ASPA is a zinc-dependent aspartoacylase that hydrolyzes the amide bond of N-acetyl-L-aspartate, producing acetate and L-aspartate. Its soluble catalytic activity contributes directly to aspartate and acetate metabolism. The enzyme also accepts selected other N-acyl-L-aspartates in vitro. Its active site lies between an N-terminal metallohydrolase-like domain and a C-terminal domain that shapes substrate access. ASPA is expressed in brain white matter, where loss of its activity causes Canavan disease, a leukodystrophy with white-matter degeneration.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:22284616 Expression and localization of myosin-1d in the developing n... | MODIFY | Summary: Refine the directly measured MYO1D interaction to myosin I binding. Reason: The human kidney-library yeast two-hybrid screen and controlled recombinant human ASPA pull-down support interaction with the MYO1D TH1 tail. The partner is a class I myosin, so myosin I binding is more informative than generic protein binding. The assay does not establish regulation of ASPA catalysis or a trafficking function. Proposed replacements: myosin I binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | UNDECIDED | Summary: The exact ACY3 assay record remains unverified despite positive curated interaction evidence. Reason: The shipped UniProt record reports ASPA interaction with ACY3 (Q96HD9; NbExp=15), providing positive corroboration. The specific assay record underlying PMID:25416956 has not been independently inspected. That database experiment count is not assigned to this one paper; unavailable pair-level evidence is not a contradiction of the curator assertion. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | UNDECIDED | Summary: The exact KEAP1 assay record remains unverified despite positive curated interaction evidence. Reason: The shipped UniProt record reports ASPA interaction with KEAP1 (Q14145; NbExp=4), providing positive corroboration. The specific assay record underlying PMID:25910212 has not been independently inspected. That database experiment count is not assigned to this one paper; unavailable pair-level evidence is not a contradiction of the curator assertion. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | UNDECIDED | Summary: The exact ACY3 assay record remains unverified despite positive curated interaction evidence. Reason: The shipped UniProt record reports ASPA interaction with ACY3 (Q96HD9; NbExp=15), providing positive corroboration. The specific assay record underlying PMID:25910212 has not been independently inspected. That database experiment count is not assigned to this one paper; unavailable pair-level evidence is not a contradiction of the curator assertion. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The exact DUSP29 assay record remains unverified despite positive curated interaction evidence. Reason: The shipped UniProt record reports ASPA interaction with DUSP29 (Q68J44; NbExp=3), providing positive corroboration. The specific assay record underlying PMID:32296183 has not been independently inspected. That database experiment count is not assigned to this one paper; unavailable pair-level evidence is not a contradiction of the curator assertion. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The exact ACY3 assay record remains unverified despite positive curated interaction evidence. Reason: The shipped UniProt record reports ASPA interaction with ACY3 (Q96HD9; NbExp=15), providing positive corroboration. The specific assay record underlying PMID:32296183 has not been independently inspected. That database experiment count is not assigned to this one paper; unavailable pair-level evidence is not a contradiction of the curator assertion. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | UNDECIDED | Summary: The exact PIAS1 assay record remains unverified despite positive curated interaction evidence. Reason: The shipped UniProt record reports ASPA interaction with PIAS1 (O75925; NbExp=3), providing positive corroboration. The specific assay record underlying PMID:32814053 has not been independently inspected. That database experiment count is not assigned to this one paper; unavailable pair-level evidence is not a contradiction of the curator assertion. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | UNDECIDED | Summary: The exact UBQLNL assay record remains unverified despite positive curated interaction evidence. Reason: The shipped UniProt record reports ASPA interaction with UBQLNL (Q8IYU4; NbExp=3), providing positive corroboration. The specific assay record underlying PMID:32814053 has not been independently inspected. That database experiment count is not assigned to this one paper; unavailable pair-level evidence is not a contradiction of the curator assertion. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | UNDECIDED | Summary: The exact UBQLN3 assay record remains unverified despite positive curated interaction evidence. Reason: The shipped UniProt record reports ASPA interaction with UBQLN3 (Q9H347; NbExp=3), providing positive corroboration. The specific assay record underlying PMID:32814053 has not been independently inspected. That database experiment count is not assigned to this one paper; unavailable pair-level evidence is not a contradiction of the curator assertion. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | UNDECIDED | Summary: The exact UBQLN2 assay record remains unverified despite positive curated interaction evidence. Reason: The shipped UniProt record reports ASPA interaction with UBQLN2 (Q9UHD9; NbExp=3), providing positive corroboration. The specific assay record underlying PMID:32814053 has not been independently inspected. That database experiment count is not assigned to this one paper; unavailable pair-level evidence is not a contradiction of the curator assertion. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | UNDECIDED | Summary: The exact COPS3 assay record remains unverified despite positive curated interaction evidence. Reason: The shipped UniProt record reports ASPA interaction with COPS3 (Q9UNS2; NbExp=3), providing positive corroboration. The specific assay record underlying PMID:32814053 has not been independently inspected. That database experiment count is not assigned to this one paper; unavailable pair-level evidence is not a contradiction of the curator assertion. Supporting Evidence: |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Reason: Nuclear localization is supported by native rodent localization and an active human GFP-ASPA fusion in COS-7 cells. Retain this contextual compartment without inferring a distinct nuclear or chromatin function. Supporting Evidence: |
| GO:0005634 nucleus | ISS GO_REF:0000024 | KEEP AS NON CORE | Reason: Nuclear localization is supported by native rodent localization and an active human GFP-ASPA fusion in COS-7 cells. Retain this contextual compartment without inferring a distinct nuclear or chromatin function. Supporting Evidence: |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | MODIFY | Reason: The cytoplasmic assignment is compatible with the evidence, and human immunofluorescence and the curated reaction support the more specific cytosol compartment. The proposed specific term is already present among the original annotations; this refinement does not add functional coverage. Proposed replacements: cytosol Supporting Evidence: GO_REF:0000052 Reactome:R-HSA-5691507 |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | MODIFY | Reason: The cytoplasmic assignment is compatible with the evidence, and human immunofluorescence and the curated reaction support the more specific cytosol compartment. The proposed specific term is already present among the original annotations; this refinement does not add functional coverage. Proposed replacements: cytosol Supporting Evidence: GO_REF:0000052 Reactome:R-HSA-5691507 |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Reason: Cytosol is the established cellular compartment for the human NAA-hydrolyzing reaction, supported independently by human immunofluorescence and Reactome. The source inference is compatible with those observations. Supporting Evidence: GO_REF:0000052 Reactome:R-HSA-5691507 |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Reason: Cytosol is the established cellular compartment for the human NAA-hydrolyzing reaction, supported independently by human immunofluorescence and Reactome. The source inference is compatible with those observations. Supporting Evidence: GO_REF:0000052 Reactome:R-HSA-5691507 |
| GO:0005829 cytosol | IEA GO_REF:0000107 | ACCEPT | Reason: Cytosol is the established cellular compartment for the human NAA-hydrolyzing reaction, supported independently by human immunofluorescence and Reactome. The source inference is compatible with those observations. Supporting Evidence: GO_REF:0000052 Reactome:R-HSA-5691507 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5691507 | ACCEPT | Reason: Cytosol is the established cellular compartment for the human NAA-hydrolyzing reaction, supported independently by human immunofluorescence and Reactome. The source inference is compatible with those observations. Supporting Evidence: GO_REF:0000052 Reactome:R-HSA-5691507 |
| GO:0006083 acetate metabolic process | IEA GO_REF:0000107 | ACCEPT | Reason: ASPA directly releases acetate by NAA hydrolysis, so it performs a reaction in acetate metabolism. |
| GO:0006531 aspartate metabolic process | IEA GO_REF:0000107 | ACCEPT | Reason: ASPA directly releases L-aspartate from N-acyl-L-aspartate and therefore participates in aspartate metabolism. |
| GO:0006532 L-aspartate biosynthetic process | IEA GO_REF:0000107 | ACCEPT | Reason: The catalytic reaction produces L-aspartate. This is direct product formation, consistent with the corresponding mouse GO-CAM activity and the established human reaction. |
| GO:0016788 hydrolase activity, acting on ester bonds | IEA GO_REF:0000002 | REMOVE | Reason: The transferred ester-hydrolase term specifies cleavage of ester bonds. The established ASPA reaction hydrolyzes the amide carbon-nitrogen bond in N-acyl-L-aspartate, supported by human substrate enzymology and intermediate-analogue structure. The existing aspartoacylase annotation already represents the correct chemistry. |
| GO:0016811 hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides | IBA GO_REF:0000033 | ACCEPT | Reason: The PAINT IBD table records linear-amide hydrolase activity at PTN007644184 with human ASPA and other descendant experimental evidence. This chemistry agrees with human ASPA enzymology. No target-specific loss or contrary phylogenetic placement is established. Retain the inherited broad activity; the existing aspartoacylase annotations already capture the human substrate specificity. |
