific than the evidence supports. GALM's role in galactose metabolism is the first, anomer-converting step of the Leloir pathway, captured by GO:0033499, an is_a descendant of galactose metabolic process that the gene already carries (IBA, TAS, IDA, IMP). Refine to that term. Proposed replacements: beta-D-galactose catabolic process via UDP-galactose, Leloir pathway Supporting Evidence: file:human/GALM/GALM-uniprot.txt Mutarotase that catalyzes the interconversion of beta-D-galactose and alpha-D-galactose during galactose metabolism (PubMed:12753898). |
| GO:0004034 aldose 1-epimerase activity | EXP PMID:12753898 Identification and characterisation of human aldose 1-epimer... | ACCEPT | Summary: Experimental demonstration that recombinant human GALM has aldose 1-epimerase activity, with confirmed catalytic residues. Reason: Core molecular function, directly demonstrated by enzyme assays on purified recombinant protein plus site-directed mutagenesis of catalytic residues. Supporting Evidence: PMID:12753898 Enzyme assays show that the protein has aldose 1-epimerase activity and exhibits a preference for galactose over glucose. Site-directed mutagenesis confirmed the involvement of three residues involved in catalysis and substrate binding. |
| GO:0004034 aldose 1-epimerase activity | TAS Reactome:R-HSA-9931926 | ACCEPT | Summary: Reactome-curated (TAS) assertion of aldose 1-epimerase activity (in the context of the defective-GALM reaction). Reason: Core molecular function; consistent with all other MF evidence. Supporting Evidence: PMID:12753898 Enzyme assays show that the protein has aldose 1-epimerase activity |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9931853 | ACCEPT | Summary: Reactome-curated (TAS) localization of GALM (the "GALM converts beta-D-GAL to alpha-D-GAL" reaction) to the cytosol. Reason: Consistent with the cytoplasmic Leloir pathway; the most specific and appropriate location term for GALM. Core localization. GALM has no signal peptide or transmembrane segment, and the GALK1 it supplies acts in the cytosol. Supporting Evidence: file:human/GALM/GALM-uniprot.txt Involved in the maintenance of the equilibrium between the beta- and alpha-anomers of galactose, therefore ensuring a sufficient supply of the alpha-anomer for GALK1 (PubMed:12753898). |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9931926 | ACCEPT | Summary: Reactome-curated (TAS) cytosol localization (defective-GALM reaction context). Duplicate of the preceding cytosol annotation from a related Reactome reaction. Reason: Correct core localization; this row reinforces the other cytosol row. Supporting Evidence: file:human/GALM/GALM-uniprot.txt Involved in the maintenance of the equilibrium between the beta- and alpha-anomers of galactose, therefore ensuring a sufficient supply of the alpha-anomer for GALK1 (PubMed:12753898). |
| GO:0004034 aldose 1-epimerase activity | IDA PMID:30451973 Biallelic GALM pathogenic variants cause a novel type of gal... | ACCEPT | Summary: Direct assay (IDA) of aldose 1-epimerase activity in the study that identified GALM deficiency as a novel galactosemia; patient/variant proteins showed altered activity. Reason: Core molecular function, independently confirmed in the disease-gene study. Supporting Evidence: PMID:30451973 GALM enzyme activities were undetectable in lymphoblastoid cell lines established from two patients. |
| GO:0004034 aldose 1-epimerase activity | IMP PMID:30451973 Biallelic GALM pathogenic variants cause a novel type of gal... | ACCEPT | Summary: Mutant-phenotype (IMP) evidence that pathogenic GALM variants reduce aldose 1-epimerase activity, linking loss of this MF to disease. Reason: Loss-of-function variants causing galactosemia type IV support the physiological relevance of this core molecular function. Supporting Evidence: PMID:30451973 In vitro GALM expression and protein stability assays revealed altered stabilities of the variant GALM proteins. |
| GO:0033499 beta-D-galactose catabolic process via UDP-galactose, Leloir pathway | IMP PMID:30451973 Biallelic GALM pathogenic variants cause a novel type of gal... | ACCEPT | Summary: Mutant-phenotype (IMP) evidence that GALM loss disrupts the Leloir pathway of galactose catabolism, causing galactose accumulation / galactosemia type IV. Reason: Biallelic GALM variants cause a novel type of galactosemia by impairing the Leloir pathway; core biological process supported by human disease genetics. Supporting Evidence: PMID:30451973 Biallelic GALM pathogenic variants cause galactosemia, suggesting the existence of type IV galactosemia. |
| GO:0033499 beta-D-galactose catabolic process via UDP-galactose, Leloir pathway | IDA PMID:30451973 Biallelic GALM pathogenic variants cause a novel type of gal... | ACCEPT | Summary: Direct-assay (IDA) evidence supporting GALM's participation in the Leloir galactose catabolic pathway. Reason: Core biological process, directly supported; reinforces the IBA/TAS Leloir-pathway rows with independent experimental backing (GALM activity is absent from patient cells, which accumulate galactose). Supporting Evidence: PMID:30451973 GALM encoding galactose mutarotase, which catalyzes epimerization between Ξ²- and Ξ±-D-galactose in the first step of the Leloir pathway |
