PFKM is the muscle isozyme of 6-phosphofructokinase (phosphofructokinase-1, PFK-1; EC 2.7.1.11), the enzyme that catalyzes the committed, rate-limiting step of glycolysis - the ATP-dependent phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate, requiring Mg2+. It is a major allosteric control point of the pathway, activated by AMP, ADP and fructose 2,6-bisphosphate and inhibited by ATP and citrate. The active enzyme is a tetramer assembled from three subunit types - PFKM (muscle), PFKL (liver) and PFKP (platelet); skeletal muscle contains essentially the M4 homotetramer, whereas erythrocytes contain a mixture of M/L hybrids. Each subunit is a two-domain protein with an N-terminal catalytic domain and a C-terminal regulatory domain that binds allosteric effectors. PFKM acts in the cytosol. Loss-of-function variants in PFKM cause glycogen storage disease type VII (Tarui disease), characterized by exercise intolerance, muscle cramps, exertional myopathy and compensated hemolysis, reflecting the block of muscle glycolysis and its knock-on effects on glycogenolysis and erythrocyte metabolism.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003872 6-phosphofructokinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function - PFKM is a 6-phosphofructokinase that phosphorylates fructose 6-phosphate to fructose 1,6-bisphosphate. Phylogenetically inferred across the PFKA family and directly supported by experimental data on the human muscle enzyme. Reason: This is the defining molecular function of PFKM, well supported across all evidence codes and by the UniProt catalytic activity annotation (EC 2.7.1.11). The IBA is at the correct level of specificity. Supporting Evidence: file:human/PFKM/PFKM-uniprot.txt Catalyzes the phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate by ATP, the first committing step of glycolysis. |
| GO:0006002 fructose 6-phosphate metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Fructose 6-phosphate is the substrate of PFKM, so participation in F6P metabolism is a direct consequence of the catalytic activity. Reason: Consistent with the reaction catalyzed; F6P is consumed by PFKM in the committed step of glycolysis. Supporting Evidence: file:human/PFKM/PFKM-uniprot.txt Catalyzes the phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate by ATP, the first committing step of glycolysis. |
| GO:0030388 fructose 1,6-bisphosphate metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Fructose 1,6-bisphosphate is the product of the PFKM-catalyzed reaction, so PFKM participates in its metabolism (production). Reason: Directly reflects the product of the catalytic reaction. Supporting Evidence: file:human/PFKM/PFKM-uniprot.txt Catalyzes the phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate by ATP, the first committing step of glycolysis. |
| GO:0061621 canonical glycolysis | IBA GO_REF:0000033 | ACCEPT | Summary: PFKM catalyzes the committed step of glycolysis and is a canonical component of the pathway. Reason: Central role in glycolysis, phylogenetically conserved and experimentally established. Appropriate biological process term. Supporting Evidence: file:human/PFKM/PFKM-uniprot.txt Carbohydrate degradation; glycolysis; D-glyceraldehyde 3- PMID:24817713 The main regulator of glycolysis, 6-phosphofructokinase (EC 2.7.1.11; Pfk), catalyzes the Mg-ATP-dependent formation of fructose 1,6-bisphosphate from fructose 6-phosphate |
| GO:0005945 6-phosphofructokinase complex | IBA GO_REF:0000033 | ACCEPT | Summary: The active PFK enzyme is a tetramer; in muscle it is the M4 homotetramer. PFKM is a subunit of the 6-phosphofructokinase complex. Reason: Well supported - the enzyme functions as a tetramer composed of PFKM, PFKL and PFKP subunits, and PFKM is part of this complex. Supporting Evidence: PMID:6444721 These data demonstrate that muscle and liver PFKs are distinct homotetramers-i.e., M(4) and L(4), respectively file:human/PFKM/PFKM-uniprot.txt Phosphofructokinase (PFK) enzyme functions as a tetramer composed of different combinations |
