Pck1 encodes cytosolic phosphoenolpyruvate carboxykinase [GTP] (PEPCK-C), a monomeric, Mn2+-dependent enzyme that converts oxaloacetate and GTP to phosphoenolpyruvate, GDP and CO2. This is the committed step that withdraws carbon from the tricarboxylic acid cycle (cataplerosis) for glucose synthesis in liver and kidney cortex, and for glyceroneogenesis (glycerol 3-phosphate for triglyceride re-esterification) in adipose tissue. Rat PEPCK-C is the principal structural and kinetic model of the GTP-dependent PEPCKs, with crystal structures showing in-line phosphoryl transfer and lid-gated active-site loops. The reaction is reversible: acetylation of Lys91 under high glucose favours the anaplerotic carboxylation of phosphoenolpyruvate, and SIRT1 deacetylation restores the gluconeogenic direction. Pck1 transcription is induced by glucagon/cAMP and glucocorticoids and repressed by insulin. It is distinct from the mitochondrial isozyme encoded by Pck2. In human cancer cells, AKT-phosphorylated PCK1 has been reported to act as a GTP-dependent protein kinase on INSIG1/2 at the endoplasmic reticulum, a function not yet examined in rat.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000287 magnesium ion binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Magnesium ion binding, transferred from human PCK1 (P35558). Reason: GTP-dependent PEPCKs use Mn2+ at the active-site M1 metal and a divalent cation (physiologically Mg2+) complexed with the nucleotide at the M2 site. The human structure (PMID:11851336) shows the nucleotide pocket; rat structures show the two-metal arrangement with Mn2+ (PMID:17685635). The nucleotide-associated Mg2+ binding is real but is a cofactor detail of the core GO:0004613 activity, so non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P35558 · PCK1 (human) SUPPORTS TRANSFER Human PCK1 IDA (PMID:11851336); the metal sites are conserved in rat. Supporting Evidence: PMID:11851336 Three phenylalanine residues form the walls of the guanine-binding pocket on the enzyme's surface PMID:17685635 illustrate inner-sphere coordination of OAA to the manganese ion file:rat/Pck1/Pck1-uniprot.txt Binds 1 Mn(2+) ion per subunit. |
| GO:0000287 magnesium ion binding | ISS PMID:11851336 Crystal structure of human cytosolic phosphoenolpyruvate car... | KEEP AS NON CORE | Summary: Magnesium ion binding, transferred from human PCK1 (P35558). Reason: GTP-dependent PEPCKs use Mn2+ at the active-site M1 metal and a divalent cation (physiologically Mg2+) complexed with the nucleotide at the M2 site. The human structure (PMID:11851336) shows the nucleotide pocket; rat structures show the two-metal arrangement with Mn2+ (PMID:17685635). The nucleotide-associated Mg2+ binding is real but is a cofactor detail of the core GO:0004613 activity, so non-core. Supporting Evidence: PMID:11851336 Three phenylalanine residues form the walls of the guanine-binding pocket on the enzyme's surface PMID:17685635 illustrate inner-sphere coordination of OAA to the manganese ion file:rat/Pck1/Pck1-uniprot.txt Binds 1 Mn(2+) ion per subunit. |
| GO:0004550 nucleoside diphosphate kinase activity | EXP PMID:1383219 Phosphorylation of carbovir enantiomers by cellular enzymes ... | MARK AS OVER ANNOTATED | Summary: Nucleoside diphosphate kinase activity (Reactome EXP, PMID:1383219), from the in vitro phosphorylation of carbovir diphosphate. Reason: GO:0004550 is ATP + NDP = ADP + NTP. The row comes from the Reactome reaction R-RNO-2162084, in which rat PCK1 converts the antiviral nucleoside analogue carbovir diphosphate to the triphosphate in vitro. The cached abstract names other kinases but not PEPCK, and the full text could not be read. The physiological reverse reaction of PEPCK transfers a phosphoryl group from PEP to GDP (PEP + CO2 + GDP -> OAA + GTP), so phosphorylation of a GDP analogue by PEPCK is most likely its own carboxykinase chemistry