GBA2 is a nonlysosomal glycosidase that hydrolyzes glucosylceramide to glucose and ceramide. Its membrane-associated activity provides an alternative to lysosomal glucosylceramide degradation. Mammalian localization studies place GBA2 at the endoplasmic reticulum and Golgi, with a cytosolic, peripheral membrane arrangement demonstrated for mouse GBA2; human cell studies also support a surface-associated activity pool. GBA2 can exchange glucose between glucosylceramide and cholesterol and can hydrolyze additional glycosides under defined conditions. Galactosylceramide analogue hydrolysis and galactosyl transfer have also been measured, but their contribution to normal lipid turnover is unresolved. Loss of GBA2 activity disrupts lipid homeostasis and can alter neuronal and reproductive cell function. Biallelic human variants cause spastic ataxia or hereditary spastic paraplegia. The functions of the shorter natural splice products remain poorly defined.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic Golgi-membrane mapping agrees with donor localization. Reason: Mouse orthology and subcellular-location mapping are consistent with the inspected Golgi-association experiments. The evidence supports peripheral membrane association in a nonlysosomal pool, not a universal topology or every human isoform. Supporting Evidence: |
| GO:0000139 Golgi membrane | ISS GO_REF:0000024 | ACCEPT | Summary: The mouse source supports Golgi-associated GBA2. Reason: Selected original PMID:23250757 localization experiments report Golgi and ER association of mouse GBA2, including membrane-proximity and extraction analyses. Retain the human similarity-based Golgi-membrane location as a plausible site of its nonlysosomal catalytic role. Association does not mean integral insertion or Golgi-lumen localization. Supporting Evidence: |
| GO:0000139 Golgi membrane | ISS GO_REF:0000024 | ACCEPT | Summary: This separate original context retains the supported Golgi-membrane assertion. Reason: The mouse-derived localization evidence supports Golgi-associated GBA2 with the same membrane-association limits. The similarity-based human assignment does not establish integral insertion, lumen exposure or a specific natural product. Supporting Evidence: |
| GO:0004336 galactosylceramidase activity | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: A separate analog-substrate assay demonstrates GalCer hydrolysis, but its physiological contribution remains unresolved. Reason: The reviewed human UniProt record separately curates GalCer hydrolysis and galactosyl transfer at ECO:0000269 with PMID:32144204, including the in-vitro lower-activity qualification. The inspected original C6-NBD-GalCer hydrolysis assay independently supports the reaction, but physiological GalCer clearance by GBA2 remains unresolved. Dedicated lysosomal GALC is relevant context; it does not establish absence of GBA2 activity in other compartments or a comparative rate. Supporting Evidence: file:human/GBA2/GBA2-deep-research-manual.md UniProtKB:Q9HCG7 Catalyzes the hydrolysis of galactosylceramides/GalCers ... in vitro with lower activity |
| GO:0004348 glucosylceramidase activity | IDA PMID:17080196 Mutation of beta-glucosidase 2 causes glycolipid storage dis... | ACCEPT | Summary: The cited study directly demonstrates human recombinant glucosylceramidase activity. Reason: PMID:17080196 distinguishes human and mouse GBA2 cDNAs in COS-cell assays. Human expression increases cleavage of fluorescent GlcCer over mock cells. The authentic radiolabeled-lipid panel uses mouse GBA2 and is retained as separate corroboration, not relabeled as a human-enzyme experiment. GlcCer hydrolysis is the principal catalytic function. Supporting Evidence: |
| GO:0004348 glucosylceramidase activity | IDA PMID:22659419 Beta-glucosidase 1 (GBA1) is a second bile acid Ξ²-glucosidas... | ACCEPT | Summary: The native-cell substrate study supports nonlysosomal glucosylceramidase activity. Reason: The inspected PMID:22659419 text separates lysosomal GBA1 from the residual nonlysosomal enzyme using genetic and biochemical comparisons. Its human Gaucher-fibroblast context and murine knockout comparisons have different attribution limits; direct human recombinant GlcCer hydrolysis independently establishes the accepted molecular function. The purified enzyme in that paper is not represented as purified GBA2. |
| GO:0004348 glucosylceramidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic assignment matches the established nonlysosomal glucosylceramidase. Reason: The ARBA, mouse orthology, InterPro and Rhea/EC sources converge on GlcCer hydrolysis. Direct human recombinant activity in PMID:17080196 independently supports this conserved catalytic function, so acceptance does not depend solely on the electronic mappings or disease association. No activity is assigned to an untested short natural product. |