| GO:0016020 membrane | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: An IBA "is_active_in membrane" annotation. PFKM is a soluble cytosolic enzyme; membrane association is at best transient/regulatory (e.g. actin, caveolin, V-ATPase in specific cell types), not the site of its core catalytic activity. Reason: The generic "membrane" location does not represent the core cytosolic localization of this glycolytic enzyme. Any membrane association is peripheral and cell-type-specific rather than a defining compartment. The cytosol annotations capture the primary localization. Supporting Evidence: file:human/PFKM/PFKM-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0070095 fructose-6-phosphate binding | IBA GO_REF:0000033 | ACCEPT | Summary: PFKM binds fructose 6-phosphate as its phosphoacceptor substrate. Substrate binding is intrinsic to the enzyme mechanism. Reason: Directly supported - F6P is the substrate and specific F6P/substrate binding residues are annotated in the structure. Kinetic F-6-P affinity has been measured for the M-type isozyme. Supporting Evidence: PMID:8780720 lower affinity for F-6-P showed by the M-type isozyme |
| GO:0003872 6-phosphofructokinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assertion of the core 6-phosphofructokinase activity via UniRule/InterPro and the RHEA:16109 / EC 2.7.1.11 mapping. Reason: Correct core molecular function, consistent with the experimental and IBA annotations of the same term. Supporting Evidence: file:human/PFKM/PFKM-uniprot.txt EC=2.7.1.11 |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: PFKM uses ATP as the phosphoryl donor and has defined ATP-binding residues; ATP binding is intrinsic to the kinase reaction. Reason: Well supported - ATP is a co-substrate; UniProt annotates multiple ATP-binding sites and ATP additionally acts as an allosteric inhibitor. Confirmed experimentally. Supporting Evidence: file:human/PFKM/PFKM-uniprot.txt /ligand="ATP" |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: PFKM is a cytoplasmic/cytosolic enzyme. Consistent with the UniProt subcellular location and the cytosol annotations. Reason: Correct localization, though the more specific "cytosol" term is preferable and is also annotated. Accepting the broader parent as-is. Supporting Evidence: file:human/PFKM/PFKM-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0006002 fructose 6-phosphate metabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: Electronic (InterPro) inference of F6P metabolism, consistent with the enzyme substrate. Reason: Correct - F6P is the substrate consumed by PFKM. Duplicates the IBA and experimental annotations of the same term. Supporting Evidence: file:human/PFKM/PFKM-uniprot.txt Catalyzes the phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate by ATP, the first committing step of glycolysis. |
| GO:0006096 glycolytic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic inference (UniRule/InterPro/UniPathway) that PFKM participates in glycolysis. This is the core biological process. Reason: PFKM catalyzes the committed step of glycolysis; the annotation is correct and at an appropriate level. Supporting Evidence: file:human/PFKM/PFKM-uniprot.txt Carbohydrate degradation; glycolysis; D-glyceraldehyde 3- |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | MARK AS OVER ANNOTATED | Summary: High-throughput protein interaction annotation from a proteome-scale human liver interactome map. "Protein binding" is uninformative about molecular function. Reason: The bare "protein binding" term conveys no specific functional information and derives from a large-scale interactome screen. Per curation policy such IPIs are marked as over-annotated rather than removed; the informative functions (kinase activity, complex assembly) are captured elsewhere. Supporting Evidence: PMID:21988832 Proteome-scale protein interaction maps are available for many organisms |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: High-throughput binary interaction from a proteome-scale human interactome (HuRI) map. Uninformative "protein binding". Reason: Bare "protein binding" from a systematic interactome screen adds no specific functional detail; retained but flagged as over-annotated per policy. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: High-throughput interaction from BioPlex 2.0 affinity-purification mass spectrometry. Uninformative "protein binding". Reason: Bare "protein binding" from a large-scale AP-MS interactome dataset; no specific molecular function conveyed. Flagged as over-annotated per policy. Supporting Evidence: PMID:28514442 we present BioPlex 2.0 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: High-throughput interaction from BioPlex 3.0 affinity-purification networks. Uninformative "protein binding". Reason: Bare "protein binding" from a proteome-scale AP-MS interactome; no specific function conveyed. Flagged as over-annotated per policy. Supporting Evidence: PMID:33961781 Through affinity-purification |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MARK AS OVER ANNOTATED | Summary: Interactions mapped by quantitative fragmentomics/affinity mapping (many PDZ-domain partners). Uninformative "protein binding". Reason: Bare "protein binding" from a high-throughput affinity-mapping study; the many PDZ partners are unlikely to reflect the core muscle glycolytic function. Flagged as over-annotated per policy. Supporting Evidence: PMID:36115835 Quantitative fragmentomics allow affinity mapping of interactomes. |
| GO:0005515 protein binding | IPI PMID:6444721 Isozymes of human phosphofructokinase: identification and su... | MARK AS OVER ANNOTATED | Summary: IPI to PFKL (P17858) from the isozyme hybridization study. The specific biology (M/L subunit tetramerization) is better captured by the complex and identical/kinase binding annotations. Bare "protein binding" is uninformative. Reason: While the underlying interaction (PFKM-PFKL) is real and biologically meaningful for hybrid tetramer formation, the generic "protein binding" term is uninformative; the same paper supports the more specific 6-phosphofructokinase complex and kinase binding annotations. Flagged as over-annotated per policy. Supporting Evidence: PMID:6444721 These multimolecular forms result from the random polymerization of two distinct subunits, M (muscle type) and L (liver type) |
| GO:0042802 identical protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: PFKM self-association (M4 homotetramer). Identical protein binding reflects the homotetrameric assembly of the muscle enzyme. Reason: The muscle enzyme is an M4 homotetramer, so PFKM binds identical subunits. This is a real, informative property, but it is a structural corollary of complex assembly rather than the primary catalytic function; kept as non-core. Supporting Evidence: PMID:6444721 muscle and liver PFKs are distinct homotetramers-i.e., M(4) and L(4) |
| GO:0042802 identical protein binding | IPI PMID:6444721 Isozymes of human phosphofructokinase: identification and su... | KEEP AS NON CORE | Summary: PFKM self-association into the M4 homotetramer, from the isozyme hybridization study. Reason: Reflects M4 homotetramer formation; a genuine structural property but secondary to the catalytic function. Kept as non-core. Supporting Evidence: PMID:6444721 muscle and liver PFKs are distinct homotetramers-i.e., M(4) and L(4) |
| GO:0005829 cytosol | IEA GO_REF:0000107 | ACCEPT | Summary: Cytosolic localization inferred by orthology (Ensembl Compara). This is the primary compartment of the glycolytic enzyme. Reason: Correct and specific localization for a glycolytic enzyme, consistent with UniProt (Cytoplasm) and the Reactome cytosol annotation. Supporting Evidence: file:human/PFKM/PFKM-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0008443 phosphofructokinase activity | IEA GO_REF:0000107 | ACCEPT | Summary: Broader parent term of 6-phosphofructokinase activity, transferred by orthology. Correct but less specific than GO:0003872. Reason: The term is correct (a parent of the specific ATP-dependent 6-phosphofructokinase activity). Broader IEA annotations are acceptable; the specific term is also annotated. Supporting Evidence: file:human/PFKM/PFKM-uniprot.txt EC=2.7.1.11 |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Identical protein binding transferred by orthology, reflecting homotetramer formation. Reason: Consistent with M4 homotetramer assembly; genuine but non-core structural property. Supporting Evidence: PMID:6444721 muscle and liver PFKs are distinct homotetramers-i.e., M(4) and L(4) |
| GO:0061621 canonical glycolysis | IEA GO_REF:0000107 | ACCEPT | Summary: Canonical glycolysis inferred by orthology. Core biological process for PFKM. Reason: Correct - PFKM catalyzes the committed step of glycolysis. Duplicates the IBA/TAS annotations. Supporting Evidence: file:human/PFKM/PFKM-uniprot.txt Carbohydrate degradation; glycolysis; D-glyceraldehyde 3- |
