Human ADA (adenosine deaminase, also called ADA1) is a zinc-dependent enzyme that hydrolyzes adenosine to inosine and 2'-deoxyadenosine to 2'-deoxyinosine. These reactions support purine breakdown and salvage and prevent toxic deoxynucleoside accumulation; loss of ADA activity causes severe combined immunodeficiency. ADA acts predominantly in the cytosol, with additional lysosomal and extracellular cell-surface pools. Surface ADA associated with CD26/DPP4 removes extracellular adenosine and thereby regulates receptor stimulation. ADA-CD26 interactions also support T-cell costimulation and integrin-mediated cell adhesion through functions separable from nucleoside hydrolysis. ADA can metabolize nucleoside analogues, including ribavirin, in drug-metabolism contexts.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004000 adenosine deaminase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) inference of the defining molecular function of ADA, the hydrolytic deamination of adenosine to inosine. This is the core catalytic activity of the protein and is supported experimentally in human ADA. Reason: Core molecular function of ADA, conserved across the adenosine deaminase family and directly demonstrated for the human enzyme by catalytic-activity and biophysicochemical studies. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000150817 SUPPORTS TRANSFER Cached PTHR11409 PAINT data contain this ancestral IBD. Conserved human catalytic and pathway evidence supports descent of the function; extant seeds are not pairwise transfer sources. Supporting Evidence: file:human/ADA/ADA-uniprot.txt Catalyzes the hydrolytic deamination of adenosine and 2- PMID:8452534 the conversion of [3H]adenosine into [3H]inosine was proportional to incubation time |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that ADA acts in the cytosol. ADA is predominantly a cytosolic enzyme, consistent with its role in intracellular purine catabolism. Reason: The cytosol is the primary site of ADA activity; UniProt and multiple Reactome/TAS annotations place the enzyme in the cytosol, and the cell-surface (ecto-ADA) pool is a secondary localization. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000150817 SUPPORTS TRANSFER Cached PTHR11409 PAINT data contain this ancestral IBD. Conserved human catalytic and pathway evidence supports descent of the function; extant seeds are not pairwise transfer sources. Supporting Evidence: PMID:11772392 an enzyme mainly localized in the cytosol but also found on the cell surface of monocytes |
| GO:0042110 T cell activation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Involvement in T cell activation, inferred phylogenetically and supported experimentally through the ecto-ADA/CD26 costimulatory axis on the T-cell surface. Reason: This is a genuine but moonlighting (extra-enzymatic / cell-surface) role of ADA, distinct from its core cytosolic catalytic function in purine catabolism. Cell-surface ADA bound to CD26 provides a costimulatory signal in T cell activation. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002605214 SUPPORTS TRANSFER Cached PAINT IBD uses human ADA T-cell activation evidence; the contextual activity is retained without treating target participation as circular. Supporting Evidence: PMID:7594462 binding to CD26 produces a costimulatory response in T cell activation events |
| GO:0045187 regulation of circadian sleep/wake cycle, sleep | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference linking ADA to regulation of sleep. Adenosine is a well-established somnogen, and the common ADA*2 (Asp8Asn) polymorphism, which lowers ADA activity, enhances deep sleep and slow-wave activity in humans. Reason: A genuine physiological consequence of ADA controlling adenosine tone in the brain, but downstream of and secondary to the core catabolic activity rather than a defining molecular function. Supported by human polymorphism data. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000150946 SUPPORTS TRANSFER Cached PAINT IBD is grounded in rat Ada (RGD:2031); the human ADA polymorphism record independently supports a sleep association. The rat primary experiment was not independently re-read. Supporting Evidence: file:human/ADA/ADA-uniprot.txt It specifically enhances deep sleep and slow-wave activity |
| GO:0006154 adenosine catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that ADA participates in adenosine catabolism. This is the core biological process for ADA, the committed step converting adenosine to inosine in the purine degradation pathway. Reason: Adenosine catabolism is the defining biological role of ADA and is directly supported by its catalytic activity and by the phenotype of ADA-deficient cells, which accumulate the substrate (deoxy)adenosine. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000150817 SUPPORTS TRANSFER Cached PTHR11409 PAINT data contain this ancestral IBD. Conserved human catalytic and pathway evidence supports descent of the function; extant seeds are not pairwise transfer sources. Supporting Evidence: file:human/ADA/ADA-uniprot.txt Plays an important role in purine PMID:9361033 the purine salvage enzyme adenosine deaminase |
| GO:0009897 external side of plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of extracellular membrane-associated ADA. Reason: The PTN000150939 IBD is grounded in human ADA evidence. Human endothelial experiments demonstrate surface-tethered ADA activity; this is a location of its core catalytic function. The target contributing experimental evidence to its ancestral assertion is legitimate PAINT provenance. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000150939 SUPPORTS TRANSFER Cached PAINT IBD is supported by human ADA experiments for this surface-associated function. Human target evidence legitimately contributes to the ancestral inference. Supporting Evidence: PMID:16670267 ADA localizes to the endothelial surface and limits the accumulation of extracellular adenosine during hypoxia |
| GO:0060169 negative regulation of adenosine receptor signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Inference that ADA negatively regulates adenosine-receptor signaling. By catabolizing extracellular adenosine (the receptor agonist), ecto-ADA reduces adenosine-receptor activation; the net effect can be complex, since ADA can also allosterically enhance receptor agonist affinity. Reason: The PTN000150939 assertion is grounded in the human endothelial evidence for removal of extracellular adenosine. Reduced agonist availability limits adenosine-receptor signaling in that context. Retain as a contextual regulatory consequence of catalysis, without generalizing the sign to every receptor-associated ADA function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000150939 SUPPORTS TRANSFER Cached PAINT IBD is supported by human ADA experiments for this surface-associated function. Human target evidence legitimately contributes to the ancestral inference. Supporting Evidence: PMID:16670267 increasing the endothelial capacity to metabolize adenosine to inosine |