| GO:0004348 glucosylceramidase activity | IMP PMID:22659419 Beta-glucosidase 1 (GBA1) is a second bile acid Ξ²-glucosidas... | ACCEPT | Summary: Perturbation and substrate measurements are consistent with GBA2-catalyzed GlcCer cleavage. Reason: The IMP context in PMID:22659419 is retained with its original evidence code. It supports enzyme attribution through the paper's loss-of-function and substrate comparisons; independent human recombinant experiments establish the same chemical reaction. This is a catalytic claim, not an inference that GBA2 performs every downstream lipid-remodeling step. |
| GO:0004348 glucosylceramidase activity | TAS Reactome:R-HSA-1861788 | ACCEPT | Summary: The Reactome event directly assigns GlcCer hydrolysis to human GBA2. Reason: R-HSA-1861788 links the glucosylceramidase catalyst to R-HSA-1861791, the human Q9HCG7 chain1β927. The modeled reaction consumes GlcCer and water and produces ceramide and glucose. This is target-specific catalytic participation, not merely pathway membership, and agrees with experimental glucosylceramidase evidence. |
| GO:0004553 hydrolase activity, hydrolyzing O-glycosyl compounds | IEA GO_REF:0000002 | MODIFY | Summary: Beta-glucosidase activity gives a supported, more informative description of this broad hydrolase class. Reason: GBA2 cleaves several beta-glucosides, including bile-acid glucosides and GlcCer. GO:0008422 has a verified is_a path to GO:0004553 and retains that substrate breadth; the GlcCer-specific activity is annotated separately. GalCer-analog cleavage remains documented under its existing over-annotated row, and is not proposed as an additional replacement. Proposed replacements: beta-glucosidase activity |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000117 | ACCEPT | Summary: Endoplasmic-reticulum localization is supported as a major membrane-associated pool. Reason: The electronic organelle claim agrees with the reticular localization and biochemical membrane-association literature. Retain the root ER assertion under the organelle policy rather than replacing it with a subcompartment; the more specific ER-membrane contexts are reviewed separately. Neither ER lumen nor integral transmembrane topology is inferred. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic ER-membrane assignment is compatible with experimental localization. Reason: The mouse and subcellular-location mappings agree with ER-associated, nonintegral GBA2 in the inspected localization work. Retain this site of lipid-substrate access while distinguishing membrane association from spanning the bilayer. Supporting Evidence: |
| GO:0005789 endoplasmic reticulum membrane | ISS GO_REF:0000024 | ACCEPT | Summary: The mouse donor supports association with the cytosolic face of ER membranes. Reason: PMID:23250757 tests tagged mouse constructs with protease-protection and extraction methods and reports ER association. This supports the human similarity claim while preserving the donor-species and construct limits. GBA2 is not described as an ER-lumen enzyme or an obligate integral membrane protein. Supporting Evidence: |
| GO:0005789 endoplasmic reticulum membrane | ISS GO_REF:0000024 | ACCEPT | Summary: The second ER-membrane context is retained without collapsing its provenance. Reason: The mouse membrane-association experiments support an ER-associated pool, with cytosolic termini in the tested constructs. The human electronic assignment is retained with that ortholog scope; no product-specific activity is inferred. Supporting Evidence: |
| GO:0005790 smooth endoplasmic reticulum | TAS PMID:11489889 Molecular cloning and expression of human bile acid beta-glu... | UNDECIDED | Summary: The precise smooth-ER compartment remains unresolved in the inspected evidence. Reason: The authentic PMID:11489889 abstract identifies a human microsomal enzyme but does not resolve smooth versus rough ER. Later selected work supports ER association without independently establishing this precise human subcompartment. Retain uncertainty about the specific TAS assertion; this is not evidence against the broader ER or membrane locations. |
| GO:0005829 cytosol | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic cytosol localization agrees with the donor topology experiments. Reason: Mouse orthology and subcellular mapping are consistent with a cytosolic-side peripheral enzyme. Retain cytosol as part of the core cellular setting, while not assigning an identical distribution or catalytic contribution to each untested human alternative product. Supporting Evidence: |