| GO:0004034 aldose 1-epimerase activity | IDA PMID:12753898 Identification and characterisation of human aldose 1-epimer... | ACCEPT | Summary: Direct assay (IDA) of aldose 1-epimerase activity on purified recombinant human GALM. Reason: Core molecular function; the foundational biochemical characterization of the enzyme. Supporting Evidence: PMID:12753898 Enzyme assays show that the protein has aldose 1-epimerase activity and exhibits a preference for galactose over glucose. |
| GO:0005975 carbohydrate metabolic process | IDA PMID:12753898 Identification and characterisation of human aldose 1-epimer... | MODIFY | Summary: Direct-assay evidence placing GALM in carbohydrate metabolism (mutarotation of hexose sugars), a high-level grouping process. Reason: Correct but very general. The specific process GALM serves is the Leloir pathway (GO:0033499, accepted in this review), an is_a descendant of carbohydrate metabolic process. GALM is described as "a key enzyme of carbohydrate metabolism" (PMID:12753898). Refine to GO:0033499, consistent with the IEA row for the same term. Proposed replacements: beta-D-galactose catabolic process via UDP-galactose, Leloir pathway Supporting Evidence: PMID:12753898 Aldose 1-epimerase or mutarotase (EC 5.1.3.3) is a key enzyme of carbohydrate metabolism catalysing the interconversion of the alpha- and beta-anomers of hexose sugars such as glucose and galactose. |
| GO:0042803 protein homodimerization activity | IDA NOT PMID:12753898 Identification and characterisation of human aldose 1-epimer... | ACCEPT | Summary: Negated (NOT) annotation: GALM does not have protein homodimerization activity. Biochemical and structural characterization established that GALM is a monomer. Reason: The NOT annotation correctly records that GALM does not homodimerize. UniProt reports the SUBUNIT as Monomer (from PMID:12753898 and PMID:15026423). Retaining the negation is informative and consistent with the monomeric solution and crystal state. Supporting Evidence: file:human/GALM/GALM-uniprot.txt SUBUNIT: Monomer. {ECO:0000269|PubMed:12753898, ECO:0000269|PubMed:15026423}. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: High-throughput mass-spectrometry (HDA) detection of GALM among proteins recovered from human urinary exosomes. Reason: Reflects broad proteomic detection in secreted exosomes rather than the enzyme's site of catalytic function, which is the cytosol. Kept as a non-core localization; not part of the core Leloir-pathway function. Supporting Evidence: PMID:19056867 we used LC-MS/MS to profile the proteome of human urinary exosomes. Overall, the analysis identified 1132 proteins unambiguously |
| GO:0006006 glucose metabolic process | IDA PMID:12753898 Identification and characterisation of human aldose 1-epimer... | KEEP AS NON CORE | Summary: Direct-assay evidence that GALM mutarotates D-glucose, participating in glucose metabolism. Reason: GALM does interconvert glucose anomers, but with lower efficiency than galactose and a demonstrated preference for galactose (PMID:12753898). A real but secondary activity, not the core physiological role. Supporting Evidence: PMID:12753898 catalysing the interconversion of the alpha- and beta-anomers of hexose sugars such as glucose and galactose |
| GO:0006012 galactose metabolic process | IDA PMID:12753898 Identification and characterisation of human aldose 1-epimer... | MODIFY | Summary: Direct-assay evidence that GALM participates in galactose metabolism via mutarotation of galactose anomers. Reason: Correct but less specific than the evidence supports: the galactose-metabolic role of GALM is the first step of the Leloir pathway, GO:0033499, an is_a descendant of galactose metabolic process already carried by the gene. Refine to that term, consistent with the IEA row for the same term. Proposed replacements: beta-D-galactose catabolic process via UDP-galactose, Leloir pathway Supporting Evidence: PMID:12753898 catalysing the interconversion of the alpha- and beta-anomers of hexose sugars such as glucose and galactose |
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Download this section (compressed HTML)Q: Spontaneous mutarotation of galactose is fast in water, yet GALM deficiency produces hypergalactosemia. Does the intracellular environment (water activity, the anomer selectivity of GALK1) make the enzyme rate-limiting in hepatocytes, and is this why GALAC4 is milder than GALT deficiency?
Q: Does GALM's glucose mutarotase activity matter physiologically in any tissue, for example in the lens or in cells where glucokinase anomer preference is relevant?
Experiment: Trace the conversion of labelled beta-D-galactose in GALM-knockout versus wild-type human hepatocyte-like cells (e.g. HepG2 GALM-/-) with and without re-expression of wild-type or catalytic-site (H176A, E307A) GALM, measuring alpha/beta anomer pools and galactose 1-phosphate formation, to quantify GALM's contribution to Leloir flux in vivo.
Type: metabolic flux analysis
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