| GO:0043103 hypoxanthine salvage | IBA GO_REF:0000033 | ACCEPT | Summary: ADA supplies inosine in a pathway generating hypoxanthine from purine derivatives. Reason: The live GO definition covers generation of hypoxanthine from its derivatives without de novo synthesis. ADA performs the adenosine-to-inosine step before purine-nucleoside phosphorylase releases hypoxanthine. PTN000150817 is the PAINT ancestral assertion, with E. coli Add (P22333) as the listed IBD seed; the conserved human reaction supports participation. This is not an assertion that ADA itself phosphoribosylates hypoxanthine. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000150817 SUPPORTS TRANSFER Cached PTHR11409 PAINT data contain this ancestral IBD. Conserved human catalytic and pathway evidence supports descent of the function; extant seeds are not pairwise transfer sources. The listed extant seed is E. coli Add, UniProtKB:P22333. The GO definition is hypoxanthine generation, not exclusively HPRT-mediated reutilization. Supporting Evidence: file:human/ADA/ADA-uniprot.txt Catalyzes the hydrolytic deamination of adenosine and 2- |
| GO:0046103 inosine biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that ADA contributes to inosine biosynthesis. Inosine is the direct reaction product of adenosine deamination by ADA. Reason: ADA directly produces inosine from adenosine, so it is genuinely involved in inosine biosynthesis. This is a valid process-level annotation directly downstream of the core catalytic reaction. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000150817 SUPPORTS TRANSFER Cached PTHR11409 PAINT data contain this ancestral IBD. Conserved human catalytic and pathway evidence supports descent of the function; extant seeds are not pairwise transfer sources. Supporting Evidence: PMID:8452534 the conversion of [3H]adenosine into [3H]inosine was proportional to incubation time |
| GO:0004000 adenosine deaminase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation (multiple IEA methods, incl. RHEA:24408 mapping) of the core adenosine deaminase activity. Duplicate of the experimentally and phylogenetically supported core MF. Reason: Correct core molecular function, consistent with the RHEA reaction and experimental catalytic-activity data. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00028660 UNRESOLVED The supplied mapping identifier is traced, but detailed rule predicates and original mapping curation were not inspected. The annotation judgment rests on independently assessed ADA biology, not a claimed rule reanalysis. InterPro:IPR028893 UNRESOLVED The supplied mapping identifier is traced, but detailed rule predicates and original mapping curation were not inspected. The annotation judgment rests on independently assessed ADA biology, not a claimed rule reanalysis. RHEA:24408 SUPPORTS TRANSFER The matching substrate/product reaction is present in the immutable human UniProt catalytic-activity record. UniProtKB:P03958 SUPPORTS TRANSFER Mouse Ada ortholog source (UniProtKB:P03958; Ensembl ENSMUSP00000017841). Human catalytic/cofactor/localization evidence independently supports this annotation; the exact historical donor assay is not re-created from the target record. ensembl:ENSMUSP00000017841 SUPPORTS TRANSFER Mouse Ada ortholog source (UniProtKB:P03958; Ensembl ENSMUSP00000017841). Human catalytic/cofactor/localization evidence independently supports this annotation; the exact historical donor assay is not re-created from the target record. Supporting Evidence: file:human/ADA/ADA-uniprot.txt Catalyzes the hydrolytic deamination of adenosine and 2- |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: The broad cytoplasm annotation includes the established cytosolic ADA pool. Reason: The broad cytoplasmic location includes the established cytosolic enzyme pool. The combined electronic assertion is consistent with human ADA biology; its broader resolution does not make the location a secondary function. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0086 SUPPORTS TRANSFER UniProt subcellular-location mapping traced to the human record and independently compared with human experimental localization. UniProtKB:P03958 SUPPORTS TRANSFER Mouse Ada ortholog source (UniProtKB:P03958; Ensembl ENSMUSP00000017841). Human catalytic/cofactor/localization evidence independently supports this annotation; the exact historical donor assay is not re-created from the target record. ensembl:ENSMUSP00000017841 SUPPORTS TRANSFER Mouse Ada ortholog source (UniProtKB:P03958; Ensembl ENSMUSP00000017841). Human catalytic/cofactor/localization evidence independently supports this annotation; the exact historical donor assay is not re-created from the target record. Supporting Evidence: PMID:11772392 an enzyme mainly localized in the cytosol but also found on the cell surface of monocytes |
| GO:0005764 lysosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic (UniProt SubCell keyword) localization to the lysosome. Corroborated by direct experimental demonstration of ADA activity in purified human fibroblast lysosomes. Reason: The study reports ADA activity in Percoll-purified human fibroblast lysosomes, accounting for approximately 10% of total ADA activity in that experimental system. This is a supported secondary compartment; the percentage is not generalized to other cell types or all human tissues. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0158 SUPPORTS TRANSFER UniProt subcellular-location mapping traced to the human record and independently compared with human experimental localization. Supporting Evidence: PMID:8452534 Human fibroblast lysosomes, purified on Percoll density gradients, contain an |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt maps the membrane-associated ecto-ADA pool to plasma membrane. Reason: The UniProt location mapping records the plasma-membrane-associated ecto-ADA pool. Human surface studies independently support this location. Retain the source resolution; this annotation does not imply that ADA spans the membrane. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0039 SUPPORTS TRANSFER UniProt subcellular-location mapping traced to the human record and independently compared with human experimental localization. Supporting Evidence: PMID:16670267 ADA localizes to the endothelial surface and limits the accumulation of extracellular adenosine during hypoxia |
| GO:0006154 adenosine catabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA machine-learning electronic annotation of the core biological process, adenosine catabolism. Duplicate of the experimentally/phylogenetically supported core BP. Reason: Correct core biological process, consistent with the enzyme's catalytic function. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00084293 UNRESOLVED The supplied mapping identifier is traced, but detailed rule predicates and original mapping curation were not inspected. The annotation judgment rests on independently assessed ADA biology, not a claimed rule reanalysis. Supporting Evidence: file:human/ADA/ADA-uniprot.txt Plays an important role in purine |