| GO:0005829 cytosol | ISS GO_REF:0000024 | ACCEPT | Summary: The mouse source supports a cytosolic, membrane-associated enzyme pool. Reason: Selected PMID:23250757 experiments identify cytosolic termini and extractable membrane association, with a soluble pool also observed. This supports cytosol localization by similarity alongside organelle-membrane locations. Cytosolic access is compatible with peripheral lipid hydrolysis and does not make the enzyme exclusively soluble. Supporting Evidence: PMID:23250757 a cytosolic protein that tightly associates with cellular membranes |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1861788 | ACCEPT | Summary: Reactome explicitly places the human GBA2 catalyst at the plasma membrane. Reason: R-HSA-1861788 links to the human Q9HCG7 chain 1β927 physical entity R-HSA-1861791 with plasma-membrane compartment. This target-specific model is consistent with the surface-associated activity literature; it is not inherited from an unrelated event participant. Other ER/Golgi pools and unresolved integral topology remain compatible. The curated localization note also records a plasma-membrane pool and alternative topology reports. Supporting Evidence: Reactome:R-HSA-1861788 UniProtKB:Q9HCG7 plasma membrane and alternative topologies |
| GO:0005975 carbohydrate metabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: GBA2 directly metabolizes carbohydrate groups in lipid-linked glucosides. Reason: GBA2 directly cleaves or transfers glucose moieties in lipid-linked glucosides, producing free glucose or a new glucoside rather than merely responding to a carbohydrate signal. Human expression and substrate assays support this carbohydrate chemistry across several aglycones. Glucosylceramide and glycoside catabolism remain separately represented with their own substrate scope. |
| GO:0006665 sphingolipid metabolic process | IEA GO_REF:0000041 | MODIFY | Summary: The broad sphingolipid-metabolism assignment can specify GlcCer breakdown. Reason: The central established sphingolipid reaction is hydrolysis of GlcCer to ceramide and glucose. GO:0006680 is a verified is_a descendant of the incoming sphingolipid-metabolism term and describes the step GBA2 catalyzes. This refinement does not assign the upstream synthesis or degradation of all sphingolipids to GBA2. Proposed replacements: glucosylceramide catabolic process |
| GO:0006680 glucosylceramide catabolic process | IDA PMID:17080196 Mutation of beta-glucosidase 2 causes glycolipid storage dis... | ACCEPT | Summary: The cited enzyme assay establishes participation in GlcCer catabolism. Reason: Human GBA2 expression increases GlcCer cleavage in PMID:17080196. The paper separately demonstrates mouse knockout lipid accumulation and mouse-enzyme radiolabeled substrate conversion. The accepted human process rests on measured enzyme chemistry, without converting every knockout phenotype into an additional process annotation. Supporting Evidence: |
| GO:0006680 glucosylceramide catabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic GlcCer-catabolism support matches direct target chemistry. Reason: The ARBA, mouse and InterPro sources are consistent with human recombinant GlcCer cleavage and the nonlysosomal enzyme assignment. GBA2 itself performs the hydrolytic step, so this process is supported by catalytic participation as well as perturbation phenotypes. |
| GO:0006680 glucosylceramide catabolic process | IMP PMID:30308956 Biochemical Characterization of the GBA2 c.1780G>C Missense ... | ACCEPT | Summary: Patient-cell activity and substrate accumulation support the GlcCer-catabolic role. Reason: PMID:30308956 examines D594H patient lymphoblastoid cells against controls and finds strong GBA2 activity loss with GlcCer accumulation. The live-cell controls address substrate access and secreted cleavage. Independent enzyme assays establish the performed hydrolysis step; compensatory GBA1 changes are distinguished from direct measurements of GBA2 protein abundance. Supporting Evidence: PMID:30308956 NLGase activity was also strongly reduced at the cell surface, showing 2β4% of residual activity |
| GO:0007417 central nervous system development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The inherited CNS-development claim is supported but is not the principal catalytic role. Reason: The exact human sequence descends from AN15/PTN000291746 in the actual PTHR12654 tree. Its human and zebrafish sources include legitimate target grounding, with no retained lineage-negative record. Human wild-type GBA2 rescues zebrafish spinal-neuron developmental defects in PMID:23332916. Retain the broader phylogenetic developmental claim as a contextual role, not as direct cytoskeletal activity or proof of every human developmental stage. |
| GO:0008202 steroid metabolic process | IEA GO_REF:0000117 | MODIFY | Summary: The steroid-metabolism class can be resolved into the demonstrated sterol and bile-acid contexts. Reason: Cholesterol glycoside turnover and bile-acid glucoside cleavage provide two supported steroid substrates. GO:0008203 and GO:0008206 each have verified is_a paths to GO:0008202. These replacements preserve the observed substrate breadth without claiming steroid biosynthesis or a dominant in-vivo bile-acid pathway. Proposed replacements: cholesterol metabolic process bile acid metabolic process |