| GO:0097228 sperm principal piece | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Localization to the sperm flagellum principal piece, transferred by orthology from mouse. Glycolytic enzymes are known to localize to the sperm principal piece in some species, but this is not a core localization of the human muscle enzyme and rests solely on Ensembl orthology transfer. Reason: This is a species/cell-type-specific localization transferred electronically from mouse, not a defining compartment for the human muscle isozyme. Retained but flagged as over-annotated; the core localization is cytosol. Supporting Evidence: file:human/PFKM/PFKM-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0061621 canonical glycolysis | TAS Reactome:R-HSA-70171 | ACCEPT | Summary: Reactome (Glycolysis) traceable assertion that PFKM participates in canonical glycolysis. Reason: Correct core biological process, supported by an authoritative pathway database. Supporting Evidence: PMID:24817713 The main regulator of glycolysis, 6-phosphofructokinase (EC 2.7.1.11; Pfk), catalyzes the Mg-ATP-dependent formation of fructose 1,6-bisphosphate from fructose 6-phosphate |
| GO:0003872 6-phosphofructokinase activity | EXP PMID:2960695 Characterization of the enzymatic defect in late-onset muscl... | ACCEPT | Summary: Experimental (Reactome-sourced) support for 6-phosphofructokinase activity from a study characterizing the enzymatic defect in late-onset muscle PFK deficiency. Reason: Core molecular function directly supported by experimental characterization of muscle PFK activity in patients. Supporting Evidence: PMID:2960695 The genetic lesion results in a total and partial loss of muscle and red cell PFK, respectively. |
| GO:0003872 6-phosphofructokinase activity | EXP PMID:6444721 Isozymes of human phosphofructokinase: identification and su... | ACCEPT | Summary: Experimental support for 6-phosphofructokinase activity from the human PFK isozyme characterization study. Reason: Core molecular function; the muscle homotetramer M4 was characterized kinetically and immunologically as a phosphofructokinase. Supporting Evidence: PMID:6444721 Isozymes of human phosphofructokinase: identification and subunit structural characterization of a new system. |
| GO:0003872 6-phosphofructokinase activity | EXP PMID:6451249 Isozymes of human phosphofructokinase in blood cells and cul... | ACCEPT | Summary: Experimental (Reactome-sourced) support for 6-phosphofructokinase activity from a study of PFK isozymes in blood cells and cultured cell lines. Reason: Core molecular function. This abstract-only record supports the trigenic (M/L/P) PFK system and the muscle-type enzyme activity; defer to the experimental annotation. Supporting Evidence: PMID:6451249 Isozymes of human phosphofructokinase in blood cells and cultured cell lines: molecular and genetic evidence for a trigenic system. |
| GO:0003872 6-phosphofructokinase activity | EXP PMID:7825568 Functional expression of human mutant phosphofructokinase in... | ACCEPT | Summary: Functional expression of human PFK-M in yeast established that PFKM confers 6-phosphofructokinase activity; a disease mutation (Gly209Asp) abolishes it. Reason: Direct experimental evidence that PFKM is an active 6-phosphofructokinase, via reconstitution of activity in a yeast strain devoid of endogenous PFK. Supporting Evidence: PMID:7825568 Gly-209-mutated protein is completely inactive in the yeast system. |
| GO:0005945 6-phosphofructokinase complex | IPI PMID:24817713 Crystallization and preliminary crystallographic analysis of... | ACCEPT | Summary: ComplexPortal assertion that PFKM is part of the 6-phosphofructokinase complex, from the crystallization study of human muscle PFK (M4). Reason: The active human muscle enzyme is a tetramer (M4); PFKM is a subunit of the 6-phosphofructokinase complex. Supporting Evidence: PMID:24817713 As in the structure of rmPfk, the physiological tetramer |
| GO:0006096 glycolytic process | NAS PMID:24817713 Crystallization and preliminary crystallographic analysis of... | ACCEPT | Summary: Non-traceable author statement (ComplexPortal) that PFKM is involved in glycolysis. Core biological process. Reason: Correct - PFKM catalyzes the committed step of glycolysis; the paper explicitly describes it as the main regulator of glycolysis. Supporting Evidence: PMID:24817713 the main regulator of glycolysis |