| GO:0009168 purine ribonucleoside monophosphate biosynthetic process | IEA GO_REF:0000002 | ACCEPT | Summary: ADA participates in purine monophosphate formation through salvage. Reason: GO:0009168 includes pathways that form purine ribonucleoside monophosphates, including salvage. ADA converts adenosine to inosine; subsequent PNP and HPRT reactions permit IMP formation, followed by AMP or GMP synthesis. Cached mouse Ada GO-CAMs explicitly model the salvage routes. The InterPro mapping is therefore biologically compatible, although its internal rule provenance was not independently reconstructed. ADA need not catalyze the terminal phosphate-containing product to participate. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR006650 UNRESOLVED The supplied mapping identifier is traced, but detailed rule predicates and original mapping curation were not inspected. The annotation judgment rests on independently assessed ADA biology, not a claimed rule reanalysis. InterPro:IPR028893 UNRESOLVED The supplied mapping identifier is traced, but detailed rule predicates and original mapping curation were not inspected. The annotation judgment rests on independently assessed ADA biology, not a claimed rule reanalysis. Supporting Evidence: file:human/ADA/ADA-uniprot.txt Plays an important role in purine |
| GO:0019239 deaminase activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO electronic mapping to the general parent term deaminase activity. Correct but less specific than adenosine deaminase activity (GO:0004000). Reason: The InterPro mappings give a broad deaminase family function. Independent human catalytic annotation and enzyme experiments establish adenosine-to-inosine chemistry, supporting refinement to the corresponding specific MF. The detailed mapping predicates were not inspected, and this refinement does not imply that every deaminase in those domain families has ADA specificity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR001365 UNRESOLVED The supplied mapping identifier is traced, but detailed rule predicates and original mapping curation were not inspected. The annotation judgment rests on independently assessed ADA biology, not a claimed rule reanalysis. InterPro:IPR006330 UNRESOLVED The supplied mapping identifier is traced, but detailed rule predicates and original mapping curation were not inspected. The annotation judgment rests on independently assessed ADA biology, not a claimed rule reanalysis. InterPro:IPR006650 UNRESOLVED The supplied mapping identifier is traced, but detailed rule predicates and original mapping curation were not inspected. The annotation judgment rests on independently assessed ADA biology, not a claimed rule reanalysis. Proposed replacements: adenosine deaminase activity Supporting Evidence: file:human/ADA/ADA-uniprot.txt Catalyzes the hydrolytic deamination of adenosine and 2- |
| GO:0060205 cytoplasmic vesicle lumen | IEA GO_REF:0000044 | UNDECIDED | Summary: The transferred cytoplasmic-vesicle-lumen localization needs source-level resolution. Reason: The UniProt SUBCELLULAR LOCATION block explicitly assigns cytoplasmic vesicle lumen by similarity to P03958, which is mouse Ada. This traces the source assertion but does not independently establish the human compartment. The underlying donor experiment was not recovered. Human lysosomal and surface ADA evidence does not by itself establish every cytoplasmic vesicle lumen or refute this particular transfer. Preserve uncertainty pending the donor experiment; lack of a signal peptide alone is not disproof. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB-SubCell:SL-0325 UNRESOLVED The mapping is identifiable, but its source evidence does not resolve this exact compartment in the accessible material. SL-0325 derives from a similarity statement to mouse P03958. |
| GO:0070161 anchoring junction | IEA GO_REF:0000044 | UNDECIDED | Summary: The cell-junction mapping has unresolved compartment specificity. Reason: The electronic source is UniProt SL-0038 (cell junction), linked to the human ADA-CD26 adhesion study. The accessible abstract establishes cell-surface ADA and effects on adhesion but does not resolve an anchoring-junction compartment. Full localization results were not accessible. This leaves the specific location unresolved without denying junctional association. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB-SubCell:SL-0038 UNRESOLVED The mapping is identifiable, but its source evidence does not resolve this exact compartment in the accessible material. SL-0038 maps cell junction to anchoring junction; the accessible adhesion-study abstract establishes only cell-surface localization. Supporting Evidence: PMID:11772392 an enzyme mainly localized in the cytosol but also found on the cell surface of monocytes |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: Generic protein binding records the BioPlex 2 POTEF association. Reason: The BioPlex 2 POTEF association supports an interaction, but protein binding does not identify a useful molecular function. Remove the generic MF under project policy without denying the interaction. The exact high-throughput pair record was not independently re-extracted; this decision concerns information content, not whether the proteins associate. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Generic protein binding records the BioPlex 3 POTEF association. Reason: The BioPlex 3 POTEF association supports an interaction, but protein binding does not identify a useful molecular function. Remove the generic MF under project policy without denying the interaction. The exact high-throughput pair record was not independently re-extracted; this decision concerns information content, not whether the proteins associate. |
| GO:0005829 cytosol | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl-Compara electronic transfer (from mouse ortholog P03958) that ADA is active in the cytosol. Duplicate of the core cytosolic localization. Reason: Correct primary localization, consistent with the IBA and Reactome/TAS cytosol annotations. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P03958 SUPPORTS TRANSFER Mouse Ada ortholog source (UniProtKB:P03958; Ensembl ENSMUSP00000017841). Human catalytic/cofactor/localization evidence independently supports this annotation; the exact historical donor assay is not re-created from the target record. ensembl:ENSMUSP00000017841 SUPPORTS TRANSFER Mouse Ada ortholog source (UniProtKB:P03958; Ensembl ENSMUSP00000017841). Human catalytic/cofactor/localization evidence independently supports this annotation; the exact historical donor assay is not re-created from the target record. Supporting Evidence: PMID:11772392 an enzyme mainly localized in the cytosol but also found on the cell surface of monocytes |
| GO:0006196 AMP catabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: ADA catalyzes the nucleoside step of AMP breakdown. Reason: After AMP dephosphorylation, ADA converts adenosine to inosine. This is direct catalytic participation in the multistep AMP catabolic process. The mouse donor P03958/MGI:87916 is explicitly modeled with this activity and process in GO-CAM 5f46c3b700003884. Human ADA conserves the relevant chemistry; direct hydrolysis of AMP by ADA is not implied. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P03958 SUPPORTS TRANSFER Mouse Ada source, represented as MGI:MGI:87916 in cached GO-CAM 5f46c3b700003884. Its explicit part_of relationship establishes the donor pathway scope. The original supporting experiments were not independently recovered; human transfer is corroborated by conserved chemistry. ensembl:ENSMUSP00000017841 SUPPORTS TRANSFER Mouse Ada source, represented as MGI:MGI:87916 in cached GO-CAM 5f46c3b700003884. Its explicit part_of relationship establishes the donor pathway scope. The original supporting experiments were not independently recovered; human transfer is corroborated by conserved chemistry. |
