Pfkfb4 encodes a bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. It both synthesizes and degrades fructose 2,6-bisphosphate, a regulator of glycolysis and gluconeogenesis. The review accepts the two catalytic activities and fructose 2,6-bisphosphate metabolism as direct functions, modifies generic catalytic activity, and keeps ATP binding, cytosol/complex, glycolysis, and gluconeogenesis as context.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005829 cytosol | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: cytosol is retained as contextual support for Pfkfb4, but it is not the core function (IBA, GO_REF:0000033). Reason: cytosol records localization or complex context for Pfkfb4, not the defining molecular function. Supporting Evidence: UniProtKB:P25114 FUNCTION: Synthesis and degradation of fructose 2,6-bisphosphate. file:rat/Pfkfb4/Pfkfb4-deep-research-falcon.md Across eukaryotes including mammals, PFK-2/FBPase-2 activities are described as **cytosolic**. |
| GO:0003873 6-phosphofructo-2-kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Pfkfb4's bifunctional synthesis and degradation of fructose 2,6-bisphosphate supports retaining 6-phosphofructo-2-kinase activity as a direct annotation (IBA, GO_REF:0000033). Reason: 6-phosphofructo-2-kinase activity directly matches Pfkfb4's documented role in bifunctional synthesis and degradation of fructose 2,6-bisphosphate. Supporting Evidence: UniProtKB:P25114 FUNCTION: Synthesis and degradation of fructose 2,6-bisphosphate. file:rat/Pfkfb4/Pfkfb4-deep-research-falcon.md Fructose-2,6-bisphosphate is produced from fructose-6-phosphate by **6-phosphofructo-2-kinase (PFK-2; EC 2.7.1.105)** and hydrolyzed by **fructose-2,6-bisphosphatase (FBPase-2; EC 3.1.3.46)**; in mammals these opposing activities occur within the same bifunctional PFKFB enzymes. |
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | MODIFY | Summary: catalytic activity captures part of Pfkfb4 biology, but a more specific replacement better represents the direct role (IEA, GO_REF:0000002). Reason: catalytic activity is directionally related to Pfkfb4 but should be replaced by the more specific term(s): 6-phosphofructo-2-kinase activity, fructose-2,6-bisphosphate 2-phosphatase activity. Proposed replacements: 6-phosphofructo-2-kinase activity fructose-2,6-bisphosphate 2-phosphatase activity Supporting Evidence: UniProtKB:P25114 FUNCTION: Synthesis and degradation of fructose 2,6-bisphosphate. |
| GO:0003873 6-phosphofructo-2-kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Pfkfb4's bifunctional synthesis and degradation of fructose 2,6-bisphosphate supports retaining 6-phosphofructo-2-kinase activity as a direct annotation (IEA, GO_REF:0000120). Reason: 6-phosphofructo-2-kinase activity directly matches Pfkfb4's documented role in bifunctional synthesis and degradation of fructose 2,6-bisphosphate. Supporting Evidence: UniProtKB:P25114 FUNCTION: Synthesis and degradation of fructose 2,6-bisphosphate. |
| GO:0004331 fructose-2,6-bisphosphate 2-phosphatase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Pfkfb4's bifunctional synthesis and degradation of fructose 2,6-bisphosphate supports retaining fructose-2,6-bisphosphate 2-phosphatase activity as a direct annotation (IEA, GO_REF:0000120). Reason: fructose-2,6-bisphosphate 2-phosphatase activity directly matches Pfkfb4's documented role in bifunctional synthesis and degradation of fructose 2,6-bisphosphate. Supporting Evidence: UniProtKB:P25114 FUNCTION: Synthesis and degradation of fructose 2,6-bisphosphate. file:rat/Pfkfb4/Pfkfb4-deep-research-falcon.md Fructose-2,6-bisphosphate is produced from fructose-6-phosphate by **6-phosphofructo-2-kinase (PFK-2; EC 2.7.1.105)** and hydrolyzed by **fructose-2,6-bisphosphatase (FBPase-2; EC 3.1.3.46)**; in mammals these opposing activities occur within the same bifunctional PFKFB enzymes. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: ATP binding is retained as contextual support for Pfkfb4, but it is not the core function (IEA, GO_REF:0000002). Reason: ATP binding records cofactor, substrate, or interaction context for Pfkfb4, but the curated core role is bifunctional synthesis and degradation of fructose 2,6-bisphosphate. Supporting Evidence: UniProtKB:P25114 FUNCTION: Synthesis and degradation of fructose 2,6-bisphosphate. |
| GO:0006000 fructose metabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: Pfkfb4's bifunctional synthesis and degradation of fructose 2,6-bisphosphate supports retaining fructose metabolic process as a direct annotation (IEA, GO_REF:0000002). Reason: fructose metabolic process is a direct process-level consequence of Pfkfb4's documented role in bifunctional synthesis and degradation of fructose 2,6-bisphosphate. Supporting Evidence: UniProtKB:P25114 FUNCTION: Synthesis and degradation of fructose 2,6-bisphosphate. |
| GO:0006003 fructose 2,6-bisphosphate metabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: Pfkfb4's bifunctional synthesis and degradation of fructose 2,6-bisphosphate supports retaining fructose 2,6-bisphosphate metabolic process as a direct annotation (IEA, GO_REF:0000002). Reason: fructose 2,6-bisphosphate metabolic process is a direct process-level consequence of Pfkfb4's documented role in bifunctional synthesis and degradation of fructose 2,6-bisphosphate. Supporting Evidence: UniProtKB:P25114 FUNCTION: Synthesis and degradation of fructose 2,6-bisphosphate. |