acting on an unnatural nucleotide rather than an ATP-dependent NDP kinase. Even taken at face value it is a xenobiotic, in vitro side activity. Not REMOVE because the experiment itself cannot be inspected. Supporting Evidence: Reactome:R-RNO-2162084 Cytosolic PCK1 (phosphoenolpyruvate carboxykinase 1) catalyzes the reaction of carbovir diphosphate and ATP to form carbovir triphosphate and ADP. PMID:1383219 Pyruvate kinase, phosphoglycerate kinase, and creatine kinase phosphorylated both enantiomers of carbovir diphosphate at similar rates. file:rat/Pck1/Pck1-uniprot.txt Cytosolic phosphoenolpyruvate carboxykinase that catalyzes the reversible decarboxylation and phosphorylation of oxaloacetate (OAA) and acts as the rate-limiting enzyme in gluconeogenesis |
| GO:0004611 phosphoenolpyruvate carboxykinase activity | IDA PMID:11440903 Mechanism of fat-induced hepatic gluconeogenesis: effect of ... | MODIFY | Summary: PEPCK activity (RGD IDA, PMID:11440903) measured in rat liver, kidney or hepatoma extracts. Reason: PEPCK activity was assayed in rat tissue or cell extracts, which supports the claim. The gene is the GTP-specific cytosolic isozyme and already carries the child term GO:0004613, which states the nucleotide specificity (oxaloacetate + GTP = PEP + GDP + CO2). Refine to that term. Proposed replacements: phosphoenolpyruvate carboxykinase (GTP) activity Supporting Evidence: PMID:11440903 Gluconeogenic enzyme activity and, where appropriate, protein and mRNA levels were measured in liver tissues. file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 |
| GO:0004611 phosphoenolpyruvate carboxykinase activity | IDA PMID:11820793 Phosphoenolpyruvate carboxykinase is induced in growth-arres... | MODIFY | Summary: PEPCK activity (RGD IDA, PMID:11820793) measured in rat liver, kidney or hepatoma extracts. Reason: PEPCK activity was assayed in rat tissue or cell extracts, which supports the claim. The gene is the GTP-specific cytosolic isozyme and already carries the child term GO:0004613, which states the nucleotide specificity (oxaloacetate + GTP = PEP + GDP + CO2). Refine to that term. Proposed replacements: phosphoenolpyruvate carboxykinase (GTP) activity Supporting Evidence: PMID:11820793 Induction of growth arrest either by contact inhibition (high culture density) or by serum deprivation correlated with significant increases in PEPCK protein and its mRNA. file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 |
| GO:0004611 phosphoenolpyruvate carboxykinase activity | IDA PMID:4303362 Gluconeogenesis in developing rat kidney cortex. | MODIFY | Summary: PEPCK activity (RGD IDA, PMID:4303362) measured in rat liver, kidney or hepatoma extracts. Reason: PEPCK activity was assayed in rat tissue or cell extracts, which supports the claim. The gene is the GTP-specific cytosolic isozyme and already carries the child term GO:0004613, which states the nucleotide specificity (oxaloacetate + GTP = PEP + GDP + CO2). Refine to that term. Proposed replacements: phosphoenolpyruvate carboxykinase (GTP) activity Supporting Evidence: PMID:4303362 Glucose 6-phosphatase and phosphoenolpyruvate carboxykinase are present in late foetal (21-22-day-old) tissue and increase rapidly postnatally. file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 |
| GO:0004611 phosphoenolpyruvate carboxykinase activity | IDA PMID:4353083 Induction and suppression of the key enzymes of glycolysis a... | MODIFY | Summary: PEPCK activity (RGD IDA, PMID:4353083) measured in rat liver, kidney or hepatoma extracts. Reason: PEPCK activity was assayed in rat tissue or cell extracts, which supports the claim. The gene is the GTP-specific cytosolic isozyme and already carries the child term GO:0004613, which states the nucleotide specificity (oxaloacetate + GTP = PEP + GDP + CO2). Refine to that term. Proposed replacements: phosphoenolpyruvate carboxykinase (GTP) activity Supporting Evidence: PMID:4353083 Measurements were made of the activities of the four key enzymes involved in gluconeogenesis file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 |