| GO:0008203 cholesterol metabolic process | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic cholesterol-metabolism transfer is consistent with donor chemistry. Reason: The mouse and UniPathway mapping is supported by direct enzymatic transformation of cholesterol-containing glycosides. The annotation does not imply that GBA2 controls all cholesterol synthesis, absorption or trafficking. Retain this secondary metabolic context with the same source limits as the donor experiments. Supporting Evidence: |
| GO:0008203 cholesterol metabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The mouse donor supports cholesterol-glycoside metabolism. Reason: The donor study PMID:26724485 directly measures GlcChol formation and reverse transfer, with mouse genetic and cellular support for GBA2-dependent levels. This establishes a cholesterol-metabolism context rather than cholesterol transport. Retain the human similarity claim outside the primary GlcCer-hydrolysis core; net reaction direction depends on substrate availability. Supporting Evidence: |
| GO:0008206 bile acid metabolic process | IDA PMID:17105727 Identification of the non-lysosomal glucosylceramidase as be... | KEEP AS NON CORE | Summary: The original bile-acid annotation is retained as a secondary catalytic context. Reason: The available PMID:17105727 abstract identifies GBA2 with the previously described bile-acid beta-glucosidase; its full experimental sections were not recovered. Independent human cloning and activity evidence supports the biological claim, so it is retained without claiming that the precise original IDA panel was independently inspected. The dominant role is nonlysosomal GlcCer metabolism. |
| GO:0008206 bile acid metabolic process | TAS PMID:11489889 Molecular cloning and expression of human bile acid beta-glu... | KEEP AS NON CORE | Summary: Human GBA2 directly cleaves bile-acid glucosides in biochemical assays. Reason: The authentic PMID:11489889 abstract reports the human-liver enzyme and active tagged human cDNA product. This supports participation in bile-acid glucoside metabolism. Mouse knockout endpoints in PMID:17080196 did not establish a major physiological bile-acid defect, so the biochemical role is retained as non-core rather than equated with the principal GlcCer pathway. |
| GO:0008422 beta-glucosidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: The actual PAINT lineage supports inherited beta-glucosidase activity. Reason: The exact 927-residue human sequence at PTHR12654 AN28 descends from the GO:0008422 IBD at AN2/PTN000291742. The retained donor set includes legitimate target evidence, and no target-lineage negative record was found. Human bile-acid glucoside cleavage and GlcCer assays support the inherited enzyme class. This broad class preserves multiple glucoside substrates. |
| GO:0008422 beta-glucosidase activity | IDA PMID:11489889 Molecular cloning and expression of human bile acid beta-glu... | ACCEPT | Summary: The human cloning study directly confirms beta-glucosidase activity. Reason: The authentic abstract of PMID:11489889 links peptides from a purified human-liver enzyme to a 927-residue cDNA and reports bile-acid beta-glucosidase activity after tagged expression in COS-7 cells. That explicit activity supports the molecular-function annotation. The abstract's putative transmembrane segment is a separate prediction and is not treated as established topology. |
| GO:0008422 beta-glucosidase activity | IDA PMID:22659419 Beta-glucosidase 1 (GBA1) is a second bile acid Ξ²-glucosidas... | ACCEPT | Summary: The source supports a nonlysosomal beta-glucosidase distinct from GBA1. Reason: The inspected PMID:22659419 substrate and inhibitor experiments distinguish residual nonlysosomal glucoside cleavage from GBA1. Their assay-dependent substrate behavior does not negate the broader beta-glucosidase function demonstrated by human GBA2 expression. The accepted activity does not imply that every assay reagent is a physiological substrate. |
| GO:0008422 beta-glucosidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic beta-glucosidase assertion agrees with direct biochemical evidence. Reason: ARBA and mouse orthology support a glucoside-hydrolyzing enzyme. Human cDNA expression and enzyme studies independently establish beta-glucosidase activity across lipid-linked substrates. Retaining this activity class accommodates substrate breadth without assigning the transfer reaction to a UDP-glucose-dependent enzyme. |