| GO:0003873 6-phosphofructo-2-kinase activity | ISO GO_REF:0000121 | ACCEPT | Summary: Pfkfb4's bifunctional synthesis and degradation of fructose 2,6-bisphosphate supports retaining 6-phosphofructo-2-kinase activity as a direct annotation (ISO, GO_REF:0000121). Reason: 6-phosphofructo-2-kinase activity directly matches Pfkfb4's documented role in bifunctional synthesis and degradation of fructose 2,6-bisphosphate. Supporting Evidence: UniProtKB:P25114 FUNCTION: Synthesis and degradation of fructose 2,6-bisphosphate. |
| GO:0006003 fructose 2,6-bisphosphate metabolic process | ISS GO_REF:0000114 | ACCEPT | Summary: Pfkfb4's bifunctional synthesis and degradation of fructose 2,6-bisphosphate supports retaining fructose 2,6-bisphosphate metabolic process as a direct annotation (ISS, GO_REF:0000114). Reason: fructose 2,6-bisphosphate metabolic process is a direct process-level consequence of Pfkfb4's documented role in bifunctional synthesis and degradation of fructose 2,6-bisphosphate. Supporting Evidence: UniProtKB:P25114 FUNCTION: Synthesis and degradation of fructose 2,6-bisphosphate. |
| GO:0006094 gluconeogenesis | NAS PMID:15581487 Regulation of the regulatory enzyme, 6-phosphofructo-2-kinas... | KEEP AS NON CORE | Summary: gluconeogenesis is retained as contextual support for Pfkfb4, but it is not the core function (NAS, PMID:15581487). Reason: gluconeogenesis is biologically related to Pfkfb4, but it is broader, downstream, or regulatory context relative to bifunctional synthesis and degradation of fructose 2,6-bisphosphate. Supporting Evidence: PMID:15581487 Regulation of the regulatory enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. file:rat/Pfkfb4/Pfkfb4-deep-research-falcon.md At **submicromolar concentrations**, it stimulates glycolysis and inhibits gluconeogenesis by: |
| GO:0006096 glycolytic process | NAS PMID:15581487 Regulation of the regulatory enzyme, 6-phosphofructo-2-kinas... | KEEP AS NON CORE | Summary: glycolytic process is retained as contextual support for Pfkfb4, but it is not the core function (NAS, PMID:15581487). Reason: glycolytic process is biologically related to Pfkfb4, but it is broader, downstream, or regulatory context relative to bifunctional synthesis and degradation of fructose 2,6-bisphosphate. Supporting Evidence: PMID:15581487 Regulation of the regulatory enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. file:rat/Pfkfb4/Pfkfb4-deep-research-falcon.md At the pathway level, PFKFB4 regulates **glycolytic flux** by controlling the concentration of **F-2,6-BP**, which directly tunes PFK1 activity. |
| GO:0043540 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase complex | IPI PMID:8805587 The crystal structure of the bifunctional enzyme 6-phosphofr... | KEEP AS NON CORE | Summary: 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase complex is retained as contextual support for Pfkfb4, but it is not the core function (IPI, PMID:8805587). Reason: 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase complex records localization or complex context for Pfkfb4, not the defining molecular function. Supporting Evidence: PMID:8805587 RESULTS: We have determined the 2.0 A crystal structure of the rat testis isozyme of this bifunctional enzyme. file:rat/Pfkfb4/Pfkfb4-deep-research-falcon.md PFKFB enzymes are **bifunctional homodimers** with **two independent catalytic domains**: an **N-terminal kinase (PFK-2)** domain that synthesizes F-2,6-BP and a **C-terminal phosphatase (FBPase-2)** domain that degrades F-2,6-BP. |
| GO:0003873 6-phosphofructo-2-kinase activity | IDA PMID:1651918 Molecular cloning of the DNA and expression and characteriza... | ACCEPT | Summary: Pfkfb4's bifunctional synthesis and degradation of fructose 2,6-bisphosphate supports retaining 6-phosphofructo-2-kinase activity as a direct annotation (IDA, PMID:1651918). Reason: 6-phosphofructo-2-kinase activity directly matches Pfkfb4's documented role in bifunctional synthesis and degradation of fructose 2,6-bisphosphate. Supporting Evidence: PMID:1651918 We have isolated and sequenced two overlapping cDNA fragments which could encode the complete amino acid sequence of rat testis fructose-6-phosphate,2-kinase:fructose-2,6-bisphosphatase. |
| GO:0004331 fructose-2,6-bisphosphate 2-phosphatase activity | IDA PMID:1651918 Molecular cloning of the DNA and expression and characteriza... | ACCEPT | Summary: Pfkfb4's bifunctional synthesis and degradation of fructose 2,6-bisphosphate supports retaining fructose-2,6-bisphosphate 2-phosphatase activity as a direct annotation (IDA, PMID:1651918). Reason: fructose-2,6-bisphosphate 2-phosphatase activity directly matches Pfkfb4's documented role in bifunctional synthesis and degradation of fructose 2,6-bisphosphate. Supporting Evidence: PMID:1651918 We have isolated and sequenced two overlapping cDNA fragments which could encode the complete amino acid sequence of rat testis fructose-6-phosphate,2-kinase:fructose-2,6-bisphosphatase. |
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