| GO:0004611 phosphoenolpyruvate carboxykinase activity | IEA GO_REF:0000120 | MODIFY | Summary: PEPCK activity, combined IEA from InterPro PEPCK-GTP family signatures and mouse ortholog. Reason: Correct family-level activity. Rat Pck1 is a GTP-dependent PEPCK (Rhea:10388 in UniProt with experimental evidence), so the more specific child GO:0004613, which the gene already carries, should be used. Proposed replacements: phosphoenolpyruvate carboxykinase (GTP) activity Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 PMID:17685635 In the PEPCK-Mn2+-GTP structure, the same water molecule displaced by the C1 carboxylate of OAA is displaced by one of the gamma-phosphate oxygens of the triphosphate nucleotide. |
| GO:0004611 phosphoenolpyruvate carboxykinase activity | ISO GO_REF:0000121 | MODIFY | Summary: PEPCK activity, ISO from mouse Pck1 (MGI:97501). Reason: Correct but general: the mouse source and rat enzyme are the GTP-specific cytosolic isozyme, captured by the child term GO:0004613 that rat Pck1 already carries. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:97501 · Pck1 (mouse) SUPPORTS TRANSFER Mouse Pck1 is the cytosolic GTP-dependent PEPCK; the transfer is sound, only the term is general. Proposed replacements: phosphoenolpyruvate carboxykinase (GTP) activity Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 |
| GO:0004613 phosphoenolpyruvate carboxykinase (GTP) activity | EXP PMID:28345895 Asymmetric Anchoring Is Required for Efficient Ω-Loop Openin... | ACCEPT | Summary: PEPCK (GTP) activity, EXP from PMID:28345895. Reason: This is the core catalytic activity of rat PEPCK-C: GTP-dependent decarboxylation and phosphorylation of oxaloacetate to phosphoenolpyruvate, reversible in vitro. Recombinant rat PEPCK-C is the main kinetic and structural model for the GTP-dependent PEPCKs (Holyoak lab, PMID:17685635, PMID:26322521, PMID:26709450, PMID:28345895, PMID:31461616) and its activity in rat liver extracts has been measured since the 1960s. Supporting Evidence: PMID:28345895 This is exemplified by a reduction in kcat for the H477R mutant by an order of magnitude in the direction of OAA synthesis, while in the direction of PEP synthesis, it decreased by a factor of only 2. file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 |
| GO:0004613 phosphoenolpyruvate carboxykinase (GTP) activity | IBA GO_REF:0000033 | ACCEPT | Summary: PEPCK (GTP) activity, IBA from PANTHER node PTN000169226. Reason: The GTP-dependent PEPCK activity is ancestral to the PTHR11561 family and is retained by both vertebrate isozymes; rat Pck1 is among the experimentally characterised members (RGD:3267 appears among the sources, as expected for a gene with its own experimental data). Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 PMID:17685635 The structures are consistent with a mechanism of direct in-line phosphoryl transfer, supported by the observed stereochemistry of the reaction. |
| GO:0004613 phosphoenolpyruvate carboxykinase (GTP) activity | IDA PMID:16125296 Response of glucose metabolism enzymes in an acute porphyria... | ACCEPT | Summary: PEPCK (GTP) activity, IDA from PMID:16125296. Reason: This is the core catalytic activity of rat PEPCK-C: GTP-dependent decarboxylation and phosphorylation of oxaloacetate to phosphoenolpyruvate, reversible in vitro. Recombinant rat PEPCK-C is the main kinetic and structural model for the GTP-dependent PEPCKs (Holyoak lab, PMID:17685635, PMID:26322521, PMID:26709450, PMID:28345895, PMID:31461616) and its activity in rat liver extracts has been measured since the 1960s. Supporting Evidence: PMID:16125296 PEPCK activity decreased about 30% in group H with respect to groups C and L file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 |
