IP6K3 encodes inositol hexakisphosphate kinase 3, a tissue-enriched member of the inositol phosphokinase family that phosphorylates soluble inositol polyphosphates. Its core activity converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/5-PP-InsP5) and can also phosphorylate InsP5/inositol pyrophosphate substrates, contributing to inositol pyrophosphate signaling. The experimentally supported localization is predominantly cytoplasmic (with detectable nuclear pool by GFP fusion in HEK293/C2C12). In addition to its catalytic role, IP6K3 has a noncatalytic scaffolding function in cerebellar Purkinje cells where it binds spectrin and adducin and is required for normal Purkinje dendritic architecture and synaptogenesis; in non-neural tissues (skeletal muscle, heart, thyroid) IP6K3 contributes to systemic metabolic regulation. Annotations implying protein phosphorylation or phosphatidylinositol-lipid metabolism should be interpreted as misapplied to a soluble inositol phosphate kinase.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Nuclear localization is not the main experimentally supported localization for human IP6K3; the original characterization describes IP6K3 as predominantly cytoplasmic. The falcon deep research summary explicitly states IP6K3 predominates in the cytoplasm, though a GFP-IP6K3 fusion can show a detectable nuclear pool in HEK293/C2C12 cells, suggesting partial nuclear accessibility rather than a primary nuclear role. Reason: Per PR #848 review feedback: a detectable nuclear pool is experimentally supported (PMID:27577108, AcGFP-IP6K3 in both cytoplasm and nucleus in C2C12 cells). The predominant/core localization remains cytoplasm/cytosol, so nucleus is retained as a valid non-core localization (changed from MARK_AS_OVER_ANNOTATED). Supporting Evidence: PMID:11502751 Intracellular disposition discriminates the three enzymes with InsP(6)K2 being exclusively nuclear, InsP(6)K3 predominating in the cytoplasm, and InsP(6)K1 displaying comparable nuclear and cytosolic densities. file:human/IP6K3/IP6K3-deep-research-manual.md PMID:11502751 reports that InsP(6)K3 is enriched in brain and predominates in the cytoplasm, whereas InsP(6)K2 is exclusively nuclear and InsP(6)K1 has comparable nuclear and cytosolic densities. file:human/IP6K3/IP6K3-deep-research-falcon.md A GFP-tagged IP6K3 fusion protein localized to **both cytoplasm and nucleus** in HEK293 cells, consistent with the idea that IP6K3-derived inositol pyrophosphates can affect both cytosolic and nuclear signaling processes. PMID:27577108 Furthermore, when an AcGFP-human IP6K3 fusion protein construct was transfected into mouse C2C12 cells, the resultant AcGFP-IP6K3 was localized to both the cytoplasm and the nucleus (Fig. S3). |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: cytoplasm localization is supported by the original characterization, which reported IP6K3 as predominantly cytoplasmic. Reason: Cytoplasmic/cytosolic localization is the experimentally supported cellular component for human IP6K3. Supporting Evidence: PMID:11502751 Intracellular disposition discriminates the three enzymes with InsP(6)K2 being exclusively nuclear, InsP(6)K3 predominating in the cytoplasm, and InsP(6)K1 displaying comparable nuclear and cytosolic densities. file:human/IP6K3/IP6K3-deep-research-falcon.md A GFP-tagged IP6K3 fusion protein localized to **both cytoplasm and nucleus** in HEK293 cells, consistent with the idea that IP6K3-derived inositol pyrophosphates can affect both cytosolic and nuclear signaling processes. |
| GO:0046854 phosphatidylinositol phosphate biosynthetic process | IBA GO_REF:0000033 | MODIFY | Summary: phosphatidylinositol phosphate biosynthetic process describes phosphatidylinositol lipid metabolism, but the evidence for IP6K3 is soluble inositol phosphate/pyrophosphate metabolism. Reason: IP6K3 is not primarily a phosphatidylinositol lipid kinase. The supported biological process is soluble inositol phosphate biosynthesis/metabolism. Proposed replacements: inositol phosphate biosynthetic process Supporting Evidence: PMID:11502751 We now report the identification, cloning, and characterization of a third InsP(7) forming enzyme designated InsP(6)K3. |