| GO:0003872 6-phosphofructokinase activity | IMP PMID:25796446 Aerobic glycolysis tunes YAP/TAZ transcriptional activity. | ACCEPT | Summary: IMP for 6-phosphofructokinase activity from the YAP/TAZ aerobic glycolysis study, which manipulated PFK1 and glycolytic flux. Reason: Core molecular function. The study depends on PFK1 glycolytic (6-phosphofructokinase) activity; the assignment to the muscle isozyme is consistent with the enzyme established function. Supporting Evidence: PMID:25796446 phosphofructokinase (PFK1), the enzyme regulating the first committed step of glycolysis |
| GO:0005515 protein binding | IPI PMID:25796446 Aerobic glycolysis tunes YAP/TAZ transcriptional activity. | MARK AS OVER ANNOTATED | Summary: IPI for protein binding (TEAD transcriptional cofactors) from the YAP/TAZ study. Uninformative "protein binding". Reason: Bare "protein binding" is uninformative. The underlying PFK1-TEAD interaction is a moonlighting/context-specific function (aerobic glycolysis-YAP/TAZ signaling in proliferating cells), not the core muscle glycolytic role; flagged as over-annotated per policy. Supporting Evidence: PMID:25796446 binds the YAP/TAZ transcriptional cofactors TEADs |
| GO:0005634 nucleus | IDA PMID:25796446 Aerobic glycolysis tunes YAP/TAZ transcriptional activity. | MARK AS OVER ANNOTATED | Summary: Nuclear localization reported in the context of PFK1 promoting YAP/TAZ-TEAD transcriptional activity. A moonlighting, context-dependent localization, not the core cytosolic compartment of the glycolytic enzyme. Reason: This is a context-specific moonlighting localization associated with transcriptional regulation in proliferating/cancer cells (CAFA IDA), not the primary compartment where PFKM performs its core glycolytic function. Retained but flagged as over-annotated; do not remove an experimental annotation. Supporting Evidence: PMID:25796446 phosphofructokinase (PFK1), the enzyme regulating the first committed step of glycolysis, binds the YAP/TAZ transcriptional cofactors TEADs |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:25796446 Aerobic glycolysis tunes YAP/TAZ transcriptional activity. | MARK AS OVER ANNOTATED | Summary: PFK1 promotes YAP/TAZ-TEAD transcriptional activity, an indirect/moonlighting role linking glycolytic flux to gene transcription in proliferating cells. Reason: This is a moonlighting, context-specific function tied to aerobic glycolysis and YAP/TAZ signaling, not the core function of the muscle glycolytic enzyme. Retained but flagged as over-annotated; the primary role is enzymatic. Supporting Evidence: PMID:25796446 promotes their functional and biochemical cooperation with YAP/TAZ |
| GO:0061615 glycolytic process through fructose-6-phosphate | IMP PMID:25796446 Aerobic glycolysis tunes YAP/TAZ transcriptional activity. | ACCEPT | Summary: Specific glycolysis term capturing the branch of glycolysis proceeding through fructose-6-phosphate - the exact step catalyzed by PFKM. Reason: Accurately describes the PFKM role - it phosphorylates F6P, committing carbon to glycolysis through the fructose-6-phosphate branch. Supporting Evidence: PMID:25796446 phosphofructokinase (PFK1), the enzyme regulating the first committed step of glycolysis |
| GO:0005829 cytosol | TAS Reactome:R-HSA-70467 | ACCEPT | Summary: Reactome traceable assertion that the PFK tetramer acts in the cytosol (PFK tetramer phosphorylates Fru(6)P). Reason: Correct core localization for the glycolytic reaction, consistent with UniProt. Supporting Evidence: file:human/PFKM/PFKM-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0016324 apical plasma membrane | IDA PMID:12649290 The a-subunit of the V-type H+-ATPase interacts with phospho... | MARK AS OVER ANNOTATED | Summary: PFK-1 was co-immunolocalized with the V-ATPase a4 subunit at the apical membrane of alpha-intercalated cells in human kidney collecting duct - a specialized, cell-type-specific localization tied to a V-ATPase interaction. Reason: This apical plasma membrane localization is specific to kidney alpha-intercalated cells and reflects the V-ATPase-PFK1 interaction that links proton pumping to glycolytic ATP supply; it is not a core localization of the muscle isozyme. Retained (experimental IDA) but flagged as over-annotated relative to the core cytosolic function. Supporting Evidence: PMID:12649290 PFK-1 co-immunolocalized with a4 in alpha-intercalated cells in the collecting ducts of human kidney. |