| GO:0004613 phosphoenolpyruvate carboxykinase (GTP) activity | IDA PMID:26322521 Inhibition and Allosteric Regulation of Monomeric Phosphoeno... | ACCEPT | Summary: PEPCK (GTP) activity, IDA from PMID:26322521. Reason: This is the core catalytic activity of rat PEPCK-C: GTP-dependent decarboxylation and phosphorylation of oxaloacetate to phosphoenolpyruvate, reversible in vitro. Recombinant rat PEPCK-C is the main kinetic and structural model for the GTP-dependent PEPCKs (Holyoak lab, PMID:17685635, PMID:26322521, PMID:26709450, PMID:28345895, PMID:31461616) and its activity in rat liver extracts has been measured since the 1960s. Supporting Evidence: PMID:26322521 PEPCK is inhibited by the binding of MPA at two discrete binding sites file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 |
| GO:0004613 phosphoenolpyruvate carboxykinase (GTP) activity | IDA PMID:26709450 Utilization of Substrate Intrinsic Binding Energy for Confor... | ACCEPT | Summary: PEPCK (GTP) activity, IDA from PMID:26709450. Reason: This is the core catalytic activity of rat PEPCK-C: GTP-dependent decarboxylation and phosphorylation of oxaloacetate to phosphoenolpyruvate, reversible in vitro. Recombinant rat PEPCK-C is the main kinetic and structural model for the GTP-dependent PEPCKs (Holyoak lab, PMID:17685635, PMID:26322521, PMID:26709450, PMID:28345895, PMID:31461616) and its activity in rat liver extracts has been measured since the 1960s. Supporting Evidence: PMID:26709450 Phosphoenolpyruvate carboxykinase (PEPCK) is an essential metabolic enzyme operating in the gluconeogenesis and glyceroneogenesis pathways. file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 |
| GO:0004613 phosphoenolpyruvate carboxykinase (GTP) activity | IDA PMID:30193097 Dynamic Acetylation of Phosphoenolpyruvate Carboxykinase Tog... | ACCEPT | Summary: PEPCK (GTP) activity, IDA from PMID:30193097. Reason: This is the core catalytic activity of rat PEPCK-C: GTP-dependent decarboxylation and phosphorylation of oxaloacetate to phosphoenolpyruvate, reversible in vitro. Recombinant rat PEPCK-C is the main kinetic and structural model for the GTP-dependent PEPCKs (Holyoak lab, PMID:17685635, PMID:26322521, PMID:26709450, PMID:28345895, PMID:31461616) and its activity in rat liver extracts has been measured since the 1960s. Supporting Evidence: PMID:30193097 dynamic acetylation of PCK1 interconverts the enzyme between gluconeogenic and anaplerotic activities file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 |
| GO:0004613 phosphoenolpyruvate carboxykinase (GTP) activity | IDA PMID:31461616 Characterization of 3-[(Carboxymethyl)thio]picolinic Acid: A... | ACCEPT | Summary: PEPCK (GTP) activity, IDA from PMID:31461616. Reason: This is the core catalytic activity of rat PEPCK-C: GTP-dependent decarboxylation and phosphorylation of oxaloacetate to phosphoenolpyruvate, reversible in vitro. Recombinant rat PEPCK-C is the main kinetic and structural model for the GTP-dependent PEPCKs (Holyoak lab, PMID:17685635, PMID:26322521, PMID:26709450, PMID:28345895, PMID:31461616) and its activity in rat liver extracts has been measured since the 1960s. Supporting Evidence: PMID:31461616 These data demonstrate that CMP acts as a competitive inhibitor at the OAA/PEP binding site file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 |
| GO:0004613 phosphoenolpyruvate carboxykinase (GTP) activity | IDA PMID:4186849 Purification of phosphoenolpyruvate carboxykinase from the c... | ACCEPT | Summary: PEPCK (GTP) activity, IDA from PMID:4186849. Reason: This is the core catalytic activity of rat PEPCK-C: GTP-dependent decarboxylation and phosphorylation of oxaloacetate to phosphoenolpyruvate, reversible in vitro. Recombinant rat PEPCK-C is the main kinetic and structural model for the GTP-dependent PEPCKs (Holyoak lab, PMID:17685635, PMID:26322521, PMID:26709450, PMID:28345895, PMID:31461616) and its activity in rat liver extracts has been measured since the 1960s. Supporting Evidence: PMID:4186849 Purification of phosphoenolpyruvate carboxykinase from the cytosol fraction of rat liver file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 |