| GO:0008422 beta-glucosidase activity | IMP PMID:22659419 Beta-glucosidase 1 (GBA1) is a second bile acid Ξ²-glucosidas... | ACCEPT | Summary: The perturbation context is consistent with the established beta-glucosidase function. Reason: The original IMP assertion is retained alongside the measured substrate responses in PMID:22659419. Genetic comparisons support attribution, and independent human expression establishes the catalytic class directly. Species, inhibitor selectivity and GBA1-versus-GBA2 distinctions are preserved rather than treating all residual activity as an isoform-resolved measurement. |
| GO:0009247 glycolipid biosynthetic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The electronic biosynthetic assertion reflects reversible glycosyl transfer. Reason: The donor-backed reaction can generate lipid glycosides under the tested conditions. GO:0009247 has broad glycosphingolipid and other lipid-glycoside biosynthesis children despite its narrow glycerol definition. Preserve the biological assertion as a conditional secondary role, without inventing a cholesterol-specific child term or claiming that GBA2 is the UDP-glucose-dependent GlcCer synthase. A GlcCer-biosynthesis term would describe the reverse-transfer product but would omit the experimentally observed sterol-glucoside product; a specific GlcChol synthesis class was not established in the inspected ontology children. Supporting Evidence: |
| GO:0009247 glycolipid biosynthetic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The donor supports context-dependent lipid-glycoside formation. Reason: Mouse GBA2 forms GlcChol and can transfer glucose back to ceramide in PMID:26724485. This is performed synthesis chemistry, not substrate necessity alone, but net cellular flux is conditional. Retain the existing similarity-based glycolipid-biosynthesis claim as non-core. The narrow glycerol wording of GO:0009247 conflicts with its broader curated children and is raised as an ontology question rather than used to deny measured glycoside formation. A GlcCer-biosynthesis term would describe the reverse-transfer product but would omit the experimentally observed sterol-glucoside product; a specific GlcChol synthesis class was not established in the inspected ontology children. Supporting Evidence: |
| GO:0016020 membrane | IDA PMID:17105727 Identification of the non-lysosomal glucosylceramidase as be... | MODIFY | Summary: The cell-surface source context can be represented by plasma membrane. Reason: The available PMID:17105727 abstract reports GBA2 at or near the cell surface, and the independently inspected Reactome chain explicitly places human GBA2 at the plasma membrane. Use the verified child term for this context without claiming that the abstract alone establishes membrane topology or that other intracellular pools are absent. Proposed replacements: plasma membrane |
| GO:0016020 membrane | IEA GO_REF:0000120 | MODIFY | Summary: The broad electronic membrane assertion can specify experimentally supported membrane pools. Reason: GBA2 is associated with ER and Golgi membranes in donor experiments, while the human Reactome catalyst explicitly occupies the plasma membrane. These three locations have verified typed paths to GO:0016020 and preserve contextual breadth. None requires integral membrane topology or exclusive localization to one compartment. |
| GO:0016020 membrane | NAS PMID:11489889 Molecular cloning and expression of human bile acid beta-glu... | MODIFY | Summary: The microsomal membrane assertion can be expressed as ER-membrane association. Reason: The human cloning abstract identifies a microsomal enzyme, and independent localization work supports the ER-associated pool. GO:0005789 provides a verified typed refinement of membrane. This does not resolve the separate smooth-ER assertion, nor does the old predicted transmembrane segment establish integral topology. Proposed replacements: endoplasmic reticulum membrane |
| GO:0016139 glycoside catabolic process | IDA PMID:17105727 Identification of the non-lysosomal glucosylceramidase as be... | ACCEPT | Summary: The nonlysosomal glucosidase is directly involved in glycoside breakdown. Reason: The available PMID:17105727 abstract reports GBA2 expression and RNA interference linked to nonlysosomal glucosylceramidase activity. Independent direct enzyme work confirms the performed cleavage chemistry. Retain the broad IDA process without claiming full inspection of the original experimental panel or restricting all activity to one glycoside substrate. |
| GO:0016139 glycoside catabolic process | NAS PMID:11489889 Molecular cloning and expression of human bile acid beta-glu... | ACCEPT | Summary: Glycoside catabolism captures the enzyme's demonstrated substrate breadth. Reason: Human GBA2 cleaves bile-acid glucosides, and independent experiments establish GlcCer hydrolysis. The incoming NAS claim is broad but reflects reactions the enzyme performs. A typed path from GO:0006680 to GO:0016139 was not found, so the GlcCer term is not presented as a hierarchical replacement; the existing specific activities retain the chemical detail. |