| GO:0008270 zinc ion binding | IEA GO_REF:0000107 | ACCEPT | Summary: ADA binds catalytic zinc; disease-variant activity and the human cofactor record support this function. Reason: The reviewed human UniProt record identifies one zinc ion per subunit. In the human H15D disease-variant study, loss of enzyme activity is interpreted using the zinc-coordinating site in a structural model based on murine ADA. This supports catalytic metal dependence; it is not a direct measurement of mutant zinc occupancy. The mouse P03958 ortholog supplies the transferred annotation, independently corroborated by the human cofactor record. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P03958 SUPPORTS TRANSFER Mouse Ada ortholog source (UniProtKB:P03958; Ensembl ENSMUSP00000017841). Human catalytic/cofactor/localization evidence independently supports this annotation; the exact historical donor assay is not re-created from the target record. ensembl:ENSMUSP00000017841 SUPPORTS TRANSFER Mouse Ada ortholog source (UniProtKB:P03958; Ensembl ENSMUSP00000017841). Human catalytic/cofactor/localization evidence independently supports this annotation; the exact historical donor assay is not re-created from the target record. Supporting Evidence: file:human/ADA/ADA-uniprot.txt Binds 1 zinc ion per subunit PMID:7599635 the first naturally occurring mutation of a residue that coordinates |
| GO:0032263 GMP salvage | IEA GO_REF:0000107 | ACCEPT | Summary: ADA contributes the adenosine-deamination step in a GMP salvage route. Reason: Mouse Ada in GO-CAM 60ff660000000882 acts before Pnp, Hprt1, Impdh and Gmps in GMP salvage. The route reuses the purine moiety via inosine, hypoxanthine and IMP. Human ADA catalyzes the same initial reaction, consistent with human purine salvage in Reactome. The annotation describes pathway participation, not guanosine deamination or direct GMP synthesis. Original donor publications were not independently recovered, so the source audit distinguishes the curated model from a fresh experimental reanalysis. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P03958 SUPPORTS TRANSFER Mouse Ada source, represented as MGI:MGI:87916 in cached GO-CAM 60ff660000000882. Its explicit part_of relationship establishes the donor pathway scope. The original supporting experiments were not independently recovered; human transfer is corroborated by conserved chemistry. ensembl:ENSMUSP00000017841 SUPPORTS TRANSFER Mouse Ada source, represented as MGI:MGI:87916 in cached GO-CAM 60ff660000000882. Its explicit part_of relationship establishes the donor pathway scope. The original supporting experiments were not independently recovered; human transfer is corroborated by conserved chemistry. |
| GO:0044209 AMP salvage | IEA GO_REF:0000107 | ACCEPT | Summary: ADA participates in an indirect AMP salvage route through inosine and IMP. Reason: GO-CAM 60ff660000001341 explicitly places mouse Ada before Pnp, Hprt1, Adss1 and Adsl in AMP salvage. This gives a mechanistic route from adenosine through inosine and IMP to AMP, distinct from direct phosphorylation by adenosine kinase. Human ADA supplies the same deamination step. The donor model and conserved chemistry support transfer; the historical primary donor experiments remain unread. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P03958 SUPPORTS TRANSFER Mouse Ada source, represented as MGI:MGI:87916 in cached GO-CAM 60ff660000001341. Its explicit part_of relationship establishes the donor pathway scope. The original supporting experiments were not independently recovered; human transfer is corroborated by conserved chemistry. ensembl:ENSMUSP00000017841 SUPPORTS TRANSFER Mouse Ada source, represented as MGI:MGI:87916 in cached GO-CAM 60ff660000001341. Its explicit part_of relationship establishes the donor pathway scope. The original supporting experiments were not independently recovered; human transfer is corroborated by conserved chemistry. |
| GO:0046059 dAMP catabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: ADA contributes to dAMP breakdown by deaminating its dephosphorylated nucleoside. Reason: Dephosphorylation of dAMP supplies 2'-deoxyadenosine for ADA, followed by deoxyinosine metabolism. The mouse donor is modeled in this role in GO-CAM 5fa76ad400000265. Human deoxyadenosine deamination is independently recorded in UniProt and Reactome. This is an enzyme performing a pathway step, not merely a metabolite-level perturbation. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P03958 SUPPORTS TRANSFER Mouse Ada source, represented as MGI:MGI:87916 in cached GO-CAM 5fa76ad400000265. Its explicit part_of relationship establishes the donor pathway scope. The original supporting experiments were not independently recovered; human transfer is corroborated by conserved chemistry. ensembl:ENSMUSP00000017841 SUPPORTS TRANSFER Mouse Ada source, represented as MGI:MGI:87916 in cached GO-CAM 5fa76ad400000265. Its explicit part_of relationship establishes the donor pathway scope. The original supporting experiments were not independently recovered; human transfer is corroborated by conserved chemistry. |
| GO:0046936 2'-deoxyadenosine deaminase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation (RHEA:28190) of 2'-deoxyadenosine deaminase activity. ADA hydrolytically deaminates 2'-deoxyadenosine to 2'-deoxyinosine; this activity is the physiologically critical one whose loss drives dATP accumulation in ADA-SCID. Reason: Correct core molecular function alongside adenosine deaminase activity, supported by the second RHEA reaction and by experimental catalytic data. Propagation Review Root cause: NO FAILURE CORE Sources checked: RHEA:28190 SUPPORTS TRANSFER The matching substrate/product reaction is present in the immutable human UniProt catalytic-activity record. UniProtKB:P03958 SUPPORTS TRANSFER Mouse Ada ortholog source (UniProtKB:P03958; Ensembl ENSMUSP00000017841). Human catalytic/cofactor/localization evidence independently supports this annotation; the exact historical donor assay is not re-created from the target record. ensembl:ENSMUSP00000017841 SUPPORTS TRANSFER Mouse Ada ortholog source (UniProtKB:P03958; Ensembl ENSMUSP00000017841). Human catalytic/cofactor/localization evidence independently supports this annotation; the exact historical donor assay is not re-created from the target record. Supporting Evidence: file:human/ADA/ADA-uniprot.txt Catalyzes the hydrolytic deamination of adenosine and 2- |
| GO:0006805 xenobiotic metabolic process | TAS Reactome:R-HSA-9748784 | KEEP AS NON CORE | Summary: Reactome (Drug ADME) annotation reflecting ADA's deamination of nucleoside analog drugs, notably ribavirin (RBV -> RBV-COOH) and cordycepin. This is a pharmacologically important but incidental substrate promiscuity. Reason: A genuine xenobiotic/drug-metabolism role arising from ADA's broad specificity for adenosine-like nucleosides, but secondary to its endogenous purine-catabolic function. Supporting Evidence: file:human/ADA/ADA-uniprot.txt responsible for the deamination of cordycepin |