| GO:0004613 phosphoenolpyruvate carboxykinase (GTP) activity | IDA PMID:6049928 Phosphoenolpyruvate carboxykinase and pyruvate carboxylase i... | ACCEPT | Summary: PEPCK (GTP) activity, IDA from PMID:6049928. Reason: This is the core catalytic activity of rat PEPCK-C: GTP-dependent decarboxylation and phosphorylation of oxaloacetate to phosphoenolpyruvate, reversible in vitro. Recombinant rat PEPCK-C is the main kinetic and structural model for the GTP-dependent PEPCKs (Holyoak lab, PMID:17685635, PMID:26322521, PMID:26709450, PMID:28345895, PMID:31461616) and its activity in rat liver extracts has been measured since the 1960s. Supporting Evidence: PMID:6049928 Similar studies of the intracellular distribution of phosphoenolpyruvate carboxykinase show that more than 90% of the activity is in the cytoplasm. file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 |
| GO:0004613 phosphoenolpyruvate carboxykinase (GTP) activity | IEA GO_REF:0000120 | ACCEPT | Summary: PEPCK (GTP) activity, combined IEA (InterPro/ARBA/ortholog). Reason: Consistent with the experimental data on rat PEPCK-C; core activity. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 |
| GO:0004613 phosphoenolpyruvate carboxykinase (GTP) activity | ISO GO_REF:0000121 | ACCEPT | Summary: PEPCK (GTP) activity, ISO from MGI:MGI:97501. Reason: Transfer from an orthologous cytosolic PEPCK; consistent with direct rat evidence for the same activity. Core. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 PMID:26709450 Phosphoenolpyruvate carboxykinase (PEPCK) is an essential metabolic enzyme operating in the gluconeogenesis and glyceroneogenesis pathways. |
| GO:0004613 phosphoenolpyruvate carboxykinase (GTP) activity | ISO GO_REF:0000121 | ACCEPT | Summary: PEPCK (GTP) activity, ISO from RGD:14022993. Reason: Transfer from an orthologous cytosolic PEPCK; consistent with direct rat evidence for the same activity. Core. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 PMID:26709450 Phosphoenolpyruvate carboxykinase (PEPCK) is an essential metabolic enzyme operating in the gluconeogenesis and glyceroneogenesis pathways. |
| GO:0004613 phosphoenolpyruvate carboxykinase (GTP) activity | ISO GO_REF:0000121 | ACCEPT | Summary: PEPCK (GTP) activity, ISO from UniProtKB:P35558. Reason: Transfer from an orthologous cytosolic PEPCK; consistent with direct rat evidence for the same activity. Core. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 PMID:26709450 Phosphoenolpyruvate carboxykinase (PEPCK) is an essential metabolic enzyme operating in the gluconeogenesis and glyceroneogenesis pathways. |
| GO:0005525 GTP binding | IDA PMID:17685635 Structures of rat cytosolic PEPCK: insight into the mechanis... | KEEP AS NON CORE | Summary: GTP binding, IDA from rat PEPCK-C crystal structures (PMID:17685635). Reason: GTP is the phosphoryl-donor substrate; the Mn2+-GTP complex structure shows its binding mode. Substrate binding is entailed by the core GO:0004613 activity and is kept as non-core. Supporting Evidence: PMID:17685635 In the PEPCK-Mn2+-GTP structure, the same water molecule displaced by the C1 carboxylate of OAA is displaced by one of the gamma-phosphate oxygens of the triphosphate nucleotide. |
| GO:0005525 GTP binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: GTP binding, IEA from InterPro IPR008209 (PEPCK, GTP-utilising). Reason: Accurate; GTP is a substrate. Non-core, entailed by GO:0004613. Supporting Evidence: PMID:17685635 In the PEPCK-Mn2+-GTP structure, the same water molecule displaced by the C1 carboxylate of OAA is displaced by one of the gamma-phosphate oxygens of the triphosphate nucleotide. |