| GO:0000828 inositol hexakisphosphate kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: inositol hexakisphosphate kinase activity fits the characterized IP6K3 catalytic activity toward soluble inositol polyphosphate and inositol pyrophosphate substrates. Reason: This is the specific molecular-function space for IP6K3. The PMID:11502751 characterization and UniProt catalytic activities support conversion of InsP6 to PP-InsP5/InsP7 and related inositol polyphosphate kinase reactions. Supporting Evidence: file:human/IP6K3/IP6K3-uniprot.txt Converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5). Converts 1,3,4,5,6-pentakisphosphate (InsP5) to PP-InsP4. file:human/IP6K3/IP6K3-deep-research-manual.md UniProt describes the curated function as conversion of InsP6 to InsP7/PP-InsP5, and conversion of InsP5 to PP-InsP4. file:human/IP6K3/IP6K3-deep-research-falcon.md Across IP6Ks (including IP6K3), the best-supported catalytic reaction is: **IP6 β 5-IP7 (5-InsP7 / 5-diphosphoinositol pentakisphosphate)**, and further phosphorylation such as **1-IP7 β InsP8**. |
| GO:0032958 inositol phosphate biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: inositol phosphate biosynthetic process is supported because IP6K3 biosynthesizes/metabolizes soluble inositol pyrophosphates from inositol phosphate substrates. Reason: This biological-process term matches the characterized IP6K3 reaction products and Reactome inositol phosphate pathway context. Supporting Evidence: file:human/IP6K3/IP6K3-uniprot.txt Converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5). file:human/IP6K3/IP6K3-deep-research-falcon.md A primary study describing IP6K (family) substrate scope notes that the **5-kinase activity** can act on multiple highly phosphorylated inositols, including: **InsP5 β 5-PP-InsP4**, **InsP6 β 5-PP-InsP5 (5-InsP7)**, **1-PP-InsP5 β InsP8**. |
| GO:0000166 nucleotide binding | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: nucleotide binding is a broad parent term that does not convey IP6K3 substrate specificity. Reason: The annotation should be interpreted through the specific inositol hexakisphosphate/inositol pyrophosphate kinase activity terms. Broad kinase, transferase, and nucleotide-binding terms are over-general. Supporting Evidence: file:human/IP6K3/IP6K3-uniprot.txt The curated function identifies IP6K3 as an inositol hexakisphosphate kinase with specific inositol polyphosphate substrates. |
| GO:0000827 inositol-1,3,4,5,6-pentakisphosphate kinase activity | IEA GO_REF:0000117 | ACCEPT | Summary: inositol-1,3,4,5,6-pentakisphosphate kinase activity fits the characterized IP6K3 catalytic activity toward soluble inositol polyphosphate and inositol pyrophosphate substrates. Reason: This is the specific molecular-function space for IP6K3. The PMID:11502751 characterization and UniProt catalytic activities support conversion of InsP6 to PP-InsP5/InsP7 and related inositol polyphosphate kinase reactions. Supporting Evidence: file:human/IP6K3/IP6K3-uniprot.txt Converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5). Converts 1,3,4,5,6-pentakisphosphate (InsP5) to PP-InsP4. |
| GO:0000828 inositol hexakisphosphate kinase activity | IEA GO_REF:0000117 | ACCEPT | Summary: inositol hexakisphosphate kinase activity fits the characterized IP6K3 catalytic activity toward soluble inositol polyphosphate and inositol pyrophosphate substrates. Reason: This is the specific molecular-function space for IP6K3. The PMID:11502751 characterization and UniProt catalytic activities support conversion of InsP6 to PP-InsP5/InsP7 and related inositol polyphosphate kinase reactions. Supporting Evidence: file:human/IP6K3/IP6K3-uniprot.txt Converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5). Converts 1,3,4,5,6-pentakisphosphate (InsP5) to PP-InsP4. |