| GO:0043101 purine-containing compound salvage | TAS Reactome:R-HSA-74217 | ACCEPT | Summary: Reactome (Purine salvage pathway) TAS annotation. ADA participates in the purine salvage/interconversion network by converting adenosine and 2'-deoxyadenosine to their inosine counterparts, which are then further metabolized. Reason: ADA is a bona fide participant in the purine salvage/interconversion pathway; this broader process term is accurate and reflects the enzyme's contribution to purine-containing compound turnover. Supporting Evidence: PMID:9361033 the purine salvage enzyme adenosine deaminase |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence assigns ADA to plasma membrane. Reason: Retain the Human Protein Atlas immunofluorescence plasma-membrane assertion with curator deference. The underlying images were not independently re-scored; independent human cell-surface studies support the broad location without assigning a more precise topology to this particular experiment. Supporting Evidence: PMID:11999881 indicating surface expression of ADA |
| GO:0004000 adenosine deaminase activity | IMP PMID:26166670 The Role of G22 A Adenosine Deaminase 1 Gene Polymorphism an... | ACCEPT | Summary: IMP annotation of adenosine deaminase activity from a study of the ADA1 G22A (Asp8Asn/ADA*2) polymorphism in fertile vs infertile men, in which ADA isoenzyme activities were measured; the low-activity GA genotype had reduced ADA1 activity. Reason: The human ADA1 G22A genotype study measures serum ADA1 activity and reports lower activity for the GA genotype. This supports the established catalytic function, while its infertility association does not establish a separate reproductive mechanism. Supporting Evidence: PMID:26166670 the ADA1 activity with GG genotype was higher than GA carriers in all population |
| GO:0046936 2'-deoxyadenosine deaminase activity | IMP PMID:9361033 An adenosine deaminase (ADA) allele contains two newly ident... | ACCEPT | Summary: Human ADA has the deoxyadenosine deaminase substrate activity; the cited variant abstract provides indirect support. Reason: The human Y97C/L106V study measures reduced or abolished expressed ADA activity and describes the deoxyadenosine/dATP toxicity mechanism. Its abstract does not resolve a separate deoxyadenosine-specific assay, so retain the curator assertion with that limitation. The exact substrate reaction is independently documented in the human UniProt catalytic-activity record. Supporting Evidence: file:human/ADA/ADA-uniprot.txt Reaction=2'-deoxyadenosine + H2O + H(+) = 2'-deoxyinosine + NH4(+) |
| GO:0019239 deaminase activity | EXP PMID:2166947 Hot spot mutations in adenosine deaminase deficiency. | MODIFY | Summary: Experimental annotation to the general parent 'deaminase activity' from characterization of hot-spot ADASCID mutations (e.g. Arg76Trp) that alter mutant ADA enzyme activity. The specific activity is adenosine deaminase activity. Reason: The paper explicitly identifies the human mutant enzyme as adenosine aminohydrolase, EC 3.5.4.4, and correlates ADA variants with distinct enzyme phenotypes. The gene and native reaction resolve the broad deaminase assertion to adenosine deaminase activity. The abstract does not expose every substrate-assay condition; the normal human reaction is independently documented in UniProt. Proposed replacements: adenosine deaminase activity Supporting Evidence: PMID:2166947 We have previously characterized mutant adenosine deaminase (ADA; adenosine file:human/ADA/ADA-uniprot.txt Catalyzes the hydrolytic deamination of adenosine and 2- |
| GO:0019239 deaminase activity | EXP PMID:2783588 Identification of a point mutation resulting in a heat-labil... | MODIFY | Summary: Experimental annotation to the general parent 'deaminase activity' from identification of the Pro297Gln mutation causing a heat-labile ADA in partial ADA deficiency. The specific activity is adenosine deaminase activity. Reason: The source identifies human P297Q ADA in partial deficiency and demonstrates expression of heat-labile ADA after mutant-cDNA transfection. This is the native adenosine-deaminating enzyme, corroborated by the human catalytic record, so the broad MF can be refined to GO:0004000. This refinement does not assert that the abstract reports a purified-protein substrate panel. Proposed replacements: adenosine deaminase activity Supporting Evidence: PMID:2783588 Transfection of the mutant cDNA into heterologous cells resulted in expression file:human/ADA/ADA-uniprot.txt Catalyzes the hydrolytic deamination of adenosine and 2- |
| GO:0019239 deaminase activity | EXP PMID:3182793 Mutant human adenosine deaminase alleles and their expressio... | MODIFY | Summary: Experimental annotation to the general parent 'deaminase activity'. Mutant ADA alleles (e.g. Arg101Trp, Arg211His, Ala329Val) expressed by transfection failed to produce functional enzyme, demonstrating loss of adenosine deaminase activity. Reason: The paper tests normal and mutant human ADA coding sequences in human fibroblasts and reports substantially greater ADA enzymatic activity for the normal sequence. Combined with the established native adenosine-to-inosine reaction, this supports the substrate-specific MF refinement. It differs from the separate drug-reaction annotation, whose substrate is ribavirin. Proposed replacements: adenosine deaminase activity Supporting Evidence: PMID:3182793 ADA-coding sequences had ADA enzymatic levels 40 times higher than cells file:human/ADA/ADA-uniprot.txt Catalyzes the hydrolytic deamination of adenosine and 2- |
| GO:0019239 deaminase activity | TAS Reactome:R-HSA-9754964 | KEEP AS NON CORE | Summary: Reactome assigns generic deaminase activity to ribavirin deamidation. Reason: R-HSA-9754964 models conversion of ribavirin to its inactive carboxy-acid metabolite in the cytosol. That substrate-specific reaction differs from adenosine-to-inosine chemistry, so GO:0004000 would change the assertion. Retain the generic deaminase term for this drug-metabolism context. The recovered Reactome summary explicitly assigns this reaction to ADA; the cytosolic participant context was inspected independently on the primary page. Supporting Evidence: Reactome:R-HSA-9754964 Ribavirin (RBV) undergoes hydrolytic deamination to its carboxylic acid derivative (RBV-COOH, ICN3297), which does not possess any antiviral activity. The reaction is catalyzed by adenosine deaminase (ADA). |
| GO:0014074 response to purine-containing compound | IDA PMID:25644539 Adenosine derived from ecto-nucleotidases in calcific aortic... | UNDECIDED | Summary: The ADA-specific response-to-purine assertion requires full experimental context. Reason: The cached abstract describes NPP1/CD73, A2a receptor signaling and mineralization in valve interstitial cells, but does not expose the ADA experiment or distinguish a responding gene product from use of ADA to remove extracellular adenosine. Full text was not accessible. This is an unresolved role question, not evidence of an incorrect gene assignment. |