| GO:0003872 6-phosphofructokinase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of 6-phosphofructokinase activity from an ortholog (P00511, rabbit muscle PFK). Correct core function. Reason: The rabbit muscle enzyme is ~96% identical and the function is conserved; the assignment is correct and consistent with the experimental evidence. Supporting Evidence: file:human/PFKM/PFKM-uniprot.txt EC=2.7.1.11 |
| GO:0003872 6-phosphofructokinase activity | IMP PMID:6444532 The molecular mechanism of the inherited phosphofructokinase... | ACCEPT | Summary: IMP for 6-phosphofructokinase activity - loss of the M subunit in Tarui disease abolishes muscle PFK activity, demonstrating PFKM is required for the activity. Reason: Direct genetic evidence - in Tarui disease the M-type subunits are absent and muscle PFK activity is lost, establishing the PFKM role in conferring 6-phosphofructokinase activity. Supporting Evidence: PMID:6444532 in Tarui disease the M-type subunits are absent |
| GO:0003872 6-phosphofructokinase activity | IDA PMID:6444721 Isozymes of human phosphofructokinase: identification and su... | ACCEPT | Summary: Direct assay of muscle PFK (M4) activity in the isozyme characterization study. Reason: Core molecular function directly demonstrated for the muscle homotetramer. Supporting Evidence: PMID:6444721 muscle and liver PFKs are distinct homotetramers-i.e., M(4) and L(4) |
| GO:0005945 6-phosphofructokinase complex | IDA PMID:6444532 The molecular mechanism of the inherited phosphofructokinase... | ACCEPT | Summary: Direct evidence that PFKM is part of the 6-phosphofructokinase complex, from analysis of PFK isozymes in Tarui disease. Reason: Loss of M subunits removes M-containing tetramers, directly demonstrating PFKM is a constituent of the PFK complex. Supporting Evidence: PMID:6444532 consisted exclusively of the L4 isozyme |
| GO:0005945 6-phosphofructokinase complex | IDA PMID:6444721 Isozymes of human phosphofructokinase: identification and su... | ACCEPT | Summary: Direct evidence that PFKM assembles into the tetrameric PFK complex (M4 and M/L hybrids), from the isozyme hybridization study. Reason: PFKM subunits polymerize into M4 and mixed tetramers; PFKM is part of the 6-phosphofructokinase complex. Supporting Evidence: PMID:6444721 result from the random polymerization of two distinct subunits, M (muscle type) and L (liver type), to form all possible tetrameters |
| GO:0006002 fructose 6-phosphate metabolic process | IMP PMID:6444532 The molecular mechanism of the inherited phosphofructokinase... | ACCEPT | Summary: IMP - loss of muscle PFK in Tarui disease blocks conversion of fructose 6-phosphate, implicating PFKM in F6P metabolism. Reason: The metabolic crossover at PFK in patients demonstrates the PFKM role in consuming F6P. Supporting Evidence: PMID:6444532 a metabolic crossover point was found at the level of PFK |
| GO:0006002 fructose 6-phosphate metabolic process | IDA PMID:6444721 Isozymes of human phosphofructokinase: identification and su... | ACCEPT | Summary: Direct assay of muscle PFK acting on fructose 6-phosphate. Reason: Consistent with PFKM catalyzing the F6P-consuming reaction; F6P metabolic process is directly supported. Supporting Evidence: PMID:6444721 the random polymerization of two distinct subunits, M (muscle type) and L (liver type) |
| GO:0006096 glycolytic process | IMP PMID:6444532 The molecular mechanism of the inherited phosphofructokinase... | ACCEPT | Summary: IMP for glycolytic process - the PFK block in Tarui disease impairs muscle glycolysis. Reason: The metabolic crossover at PFK demonstrates the PFKM role in glycolysis; core biological process. Supporting Evidence: PMID:6444532 a metabolic crossover point was found at the level of PFK |