| GO:0021954 central nervous system neuron development | IMP PMID:23332916 Loss of function of glucocerebrosidase GBA2 is responsible f... | KEEP AS NON CORE | Summary: The human-rescue experiment supports a neuronal developmental context. Reason: PMID:23332916 tests zebrafish gba2 loss with human wild-type versus R630W rescue. Spinal motor-axon length and branching are measured developmental outcomes, alongside behavior. Retain the original IMP claim as a non-core biological context; this does not establish direct tubulin binding, a human embryo assay or equivalent functions for all natural GBA2 products. Supporting Evidence: PMID:23332916 were rescued by the human wild-type mRNA |
| GO:0030833 regulation of actin filament polymerization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic transfer of the actin-regulatory phenotype is supportable with donor limits. Reason: The mouse phenotype includes a polymerization readout rather than morphology alone. Its causal link to GBA2 loss and lipid accumulation supports this secondary regulatory process, while the human orthology transfer remains distinct from a direct human actin assay. No specific small-GTPase regulatory activity is inferred. Supporting Evidence: |
| GO:0030833 regulation of actin filament polymerization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The mouse donor links GBA2-dependent lipid turnover to actin assembly. Reason: PMID:25803043 measures an increased F/G-actin ratio and altered actin structures after mouse Gba2 loss, with inhibitor corroboration. These data support downstream regulation of actin polymerization through lipid metabolism. Retain the similarity-based process as non-core; GBA2 is not assigned an actin-binding or polymerase molecular function. Supporting Evidence: PMID:25803043 The F-actin/G-actin ratio was significantly higher in GBA2 knockout-fibroblasts |
| GO:0031113 regulation of microtubule polymerization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The electronic microtubule-regulation claim retains the actual donor readout. Reason: The mouse-derived evidence concerns persistence and organization after altered lipid turnover. It does not establish faster microtubule growth. Retain this non-core regulatory context under the term's extent-based scope, keeping the biochemical GBA2 role separate from the cytoskeletal consequence. Supporting Evidence: |
| GO:0031113 regulation of microtubule polymerization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The donor supports altered microtubule persistence in a lipid-metabolic context. Reason: In PMID:25803043, mouse knockout fibroblasts show longer microtubule persistence, while measured growth rate is unchanged. The original process term covers extent as well as rate; the annotation is retained for this bounded regulatory phenotype, not as proof that GBA2 accelerates microtubule growth or binds tubulin directly. Supporting Evidence: PMID:25803043 growth rate was not different between genotypes, but microtubules in GBA2 knockout-fibroblasts persisted significantly longer |
| GO:0046479 glycosphingolipid catabolic process | TAS Reactome:R-HSA-9840310 | MODIFY | Summary: The pathway-wide catabolism annotation can name the GlcCer step catalyzed by GBA2. Reason: R-HSA-9840310 explicitly contains R-HSA-1861788, whose catalyst is human GBA2 chain1β927. That step hydrolyzes GlcCer, so GO:0006680 is the supported, verified is_a descendant of GO:0046479. The broad pathway's lysosomal compartments and upstream ganglioside reactions are not transferred to GBA2. Proposed replacements: glucosylceramide catabolic process Supporting Evidence: Reactome:R-HSA-9840310 Reactome:R-HSA-1861788 |
| GO:0046527 glucosyltransferase activity | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The electronic transfer annotation agrees with measured lipid transglucosylation. Reason: The mouse-derived electronic assertion is supported by donor experiments and by the human GBA2 glucosyl-transfer control reported in PMID:33361282. Transfer chemistry is distinct from that paper's negative transxylosylation assay. Physiological substrate flux remains context dependent. Preserve glucosyltransferase activity for the GlcCer donor reaction without replacing it with a UDP-specific term. The reviewed human record also reports bile-acid glucosyl-transfer chemistry, a separate substrate context from GlcCer-to-cholesterol transfer. Supporting Evidence: UniProtKB:Q9HCG7 a bile acid glucosyl transferase activity |