| GO:0046085 adenosine metabolic process | IDA PMID:25644539 Adenosine derived from ecto-nucleotidases in calcific aortic... | ACCEPT | Summary: Adenosine metabolism is a supported core process for ADA. Reason: ADA directly hydrolyzes adenosine and therefore participates in this broad metabolic process. Retain the existing curator assertion, independently corroborated by human ADA catalytic evidence. The valve-study abstract does not disclose its ADA-specific assay, so do not infer its preparation, intervention or flux measurement. Supporting Evidence: file:human/ADA/ADA-uniprot.txt Catalyzes the hydrolytic deamination of adenosine and 2- |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9734745 | ACCEPT | Summary: The disease reaction retains the cytosolic compartment of normal ADA. Reason: The inspected Reactome event explicitly models failure of deamination by mutant ADA in the cytosol. This is a compartment assertion; mutant loss of activity is not evidence that the normal enzyme lacks its function. Independent normal-reaction and human localization records corroborate cytosolic ADA. Supporting Evidence: PMID:11772392 an enzyme mainly localized in the cytosol but also found on the cell surface of monocytes |
| GO:0005829 cytosol | TAS Reactome:R-HSA-74241 | ACCEPT | Summary: Reactome TAS cytosolic localization (ADA catalyzes the deamination of (deoxy)adenosine). Consistent with the core cytosolic site of ADA activity. Reason: Correct primary localization, redundant with the other cytosol annotations. Supporting Evidence: PMID:11772392 an enzyme mainly localized in the cytosol but also found on the cell surface of monocytes |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9754964 | ACCEPT | Summary: The ribavirin deamidation event is assigned to cytosolic ADA. Reason: The inspected primary Reactome page places the ADA-catalyzed ribavirin reaction in the cytosol. This agrees with the established intracellular enzyme location; the drug substrate does not change the compartment judgment. Supporting Evidence: PMID:11772392 an enzyme mainly localized in the cytosol but also found on the cell surface of monocytes |
| GO:0004000 adenosine deaminase activity | IDA PMID:8894685 Full genetic rescue of adenosine deaminase-deficient mice th... | ACCEPT | Summary: Human ADA transgenic rescue demonstrates functional complementation in an ADA-deficient mouse host. Reason: Introduction of the human ADA locus rescues ADA-deficient mice. This is genuine functional evidence for the human gene in a mouse host, corroborating its established catalytic function; it is not described here as an isolated purified-enzyme kinetic assay. Supporting Evidence: PMID:8894685 human ADA can complement murine ADA in |
| GO:0006154 adenosine catabolic process | IDA PMID:8894685 Full genetic rescue of adenosine deaminase-deficient mice th... | ACCEPT | Summary: IDA annotation that ADA acts upstream of or within adenosine catabolism, from mouse genetic rescue showing the lethal ADA-deficient phenotype is corrected by restoring ADA function. Reason: Human ADA transgenic rescue restores viability and normal phenotypes in ADA-deficient mice. Together with the established human substrate reaction, this supports participation in adenosine catabolism; the host species does not make the human-gene evidence a misattribution. Supporting Evidence: PMID:8894685 lethal phenotype of ADA-deficient mice is due to the absence |
| GO:0046103 inosine biosynthetic process | IDA PMID:8894685 Full genetic rescue of adenosine deaminase-deficient mice th... | ACCEPT | Summary: The human ADA reaction produces inosine; the cited transgenic-rescue study supports gene function in vivo. Reason: Human ADA produces inosine by its defined catalytic reaction. The cited study provides human-gene rescue in deficient mice rather than a product-specific flux measurement in its abstract. Retain the curator assertion, corroborated independently by the human catalytic record. Supporting Evidence: PMID:8894685 restoration of viability through introduction of the |
| GO:0004000 adenosine deaminase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity (ISS from mouse P03958) transfer of the core adenosine deaminase activity. Redundant with the directly demonstrated human activity. Reason: Correct core molecular function, well supported by experimental data for the human enzyme. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P03958 SUPPORTS TRANSFER Mouse Ada ortholog source (UniProtKB:P03958; Ensembl ENSMUSP00000017841). Human catalytic/cofactor/localization evidence independently supports this annotation; the exact historical donor assay is not re-created from the target record. Supporting Evidence: file:human/ADA/ADA-uniprot.txt Catalyzes the hydrolytic deamination of adenosine and 2- |
| GO:0006154 adenosine catabolic process | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity (ISS) transfer of the core adenosine catabolic process. Redundant with experimentally supported annotations. Reason: Correct core biological process. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P03958 SUPPORTS TRANSFER Mouse Ada ortholog source (UniProtKB:P03958; Ensembl ENSMUSP00000017841). Human catalytic/cofactor/localization evidence independently supports this annotation; the exact historical donor assay is not re-created from the target record. Supporting Evidence: file:human/ADA/ADA-uniprot.txt Plays an important role in purine |
| GO:0008270 zinc ion binding | ISS GO_REF:0000024 | ACCEPT | Summary: ADA binds catalytic zinc; disease-variant activity and the human cofactor record support this function. Reason: The reviewed human UniProt record identifies one zinc ion per subunit. In the human H15D disease-variant study, loss of enzyme activity is interpreted using the zinc-coordinating site in a structural model based on murine ADA. This supports catalytic metal dependence; it is not a direct measurement of mutant zinc occupancy. The mouse P03958 ortholog supplies the transferred annotation, independently corroborated by the human cofactor record. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P03958 SUPPORTS TRANSFER Mouse Ada ortholog source (UniProtKB:P03958; Ensembl ENSMUSP00000017841). Human catalytic/cofactor/localization evidence independently supports this annotation; the exact historical donor assay is not re-created from the target record. Supporting Evidence: file:human/ADA/ADA-uniprot.txt Binds 1 zinc ion per subunit PMID:7599635 the first naturally occurring mutation of a residue that coordinates |
| GO:0046103 inosine biosynthetic process | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity (ISS) transfer of inosine biosynthetic process; inosine is the direct product of ADA-catalyzed adenosine deamination. Reason: Valid process downstream of the core catalytic reaction. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P03958 SUPPORTS TRANSFER Mouse Ada ortholog source (UniProtKB:P03958; Ensembl ENSMUSP00000017841). Human catalytic/cofactor/localization evidence independently supports this annotation; the exact historical donor assay is not re-created from the target record. Supporting Evidence: PMID:8452534 the conversion of [3H]adenosine into [3H]inosine was proportional to incubation time |