| GO:0000829 diphosphoinositol pentakisphosphate kinase activity | IEA GO_REF:0000117 | ACCEPT | Summary: diphosphoinositol pentakisphosphate kinase activity fits the characterized IP6K3 catalytic activity toward soluble inositol polyphosphate and inositol pyrophosphate substrates. Reason: This is the specific molecular-function space for IP6K3. The PMID:11502751 characterization and UniProt catalytic activities support conversion of InsP6 to PP-InsP5/InsP7 and related inositol polyphosphate kinase reactions. Supporting Evidence: file:human/IP6K3/IP6K3-uniprot.txt Converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5). Converts 1,3,4,5,6-pentakisphosphate (InsP5) to PP-InsP4. |
| GO:0000832 inositol hexakisphosphate 5-kinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: inositol hexakisphosphate 5-kinase activity fits the characterized IP6K3 catalytic activity toward soluble inositol polyphosphate and inositol pyrophosphate substrates. Reason: This is the specific molecular-function space for IP6K3. The PMID:11502751 characterization and UniProt catalytic activities support conversion of InsP6 to PP-InsP5/InsP7 and related inositol polyphosphate kinase reactions. Supporting Evidence: file:human/IP6K3/IP6K3-uniprot.txt Converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5). Converts 1,3,4,5,6-pentakisphosphate (InsP5) to PP-InsP4. |
| GO:0005524 ATP binding | IEA GO_REF:0000043 | ACCEPT | Summary: ATP binding is required because IP6K3 uses ATP as the phosphate donor for inositol polyphosphate kinase reactions. Reason: ATP binding is mechanistically relevant, though less specific than the inositol phosphate kinase activity terms. Supporting Evidence: file:human/IP6K3/IP6K3-uniprot.txt Catalytic reactions list ATP as substrate and ADP as product for IP6K3 reactions. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: cytoplasm localization is supported by the original characterization, which reported IP6K3 as predominantly cytoplasmic. Reason: Cytoplasmic/cytosolic localization is the experimentally supported cellular component for human IP6K3. Supporting Evidence: PMID:11502751 Intracellular disposition discriminates the three enzymes with InsP(6)K2 being exclusively nuclear, InsP(6)K3 predominating in the cytoplasm, and InsP(6)K1 displaying comparable nuclear and cytosolic densities. |
| GO:0016301 kinase activity | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: kinase activity is a broad parent term that does not convey IP6K3 substrate specificity. Reason: The annotation should be interpreted through the specific inositol hexakisphosphate/inositol pyrophosphate kinase activity terms. Broad kinase, transferase, and nucleotide-binding terms are over-general. Supporting Evidence: file:human/IP6K3/IP6K3-uniprot.txt The curated function identifies IP6K3 as an inositol hexakisphosphate kinase with specific inositol polyphosphate substrates. |
| GO:0016740 transferase activity | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: transferase activity is a broad parent term that does not convey IP6K3 substrate specificity. Reason: The annotation should be interpreted through the specific inositol hexakisphosphate/inositol pyrophosphate kinase activity terms. Broad kinase, transferase, and nucleotide-binding terms are over-general. Supporting Evidence: file:human/IP6K3/IP6K3-uniprot.txt The curated function identifies IP6K3 as an inositol hexakisphosphate kinase with specific inositol polyphosphate substrates. |
| GO:0032958 inositol phosphate biosynthetic process | IEA GO_REF:0000002 | ACCEPT | Summary: inositol phosphate biosynthetic process is supported because IP6K3 biosynthesizes/metabolizes soluble inositol pyrophosphates from inositol phosphate substrates. Reason: This biological-process term matches the characterized IP6K3 reaction products and Reactome inositol phosphate pathway context. Supporting Evidence: file:human/IP6K3/IP6K3-uniprot.txt Converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5). |