| GO:0046527 glucosyltransferase activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse-supported transglucosylation is a real GBA2 catalytic capacity. Reason: PMID:26724485 directly tests mouse GBA2-mediated transfer from GlcCer to cholesterol, with reverse transfer also observed. Mouse genetic and cellular experiments support context-dependent GlcChol formation. Retain the human similarity inference as a secondary catalytic facet; no specific modern human product or universal net biosynthetic direction is established. GO:0046527 does not require UDP-glucose as donor. Supporting Evidence: PMID:26724485 transfer of glucosyl-moieties from GlcCer to cholesterol, and vice versa. UniProtKB:Q9HCG7 |
| GO:0050295 steryl-beta-glucosidase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: The electronic glucosylcholesterol hydrolase assertion has source-specific donor support. Reason: The mouse/Rhea-derived assertion is consistent with the explicit hydrolysis result in PMID:26724485. Evidence for GlcChol metabolism does not make every observed transfer or hydrolysis direction dominant in human cells. Preserve this supported capacity outside the primary GlcCer-hydrolysis core and retain the exact incoming mapping. Supporting Evidence: |
| GO:0050295 steryl-beta-glucosidase activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Glucosylcholesterol hydrolysis is reported for the mouse GBA2 donor. Reason: PMID:26724485 main Results explicitly reports GBA2-mediated GlcChol hydrolysis, distinct from reverse transglucosylation to ceramide. Its referenced supplementary quantitative table was not inspected, so no rate or modern human isoform mapping is claimed. This supports retaining the specific similarity-based activity as a secondary biochemical capacity. Supporting Evidence: PMID:26724485 GBA2 is equally able to degrade GlcChol. |
| GO:0097035 regulation of membrane lipid distribution | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic transfer of membrane-lipid organization is consistent with the donor study. Reason: The donor evidence measures a membrane-order phenotype associated with disrupted GlcCer turnover. This supports the broad regulation term with its proportions/arrangement definition. It does not identify a direct transport mechanism, uniform versus local lipid accumulation, or a distinct function of a particular human short product. Supporting Evidence: |
| GO:0097035 regulation of membrane lipid distribution | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The donor supports altered membrane lipid organization following GBA2 loss. Reason: PMID:25803043 combines GlcCer accumulation with altered packing in isolated plasma-membrane vesicles, and inhibition recapitulates the effect. GO:0097035 includes lipid proportions or spatial arrangement, so it does not require a lipid-translocation assay. Retain this secondary regulatory context without claiming a direct transporter or a resolved leaflet-by-leaflet distribution. Supporting Evidence: |
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Download this section (compressed HTML)Q: How do the 877- and 640-residue natural products differ from the displayed 927-residue GBA2 in activity, membrane association and tissue expression? Existing full-length, mutant and tagged reagents do not resolve all three products.
Q: Under which physiological conditions does GBA2-mediated glucosyl exchange with cholesterol make a substantial contribution to lipid flux, and does the weaker galactosylceramide activity contribute in vivo?
Q: How are the peripheral ER/Golgi-associated pool and the human cell-surface activity pool related, and what experimentally distinguishes smooth ER from the broader microsomal or ER assignment?
Q: Should the definition of GO:0009247 glycolipid biosynthetic process be reconciled with its broader typed children and sterol-glycoside formation? Its current definition specifies a diacylglycerol backbone, while children include glycosphingolipid and dolichol-linked synthesis.
Q: Is a more specific GO glucosyltransferase activity appropriate for the reversible GlcCerβcholesterol reaction represented by RHEA:58264? The inspected immediate GO:0046527 children did not establish a matching activity, and a UDP-glucose-specific term would misstate the donor.
Experiment: Compare sequence-verified natural GBA2 products in matched expression and membrane-fractionation assays, quantifying GlcCer hydrolysis and cytosolic versus membrane-associated protein without assuming that a sequence deletion abolishes activity.
Type: Isoform-resolved enzymology and localization
Experiment: Measure isotope-resolved GlcCer, GlcChol and GalCer flux after selective endogenous GBA2 perturbation and rescue with catalytically active or inactive sequence-verified products. Separate glycosyl transfer from hydrolysis and control lipid accessibility and GBA1 activity.
Type: Cellular lipid flux analysis
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