| GO:0005515 protein binding | IPI PMID:8101391 Direct association of adenosine deaminase with a T cell acti... | REMOVE | Summary: Generic protein binding records the direct extracellular CD26-ADA association. Reason: The direct extracellular CD26-ADA association supports an interaction, but protein binding does not identify a useful molecular function. Remove the generic MF under project policy without denying the interaction. The established localization and context-dependent T-cell or adhesion processes retain the biological information; no untested adaptor or receptor MF is substituted. Supporting Evidence: PMID:8101391 an in vitro binding assay showed that the binding was through the extracellular domain of CD26 |
| GO:0004000 adenosine deaminase activity | IDA PMID:11999881 Anti-adenosine deaminase antibodies in lupus erythematosus. | ACCEPT | Summary: Retain the established adenosine deaminase function with source-level caution. Reason: The lupus study abstract describes anti-ADA antibodies, a commercial ADA preparation and cellular reactivity, without exposing a substrate-turnover assay or the preparation species. It supports ADA1 identity and surface recognition, while the exact IDA assay remains unread. The human catalytic function is independently established, so retain it with curator deference rather than inventing a new assay claim. Supporting Evidence: PMID:11999881 corresponding to ADA1, the major component file:human/ADA/ADA-uniprot.txt Catalyzes the hydrolytic deamination of adenosine and 2- |
| GO:0016020 membrane | IDA PMID:11999881 Anti-adenosine deaminase antibodies in lupus erythematosus. | MODIFY | Summary: IDA annotation to the very general term 'membrane', from immunofluorescence showing anti-ADA antibodies stain the cell surface of HEp-2 cells and lymphocytes. The staining reflects the ecto-ADA (cell-surface) pool. Reason: The lupus study reports antibody recognition at the surface of viable cells, supporting cell surface as the more informative location. The fixed-cell nuclear pattern is a separate observation and is not used to infer intracellular access in live cells. Proposed replacements: cell surface Supporting Evidence: PMID:11999881 surface of HEp-2 cells and lymphocytes, indicating surface expression of ADA |
| GO:0001666 response to hypoxia | IDA PMID:16670267 Endothelial catabolism of extracellular adenosine during hyp... | KEEP AS NON CORE | Summary: IDA annotation that ADA participates in the hypoxia response; endothelial ADA (and its partner CD26) are induced by hypoxia at mRNA and protein levels, localizing ADA activity to the cell surface to clear elevated extracellular adenosine. Reason: The study reports induction of ADA and CD26 and increased surface ADA activity in human endothelial hypoxia, with separate mouse vascular experiments. Retain this hypoxia-responsive physiological context as non-core rather than presenting ADA as a hypoxia sensor. Supporting Evidence: PMID:16670267 hypoxia induces endothelial ADA and CD26 |
| GO:0004000 adenosine deaminase activity | IDA PMID:16670267 Endothelial catabolism of extracellular adenosine during hyp... | ACCEPT | Summary: IDA annotation of adenosine deaminase activity; the study confirmed induction of enzymatically active ADA in hypoxic endothelium, degrading extracellular adenosine to inosine. Reason: Human endothelial experiments in the accessible abstract and discussion report catalytically active surface ADA tethered through CD26. This directly supports adenosine hydrolysis; the cached extraction omits Methods and Results, so no additional assay details are inferred. Supporting Evidence: PMID:16670267 increasing the endothelial capacity to metabolize adenosine to inosine |
| GO:0004000 adenosine deaminase activity | IDA PMID:8452534 Demonstration of adenosine deaminase activity in human fibro... | ACCEPT | Summary: IDA annotation of adenosine deaminase activity, from direct assay of ADA activity (adenosine to inosine, Km 37 uM) in purified human fibroblast lysosomes. Reason: Direct biochemical demonstration of the core adenosine deaminase activity of the human enzyme. Supporting Evidence: PMID:8452534 the conversion of [3H]adenosine into [3H]inosine was proportional to incubation time |
| GO:0004000 adenosine deaminase activity | IDA PMID:9361033 An adenosine deaminase (ADA) allele contains two newly ident... | ACCEPT | Summary: IDA annotation of adenosine deaminase activity from expression of wild-type and mutant ADA cDNAs; the Y97C mutant retained only detectable but markedly reduced activity, and wild-type ADA showed normal activity. Reason: Directly measured expressed ADA activity supports the core adenosine deaminase function. Supporting Evidence: PMID:9361033 detectable but markedly reduced activity |
| GO:0005515 protein binding | IPI PMID:14684150 3D structure of the CD26-ADA complex obtained by cryo-EM and... | REMOVE | Summary: Generic protein binding records the cryo-EM CD26-ADA complex. Reason: The cryo-EM CD26-ADA complex supports an interaction, but protein binding does not identify a useful molecular function. Remove the generic MF under project policy without denying the interaction. The established localization and context-dependent T-cell or adhesion processes retain the biological information; no untested adaptor or receptor MF is substituted. Supporting Evidence: PMID:14684150 ADA binding occurs at the outer edges of the |
| GO:0005515 protein binding | IPI PMID:7594462 Expression of ecto-adenosine deaminase and CD26 in human T c... | REMOVE | Summary: Generic protein binding records the ADA-CD26 association in activated human T cells. Reason: The ADA-CD26 association in activated human T cells supports an interaction, but protein binding does not identify a useful molecular function. Remove the generic MF under project policy without denying the interaction. The established localization and context-dependent T-cell or adhesion processes retain the biological information; no untested adaptor or receptor MF is substituted. Supporting Evidence: PMID:7594462 addition of ADA produced an enzyme-independent synergism |
| GO:0005764 lysosome | IDA PMID:8452534 Demonstration of adenosine deaminase activity in human fibro... | KEEP AS NON CORE | Summary: IDA localization to the lysosome, from direct demonstration of ADA activity in Percoll-purified human fibroblast lysosomes (~10% of total cellular ADA activity). Reason: The study reports ADA activity in Percoll-purified human fibroblast lysosomes, accounting for approximately 10% of total ADA activity in that experimental system. This is a supported secondary compartment; the percentage is not generalized to other cell types or all human tissues. Supporting Evidence: PMID:8452534 adenosine deaminase (ADA) activity that accounts for approximately 10% of the total ADA activity |
| GO:0006154 adenosine catabolic process | IDA PMID:16670267 Endothelial catabolism of extracellular adenosine during hyp... | ACCEPT | Summary: IDA annotation of adenosine catabolic process; hypoxia-induced endothelial ADA (with CD26) increases the capacity to catabolize extracellular adenosine to inosine. Reason: Direct demonstration of ADA's core biological process (adenosine catabolism) in a physiological setting. Supporting Evidence: PMID:16670267 increasing the endothelial capacity to metabolize adenosine to inosine |