| GO:0043647 inositol phosphate metabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: inositol phosphate metabolic process is supported because IP6K3 biosynthesizes/metabolizes soluble inositol pyrophosphates from inositol phosphate substrates. Reason: This biological-process term matches the characterized IP6K3 reaction products and Reactome inositol phosphate pathway context. Supporting Evidence: file:human/IP6K3/IP6K3-uniprot.txt Converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5). |
| GO:0046488 phosphatidylinositol metabolic process | IEA GO_REF:0000117 | MODIFY | Summary: phosphatidylinositol metabolic process describes phosphatidylinositol lipid metabolism, but the evidence for IP6K3 is soluble inositol phosphate/pyrophosphate metabolism. Reason: IP6K3 is not primarily a phosphatidylinositol lipid kinase. The supported biological process is soluble inositol phosphate biosynthesis/metabolism. Proposed replacements: inositol phosphate biosynthetic process Supporting Evidence: PMID:11502751 We now report the identification, cloning, and characterization of a third InsP(7) forming enzyme designated InsP(6)K3. file:human/IP6K3/IP6K3-deep-research-manual.md The available reviewed function text and the PMID:11502751 abstract support inositol phosphate kinase activity rather than direct phosphorylation of protein substrates. |
| GO:0052836 inositol 5-diphosphate pentakisphosphate 5-kinase activity | IEA GO_REF:0000117 | ACCEPT | Summary: inositol 5-diphosphate pentakisphosphate 5-kinase activity fits the characterized IP6K3 catalytic activity toward soluble inositol polyphosphate and inositol pyrophosphate substrates. Reason: This is the specific molecular-function space for IP6K3. The PMID:11502751 characterization and UniProt catalytic activities support conversion of InsP6 to PP-InsP5/InsP7 and related inositol polyphosphate kinase reactions. Supporting Evidence: file:human/IP6K3/IP6K3-uniprot.txt Converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5). Converts 1,3,4,5,6-pentakisphosphate (InsP5) to PP-InsP4. |
| GO:0052839 diphosphoinositol tetrakisphosphate kinase activity | IEA GO_REF:0000117 | ACCEPT | Summary: diphosphoinositol tetrakisphosphate kinase activity fits the characterized IP6K3 catalytic activity toward soluble inositol polyphosphate and inositol pyrophosphate substrates. Reason: This is the specific molecular-function space for IP6K3. The PMID:11502751 characterization and UniProt catalytic activities support conversion of InsP6 to PP-InsP5/InsP7 and related inositol polyphosphate kinase reactions. Supporting Evidence: file:human/IP6K3/IP6K3-uniprot.txt Converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5). Converts 1,3,4,5,6-pentakisphosphate (InsP5) to PP-InsP4. |
| GO:0090407 organophosphate biosynthetic process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Organophosphate biosynthetic process is too broad for IP6K3 when inositol phosphate biosynthetic process is already annotated. Reason: The more informative process is soluble inositol phosphate/pyrophosphate biosynthesis. This broad parent term obscures the pathway specificity. Supporting Evidence: file:human/IP6K3/IP6K3-uniprot.txt IP6K3 converts inositol hexakisphosphate to diphosphoinositol pentakisphosphate. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Generic protein binding from a high-throughput interactome screen does not describe IP6K3 catalytic function. Reason: GO:0005515 is uninformative here. The core annotation should focus on inositol phosphate kinase activity and inositol phosphate biosynthesis. Supporting Evidence: file:human/IP6K3/IP6K3-uniprot.txt The curated function describes conversion of inositol phosphate substrates, while listed interactions are high-throughput IntAct records. |