| GO:0016811 hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides | IEA GO_REF:0000002 | MODIFY | Reason: Linear-amide hydrolysis is chemically correct but broad. Direct human enzymology establishes N-acyl-L-aspartate hydrolysis, represented more specifically by aspartoacylase activity. The proposed specific term is already present among the original annotations; this refinement does not add functional coverage. Proposed replacements: aspartoacylase activity |
| GO:0019807 aspartoacylase activity | EXP PMID:12706335 Purification and preliminary characterization of brain aspar... | ACCEPT | Reason: Recombinant human enzyme kinetics demonstrate hydrolysis of NAA and selected N-acyl analogues. Supporting Evidence: |
| GO:0019807 aspartoacylase activity | EXP PMID:17027983 Identification of the zinc binding ligands and the catalytic... | ACCEPT | Reason: Recombinant human enzyme kinetics and active-site mutagenesis directly support zinc-dependent aspartoacylase activity. |
| GO:0019807 aspartoacylase activity | EXP PMID:18293939 Examination of the mechanism of human brain aspartoacylase t... | ACCEPT | Reason: The human enzyme bound to a tetrahedral intermediate analogue supports the mechanism of NAA amide hydrolysis; independent human kinetic experiments establish the same activity. |
| GO:0019807 aspartoacylase activity | EXP PMID:24036223 New T530C mutation in the aspartoacylase gene caused Canavan... | ACCEPT | Reason: The case report records loss of ASPA activity in I177T siblings. Its detailed assay is unread, but the normal human catalytic function is independently established by recombinant enzyme studies, so the original curator assertion is retained. |
| GO:0019807 aspartoacylase activity | EXP PMID:28101991 Clinically Distinct Phenotypes of Canavan Disease Correlate ... | ACCEPT | Reason: Wild-type human ASPA expressed in HEK293 cells produces aspartate from NAA in a controlled LC-MS/MS assay; variant effects do not change the wild-type function. |
| GO:0019807 aspartoacylase activity | IDA PMID:8252036 Cloning of the human aspartoacylase cDNA and a common missen... | ACCEPT | Reason: Cloned human ASPA cDNA expressed in bacteria produces aspartoacylase activity. The historical catalytic-triad speculation is not required for this functional conclusion. |
| GO:0019807 aspartoacylase activity | IEA GO_REF:0000120 | ACCEPT | Reason: The EC and RHEA reaction mappings describe N-acyl-L-aspartate hydrolysis and agree with direct human enzymology. |
| GO:0042802 identical protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | KEEP AS NON CORE | Reason: The original screen self-pair has not been independently inspected, but human crystallographic evidence independently supports ASPA self-association. Retain the curator assertion as an association property without making it a second catalytic core or asserting obligatory dimerization in every compartment. Supporting Evidence: |
| GO:0042802 identical protein binding | IPI PMID:17194761 Structure of aspartoacylase, the brain enzyme impaired in Ca... | KEEP AS NON CORE | Reason: Human and rat crystal structures show analogous ASPA dimers. This supports self-association; it does not establish that all native ASPA is an obligate dimer. Supporting Evidence: |
| GO:0043209 myelin sheath | IEA GO_REF:0000107 | KEEP AS NON CORE | Reason: The mouse-derived myelin assignment is supported by biochemical, proteomic and immunoblot evidence in purified mouse myelin. Retain this tissue-specific compartment separately from the broadly supported cytosolic catalytic core; no direct human myelin assay is claimed. Supporting Evidence: |
| GO:0008270 zinc ion binding | IDA PMID:17194761 Structure of aspartoacylase, the brain enzyme impaired in Ca... | NEW | Summary: Human ASPA directly coordinates a catalytic zinc ion. Reason: Human ASPA crystal structures identify zinc-coordinating residues, and human active-site mutagenesis independently identifies His21, Glu24 and His116 as zinc ligands. This is a physical binding function of ASPA itself, distinct from its existing catalytic-reaction annotations. The zinc supports the single aspartoacylase mechanism rather than a separate physiological function. |
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Download this section (compressed HTML)Q: What evidence in the source interaction records establishes the ten remaining ASPA partner pairs, and do any have a reproducible effect on catalysis or localization?
Q: How do native nuclear, cytosolic and myelin-associated ASPA pools differ in activity and assembly?
Q: Does the current InterPro mapping to ester-bond hydrolysis reflect a family-level mapping error for ASPA?
Experiment: Measure NAA hydrolysis by purified human ASPA with and without MYO1D tail under matched conditions, independently controlling for protein concentration and zinc availability.
Hypothesis: MYO1D binding may modulate ASPA activity, but the existing physical interaction experiments do not establish regulation.
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