| GO:0009897 external side of plasma membrane | IDA PMID:16670267 Endothelial catabolism of extracellular adenosine during hyp... | ACCEPT | Summary: The endothelial study demonstrates catalytically active ADA on the external membrane surface. Reason: Human endothelial surface ADA is catalytically active and tethered extracellularly through CD26 in the hypoxia study. This compartment supports the same adenosine-catabolic chemistry as intracellular ADA, so it is a core enzyme location. The mouse vascular experiments are separate physiological evidence. Supporting Evidence: PMID:16670267 ADA localizes to the endothelial surface and limits the accumulation of extracellular adenosine during hypoxia |
| GO:0009897 external side of plasma membrane | IDA PMID:7759315 Surface adenosine deaminase. A novel B-cell marker in chroni... | ACCEPT | Summary: Flow cytometry detects ADA on the surface of human blood and leukemia cells. Reason: Flow cytometry detects surface ADA on human mononuclear and leukemia cells. This independently supports the ecto-ADA location; expression differences among leukemia populations do not establish a separate catalytic function. Supporting Evidence: PMID:7759315 surface ADA might be considered a novel marker for CLL |
| GO:0009986 cell surface | IDA PMID:11772392 Regulation of epithelial and lymphocyte cell adhesion by ade... | ACCEPT | Summary: The adhesion study locates ADA on the human cell surface. Reason: The human Jurkat/CEM and Caco-2 adhesion study explicitly locates ADA at the cell surface and tests the ADA-CD26 association. Retain that measured cellular location without extending it to a particular anchoring-junction structure. Supporting Evidence: PMID:11772392 an enzyme mainly localized in the cytosol but also found on the cell surface of monocytes |
| GO:0009986 cell surface | IDA PMID:7594462 Expression of ecto-adenosine deaminase and CD26 in human T c... | ACCEPT | Summary: Activated human T cells display ADA associated with surface CD26. Reason: Flow cytometry and microscopy identify ADA on the surface of activated human T cells, associated with CD26. The location is shared by the ecto-enzyme and its context-dependent costimulatory role. Supporting Evidence: PMID:7594462 colocalized on the surface of T cells |
| GO:0032261 purine nucleotide salvage | IMP PMID:9361033 An adenosine deaminase (ADA) allele contains two newly ident... | ACCEPT | Summary: ADA performs a catalytic step in purine nucleotide salvage. Reason: The mutation study identifies ADA as a purine salvage enzyme and measures mutant loss of activity. ADA supplies inosine for subsequent purine recycling; pathway involvement does not require direct nucleotide phosphorylation. This broad process is also supported by human Reactome salvage and the mouse pathway models. Supporting Evidence: PMID:9361033 the purine salvage enzyme adenosine deaminase |
| GO:0033632 regulation of cell-cell adhesion mediated by integrin | IDA PMID:11772392 Regulation of epithelial and lymphocyte cell adhesion by ade... | KEEP AS NON CORE | Summary: IDA annotation from experiments showing the ADA-CD26 interaction regulates lymphocyte-epithelial cell adhesion, with exogenous ADA increasing expression of activated integrins on T-cell lines (integrin activation assays). Reason: A genuine extra-enzymatic (moonlighting) role of ecto-ADA via CD26 in modulating integrin-mediated cell adhesion; secondary to the core catabolic function. Supporting Evidence: PMID:11772392 FACS analysis revealed a higher expression of activated |
| GO:0042110 T cell activation | IDA PMID:7594462 Expression of ecto-adenosine deaminase and CD26 in human T c... | KEEP AS NON CORE | Summary: IDA annotation that ADA acts in T cell activation; exogenous ADA binding to CD26 produces a costimulatory (enzyme-independent) synergism in the TCR-CD3 activation response. Reason: A genuine moonlighting immunological role of ecto-ADA via CD26, distinct from and secondary to the core cytosolic catalytic function. Supporting Evidence: PMID:7594462 binding to CD26 produces a costimulatory response in T cell activation events |
| GO:0060169 negative regulation of adenosine receptor signaling pathway | IDA PMID:16670267 Endothelial catabolism of extracellular adenosine during hyp... | KEEP AS NON CORE | Summary: IDA annotation that ADA negatively regulates adenosine-receptor signaling by clearing extracellular adenosine (the receptor agonist), limiting adenosine accumulation and downstream signaling in hypoxic endothelium. Reason: In the endothelial hypoxia context, ADA removes extracellular adenosine and limits receptor stimulation by reducing agonist availability. Retain this context-dependent negative regulation. This is not an assertion that ADA directly inhibits every adenosine receptor or that every ADA-receptor interaction has this sign. Supporting Evidence: PMID:16670267 ADA localizes to the endothelial surface and limits the accumulation of extracellular adenosine during hypoxia |
| GO:0004000 adenosine deaminase activity | IDA PMID:3182793 Mutant human adenosine deaminase alleles and their expressio... | ACCEPT | Summary: IDA annotation of adenosine deaminase activity; wild-type ADA cDNA expressed by transfection produced ADA enzymatic levels ~40-fold higher than mutant sequences, confirming the enzyme's catalytic activity. Reason: Directly measured expressed ADA enzyme activity supports the core adenosine deaminase function; mutant alleles failed to encode functional enzyme. Supporting Evidence: PMID:3182793 they do not encode a |
| GO:0008270 zinc ion binding | IMP PMID:7599635 Four new adenosine deaminase mutations, altering a zinc-bind... | ACCEPT | Summary: ADA binds catalytic zinc; disease-variant activity and the human cofactor record support this function. Reason: The reviewed human UniProt record identifies one zinc ion per subunit. In the human H15D disease-variant study, loss of enzyme activity is interpreted using the zinc-coordinating site in a structural model based on murine ADA. This supports catalytic metal dependence; it is not a direct measurement of mutant zinc occupancy. Retain the experimental assertion at this bounded source scope. Supporting Evidence: file:human/ADA/ADA-uniprot.txt Binds 1 zinc ion per subunit PMID:7599635 the first naturally occurring mutation of a residue that coordinates |
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Download this section (compressed HTML)Q: What donor experiment supports the mouse Ada cytoplasmic-vesicle-lumen annotation, and does the human ADA-CD26 adhesion study resolve a defined anchoring-junction compartment?
Q: How is cytosolic ADA delivered to the extracellular surface, and how do catalytic clearance and CD26-dependent costimulation contribute in different human cell types?
Q: Does the valve-mineralization study demonstrate ADA participating in a cellular response to purines, or use added ADA as a reagent to remove extracellular adenosine?
Experiment: Catalytically-dead (e.g. zinc-site) ADA knock-in versus wild-type rescue in ADA-deficient lymphocytes to dissect enzyme-dependent versus CD26-binding (moonlighting) contributions to T-cell activation and adhesion.
Experiment: Quantitative subcellular fractionation plus surface biotinylation across cell types to measure the relative sizes of the cytosolic, lysosomal, and ecto-ADA pools and their dependence on CD26 expression.
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