| GO:0005634 nucleus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Nuclear localization is not the main experimentally supported localization for human IP6K3; the original characterization describes IP6K3 as predominantly cytoplasmic. Reason: Per PR #848 review feedback: a detectable nuclear pool is experimentally supported (PMID:27577108, AcGFP-IP6K3 in both cytoplasm and nucleus in C2C12 cells). The predominant/core localization remains cytoplasm/cytosol, so nucleus is retained as a valid non-core localization (changed from MARK_AS_OVER_ANNOTATED). Supporting Evidence: PMID:11502751 Intracellular disposition discriminates the three enzymes with InsP(6)K2 being exclusively nuclear, InsP(6)K3 predominating in the cytoplasm, and InsP(6)K1 displaying comparable nuclear and cytosolic densities. |
| GO:0043647 inositol phosphate metabolic process | TAS Reactome:R-HSA-1855167 | ACCEPT | Summary: inositol phosphate metabolic process is supported because IP6K3 biosynthesizes/metabolizes soluble inositol pyrophosphates from inositol phosphate substrates. Reason: This biological-process term matches the characterized IP6K3 reaction products and Reactome inositol phosphate pathway context. Supporting Evidence: file:human/IP6K3/IP6K3-uniprot.txt Converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5). |
| GO:0000828 inositol hexakisphosphate kinase activity | TAS Reactome:R-HSA-1855227 | ACCEPT | Summary: inositol hexakisphosphate kinase activity fits the characterized IP6K3 catalytic activity toward soluble inositol polyphosphate and inositol pyrophosphate substrates. Reason: This is the specific molecular-function space for IP6K3. The PMID:11502751 characterization and UniProt catalytic activities support conversion of InsP6 to PP-InsP5/InsP7 and related inositol polyphosphate kinase reactions. Supporting Evidence: file:human/IP6K3/IP6K3-uniprot.txt Converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5). Converts 1,3,4,5,6-pentakisphosphate (InsP5) to PP-InsP4. |
| GO:0000829 diphosphoinositol pentakisphosphate kinase activity | TAS Reactome:R-HSA-1855194 | ACCEPT | Summary: diphosphoinositol pentakisphosphate kinase activity fits the characterized IP6K3 catalytic activity toward soluble inositol polyphosphate and inositol pyrophosphate substrates. Reason: This is the specific molecular-function space for IP6K3. The PMID:11502751 characterization and UniProt catalytic activities support conversion of InsP6 to PP-InsP5/InsP7 and related inositol polyphosphate kinase reactions. Supporting Evidence: file:human/IP6K3/IP6K3-uniprot.txt Converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5). Converts 1,3,4,5,6-pentakisphosphate (InsP5) to PP-InsP4. |
| GO:0052836 inositol 5-diphosphate pentakisphosphate 5-kinase activity | TAS Reactome:R-HSA-1855158 | ACCEPT | Summary: inositol 5-diphosphate pentakisphosphate 5-kinase activity fits the characterized IP6K3 catalytic activity toward soluble inositol polyphosphate and inositol pyrophosphate substrates. Reason: This is the specific molecular-function space for IP6K3. The PMID:11502751 characterization and UniProt catalytic activities support conversion of InsP6 to PP-InsP5/InsP7 and related inositol polyphosphate kinase reactions. Supporting Evidence: file:human/IP6K3/IP6K3-uniprot.txt Converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5). Converts 1,3,4,5,6-pentakisphosphate (InsP5) to PP-InsP4. |
| GO:0052839 diphosphoinositol tetrakisphosphate kinase activity | TAS Reactome:R-HSA-1855193 | ACCEPT | Summary: diphosphoinositol tetrakisphosphate kinase activity fits the characterized IP6K3 catalytic activity toward soluble inositol polyphosphate and inositol pyrophosphate substrates. Reason: This is the specific molecular-function space for IP6K3. The PMID:11502751 characterization and UniProt catalytic activities support conversion of InsP6 to PP-InsP5/InsP7 and related inositol polyphosphate kinase reactions. Supporting Evidence: file:human/IP6K3/IP6K3-uniprot.txt Converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5). Converts 1,3,4,5,6-pentakisphosphate (InsP5) to PP-InsP4. |