| GO:0019900 kinase binding | IPI PMID:6444721 Isozymes of human phosphofructokinase: identification and su... | KEEP AS NON CORE | Summary: IPI to PFKL (a kinase) reflecting hetero-oligomerization of the muscle subunit with the liver subunit to form hybrid PFK tetramers. Reason: PFKM binds PFKL (itself a phosphofructokinase/kinase) during hybrid tetramer formation, so "kinase binding" is defensible and more informative than bare protein binding. However it is a structural corollary of complex assembly rather than the core catalytic function; kept as non-core. Supporting Evidence: PMID:6444721 the random polymerization of two distinct subunits, M (muscle type) and L (liver type) |
| GO:0046716 muscle cell cellular homeostasis | IMP PMID:6444532 The molecular mechanism of the inherited phosphofructokinase... | KEEP AS NON CORE | Summary: IMP linking PFKM to muscle cell homeostasis - PFK-M deficiency causes exertional myopathy, reflecting impaired energy metabolism in muscle. Reason: This is a valid downstream physiological consequence of the enzymatic function (Tarui disease myopathy), but it is a phenotypic/organismal process rather than the core molecular role; kept as non-core. Supporting Evidence: PMID:6444532 the inherited erythrocyte PFK deficiency associated with myopathy and hemolysis (Tarui disease) |
| GO:0003872 6-phosphofructokinase activity | IDA PMID:8780720 Isozyme analysis of human polymorphonuclear leukocyte phosph... | ACCEPT | Summary: Direct assay of M-type PFK activity and kinetics in leukocyte isozyme analysis. Reason: Core molecular function directly measured for the M-type isozyme (including its kinetic properties). Supporting Evidence: PMID:8780720 a 30% decrease was observed in the activity of M-type isozyme |
| GO:0005524 ATP binding | IDA PMID:8780720 Isozyme analysis of human polymorphonuclear leukocyte phosph... | ACCEPT | Summary: Direct evidence of ATP interaction with the M-type isozyme, inferred from its ATP-dependent kinetics and altered ATP inhibition. Reason: ATP is the phosphoryl donor and an allosteric inhibitor of PFK; the study characterized ATP inhibition of the isozymes. Consistent with defined ATP-binding sites. Supporting Evidence: PMID:8780720 the decreased sensitivity to ATP inhibition |
| GO:0070061 fructose binding | IDA PMID:8780720 Isozyme analysis of human polymorphonuclear leukocyte phosph... | ACCEPT | Summary: Direct kinetic evidence of the M-type isozyme interaction with fructose 6-phosphate (its substrate), reported as altered F-6-P affinity. Reason: The M-type isozyme affinity for fructose 6-phosphate was measured; binding of the fructose-phosphate substrate is intrinsic to the enzyme. Consistent with the more specific fructose-6-phosphate binding annotation. Supporting Evidence: PMID:8780720 lower affinity for F-6-P showed by the M-type isozyme |
| GO:0005515 protein binding | IPI PMID:12649290 The a-subunit of the V-type H+-ATPase interacts with phospho... | MARK AS OVER ANNOTATED | Summary: IPI to the V-ATPase a-subunit (ATP6V0A4/a4, Q9HBG4). "Protein binding" is uninformative; the interaction links PFK1 to V-ATPase-mediated proton transport in kidney. Reason: The bare "protein binding" term is uninformative. The specific PFK1-V-ATPase a-subunit interaction is a kidney-specific regulatory link (coupling glycolysis to proton pumping) rather than a core function of the muscle enzyme; flagged as over-annotated per policy. Supporting Evidence: PMID:12649290 co-immunoprecipitation of a4 with PFK-1 from solubilized human kidney membrane proteins |
| GO:0006110 regulation of glycolytic process | IDA file:human/PFKM/PFKM-uniprot.txt | NEW | Summary: PFK-1 is the principal allosteric control point of glycolysis; PFKM activity is regulated by allosteric effectors (activated by AMP, ADP, fructose 2,6-bisphosphate; inhibited by ATP, citrate), making the enzyme a key regulator of glycolytic flux. Not present in the current GOA set but strongly supported by UniProt and the literature. Reason: The regulatory (rate-limiting/allosteric control) role of PFKM is a defining feature of the enzyme and is captured in core_functions, but is not represented among the existing annotations. Proposed as a new annotation. Supporting Evidence: file:human/PFKM/PFKM-uniprot.txt Allosterically activated by ADP, AMP, or fructose 2,6-bisphosphate, and allosterically inhibited by ATP or citrate. PMID:24817713 the main regulator of glycolysis |
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