| GO:0000827 inositol-1,3,4,5,6-pentakisphosphate kinase activity | TAS Reactome:R-HSA-1855223 | ACCEPT | Summary: inositol-1,3,4,5,6-pentakisphosphate kinase activity fits the characterized IP6K3 catalytic activity toward soluble inositol polyphosphate and inositol pyrophosphate substrates. Reason: This is the specific molecular-function space for IP6K3. The PMID:11502751 characterization and UniProt catalytic activities support conversion of InsP6 to PP-InsP5/InsP7 and related inositol polyphosphate kinase reactions. Supporting Evidence: file:human/IP6K3/IP6K3-uniprot.txt Converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5). Converts 1,3,4,5,6-pentakisphosphate (InsP5) to PP-InsP4. |
| GO:0000828 inositol hexakisphosphate kinase activity | IDA PMID:11502751 Identification and characterization of a novel inositol hexa... | ACCEPT | Summary: inositol hexakisphosphate kinase activity fits the characterized IP6K3 catalytic activity toward soluble inositol polyphosphate and inositol pyrophosphate substrates. Reason: This is the specific molecular-function space for IP6K3. The PMID:11502751 characterization and UniProt catalytic activities support conversion of InsP6 to PP-InsP5/InsP7 and related inositol polyphosphate kinase reactions. Supporting Evidence: file:human/IP6K3/IP6K3-uniprot.txt Converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5). Converts 1,3,4,5,6-pentakisphosphate (InsP5) to PP-InsP4. file:human/IP6K3/IP6K3-deep-research-falcon.md IP6K3 (inositol hexakisphosphate kinase 3; EC 2.7.4.21)** is a human inositol phosphate kinase that catalyzes pyrophosphate formation on highly phosphorylated inositols, most prominently converting **InsP6 (IP6) to 5-InsP7 (5-IP7)** and participating in downstream generation of **InsP8**. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1855158 | ACCEPT | Summary: cytosol localization is supported by the original characterization, which reported IP6K3 as predominantly cytoplasmic. Reason: Cytoplasmic/cytosolic localization is the experimentally supported cellular component for human IP6K3. Supporting Evidence: PMID:11502751 Intracellular disposition discriminates the three enzymes with InsP(6)K2 being exclusively nuclear, InsP(6)K3 predominating in the cytoplasm, and InsP(6)K1 displaying comparable nuclear and cytosolic densities. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1855193 | ACCEPT | Summary: cytosol localization is supported by the original characterization, which reported IP6K3 as predominantly cytoplasmic. Reason: Cytoplasmic/cytosolic localization is the experimentally supported cellular component for human IP6K3. Supporting Evidence: PMID:11502751 Intracellular disposition discriminates the three enzymes with InsP(6)K2 being exclusively nuclear, InsP(6)K3 predominating in the cytoplasm, and InsP(6)K1 displaying comparable nuclear and cytosolic densities. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1855194 | ACCEPT | Summary: cytosol localization is supported by the original characterization, which reported IP6K3 as predominantly cytoplasmic. Reason: Cytoplasmic/cytosolic localization is the experimentally supported cellular component for human IP6K3. Supporting Evidence: PMID:11502751 Intracellular disposition discriminates the three enzymes with InsP(6)K2 being exclusively nuclear, InsP(6)K3 predominating in the cytoplasm, and InsP(6)K1 displaying comparable nuclear and cytosolic densities. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1855223 | ACCEPT | Summary: cytosol localization is supported by the original characterization, which reported IP6K3 as predominantly cytoplasmic. Reason: Cytoplasmic/cytosolic localization is the experimentally supported cellular component for human IP6K3. Supporting Evidence: PMID:11502751 Intracellular disposition discriminates the three enzymes with InsP(6)K2 being exclusively nuclear, InsP(6)K3 predominating in the cytoplasm, and InsP(6)K1 displaying comparable nuclear and cytosolic densities. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1855227 | ACCEPT | Summary: cytosol localization is supported by the original characterization, which reported IP6K3 as predominantly cytoplasmic. Reason: Cytoplasmic/cytosolic localization is the experimentally supported cellular component for human IP6K3. Supporting Evidence: PMID:11502751 Intracellular disposition discriminates the three enzymes with InsP(6)K2 being exclusively nuclear, InsP(6)K3 predominating in the cytoplasm, and InsP(6)K1 displaying comparable nuclear and cytosolic densities. |
| GO:0000831 inositol hexakisphosphate 6-kinase activity | IDA PMID:11502751 Identification and characterization of a novel inositol hexa... | MARK AS OVER ANNOTATED | Summary: Per PR #848 review feedback: the falcon deep research and Reactome both establish IP6K3's physiological activity as a 5-kinase (InsP6 β 5-PP-InsP5 / 5-InsP7), captured by the separately-ACCEPTed GO:0000832 (inositol hexakisphosphate 5-kinase activity). The 6-position assignment in this older IDA annotation (PMID:11502751, 2001) is not the established physiological positional specificity for IP6K3, so this annotation is downgraded ACCEPT β MARK_AS_OVER_ANNOTATED. Reason: IP6K3's experimentally and physiologically established activity is 5-kinase (5-PP-InsP5), not 6-kinase; all Reactome IP6K3 reactions and the falcon evidence describe 5-position pyrophosphorylation. The correct MF is GO:0000832 (5-kinase), already ACCEPTed. Supporting Evidence: file:human/IP6K3/IP6K3-deep-research-falcon.md Reported IP6K 5-kinase activity includes pyrophosphorylation of **InsP5 β 5-PP-InsP4**, **InsP6 β 5-PP-InsP5 (5-InsP7)**, and **1-PP-InsP5 β InsP8**; thus IP6K3 shares family substrate scope for highly phosphorylated inositols, with best-established physiological product **5-InsP7**. |
| GO:0032958 inositol phosphate biosynthetic process | IDA PMID:11502751 Identification and characterization of a novel inositol hexa... | ACCEPT | Summary: inositol phosphate biosynthetic process is supported because IP6K3 biosynthesizes/metabolizes soluble inositol pyrophosphates from inositol phosphate substrates. Reason: This biological-process term matches the characterized IP6K3 reaction products and Reactome inositol phosphate pathway context. Supporting Evidence: file:human/IP6K3/IP6K3-uniprot.txt Converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5). file:human/IP6K3/IP6K3-deep-research-falcon.md In mammals, **IP6Ks** (IP6K1/2/3) are central enzymes that produce **5-InsP7 (5-IP7)** from **InsP6 (IP6)** and can contribute to production of **InsP8** from **1-IP7**. |
| GO:0006468 protein phosphorylation | IDA PMID:11502751 Identification and characterization of a novel inositol hexa... | REMOVE | Summary: IP6K3 is an inositol polyphosphate kinase, not a protein kinase. The characterized substrates are InsP6, InsP5, and related inositol pyrophosphates. Reason: The evidence supports phosphorylation of soluble inositol phosphate substrates, not protein phosphorylation. This row should not remain as a protein phosphorylation BP annotation. Supporting Evidence: PMID:11502751 We now report the identification, cloning, and characterization of a third InsP(7) forming enzyme designated InsP(6)K3. |
| GO:0046488 phosphatidylinositol metabolic process | IDA PMID:11502751 Identification and characterization of a novel inositol hexa... | MODIFY | Summary: phosphatidylinositol metabolic process describes phosphatidylinositol lipid metabolism, but the evidence for IP6K3 is soluble inositol phosphate/pyrophosphate metabolism. Reason: IP6K3 is not primarily a phosphatidylinositol lipid kinase. The supported biological process is soluble inositol phosphate biosynthesis/metabolism. Proposed replacements: inositol phosphate biosynthetic process Supporting Evidence: PMID:11502751 We now report the identification, cloning, and characterization of a third InsP(7) forming enzyme designated InsP(6)K3. |
| GO:0005737 cytoplasm | IDA PMID:11502751 Identification and characterization of a novel inositol hexa... | ACCEPT | Summary: cytoplasm localization is supported by the original characterization, which reported IP6K3 as predominantly cytoplasmic. Reason: Cytoplasmic/cytosolic localization is the experimentally supported cellular component for human IP6K3. Supporting Evidence: PMID:11502751 Intracellular disposition discriminates the three enzymes with InsP(6)K2 being exclusively nuclear, InsP(6)K3 predominating in the cytoplasm, and InsP(6)K1 displaying comparable nuclear and cytosolic densities. file:human/IP6K3/IP6K3-deep-research-falcon.md In mouse cerebellum, immunostaining supports localization within the **molecular layer/Purkinje cell compartment**, consistent with Purkinje-cell phenotypes observed in knockout animals. |
| GO:0030674 protein-macromolecule adaptor activity | IPI PMID:26245967 Inositol Hexakisphosphate Kinase-3 Regulates the Morphology ... | NEW | Summary: Beyond its catalytic kinase activity, IP6K3 has a distinct, experimentally demonstrated noncatalytic scaffolding/adaptor molecular function in cerebellar Purkinje cells: it physiologically binds Ξ±/Ξ²-adducin and Ξ±2/Ξ²2-spectrin and promotes their mutual interaction. Critically, this activity is independent of catalysis (the kinase-dead K217A mutant retains it), establishing it as a bona fide molecular function rather than a downstream phenotype. Added as a NEW adaptor-activity annotation per PR #848 review feedback. Provenance corrected per PR #848 re-review: the primary evidence is the direct physical interaction reported in PMID:26245967, so the annotation now uses evidence_type IPI with original_reference_id PMID:26245967 (the falcon deep research file is retained as corroborating support). Reason: A specific protein-macromolecule adaptor activity captures IP6K3's kinase-independent scaffolding role (linking spectrin and adducin) far better than generic protein binding; it is the primary reason IP6K3 is biologically distinctive among the IP6K family. Supporting Evidence: PMID:26245967 IP6K3 physiologically binds to the cytoskeletal proteins adducin and spectrin, whose mutual interactions are perturbed in IP6K3-null mutants. file:human/IP6K3/IP6K3-deep-research-falcon.md IP6K3 co-immunoprecipitates with **Ξ±/Ξ²-adducin** and **Ξ±2/Ξ²2-spectrin**, and these interactions were reported as **specific to IP6K3** (not observed similarly for IP6K1/2 in that study). Importantly, IP6K3's promotion of spectrinβadducin interaction was reported to be **independent of kinase activity**, consistent with a **noncatalytic scaffolding role** (kinase-dead mutant K217A still promotes binding). |
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Download this section (compressed HTML)Q: What fraction of endogenous IP6K3 is nuclear in human neurons compared with the predominant cytoplasmic pool?
Suggested experts: inositol phosphate biochemists, neurocell biologists
Q: Which inositol pyrophosphate products are generated by IP6K3 in brain tissue under physiological conditions?
Suggested experts: metabolomics experts, neurochemists
Experiment: Quantify inositol pyrophosphate species in IP6K3 knockout and rescue neuronal models.
Hypothesis: IP6K3 loss reduces specific InsP7/PP-InsP products in brain-derived cells.
Type: Targeted metabolomics
Experiment: Use validated IP6K3 antibodies or tagged knock-in alleles to measure cytoplasmic versus nuclear localization in neuronal cells.
Hypothesis: Endogenous IP6K3 is predominantly cytoplasmic, consistent with the original characterization.
Type: Endogenous localization
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