| GO:0005525 GTP binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: GTP binding, ISO from human PCK1. Reason: Accurate; GTP is a substrate (rat structure, PMID:17685635). Non-core, entailed by GO:0004613. Supporting Evidence: PMID:17685635 In the PEPCK-Mn2+-GTP structure, the same water molecule displaced by the C1 carboxylate of OAA is displaced by one of the gamma-phosphate oxygens of the triphosphate nucleotide. PMID:11851336 Three phenylalanine residues form the walls of the guanine-binding pocket on the enzyme's surface |
| GO:0005737 cytoplasm | IDA PMID:4186849 Purification of phosphoenolpyruvate carboxykinase from the c... | MODIFY | Summary: Cytoplasm, IDA from the purification of the enzyme from the rat liver cytosol fraction (PMID:4186849). Reason: The enzyme was purified from the soluble (cytosol) fraction of rat liver and distinguished from the mitochondrial isozyme. The location is correct but cytoplasm is broader than the evidence: the gene already carries GO:0005829 cytosol, a part_of child of cytoplasm, which is the precise compartment. Proposed replacements: cytosol Supporting Evidence: PMID:4186849 Purification of phosphoenolpyruvate carboxykinase from the cytosol fraction of rat liver PMID:6049928 Similar studies of the intracellular distribution of phosphoenolpyruvate carboxykinase show that more than 90% of the activity is in the cytoplasm. file:rat/Pck1/Pck1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | REMOVE | Summary: Mitochondrion, IBA from PANTHER node PTN000169230. Reason: Vertebrates have two PEPCK-GTP isozymes: cytosolic Pck1 and mitochondrial Pck2. The IBA donors (MGI:1860456 Pck2, UniProtKB:Q16822 human PCK2) are both the mitochondrial paralog. Rat Pck1 is the cytosolic form: it was purified from the cytosol fraction and is immunochemically distinct from the mitochondrial enzyme (PMID:4186849), >90% of adult rat liver PEPCK activity is cytoplasmic (PMID:6049928), and in rat islets, which lack PEPCK-C, all PEPCK activity is mitochondrial PEPCK-M (PMID:19635791). The mitochondrial location belongs to the PCK2 branch and should not propagate to PCK1. This is an over-propagated IBA argued against on biological grounds. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN000169230 SUPPORTS SOURCE BUT NOT TARGET Location seeded only by PCK2 (mitochondrial) members; the PCK1 branch is cytosolic. MGI:MGI:1860456 · Pck2 (mouse) SUPPORTS SOURCE BUT NOT TARGET Mouse mitochondrial paralog Pck2. UniProtKB:Q16822 · PCK2 (human) SUPPORTS SOURCE BUT NOT TARGET Human mitochondrial paralog PCK2. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt In eukaryotes there are two isozymes: a cytoplasmic one and a mitochondrial one. PMID:6049928 Similar studies of the intracellular distribution of phosphoenolpyruvate carboxykinase show that more than 90% of the activity is in the cytoplasm. PMID:19635791 PEPCK-M but not PEPCK-C is present in INS-1 832/13 cells, rat islets, and mouse islets. PMID:19635791 Because insulin-secreting cells lack PEPCK-C |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Endoplasmic reticulum, IEA from human PCK1 (P35558) / mouse Pck1. Reason: The ER location rests on human PCK1 in HCC cells, where AKT phosphorylation at Ser90 drives translocation of a fraction of PCK1 to the ER (PMID:32322062); UniProt carries it for rat "By similarity". The organelle claim is the observed one (no sub-compartment can be resolved from it). It is a conditional, signalling-dependent pool, not the location of the enzyme's metabolic activity (cytosol), so it is kept as non-core. Checked source: human IDA (PMID:32322062). Supporting Evidence: PMID:32322062 Phosphorylated PCK1 translocates to the endoplasmic reticulum, where it uses GTP as a phosphate donor to phosphorylate INSIG1 at Ser207 and INSIG2 at Ser151. file:rat/Pck1/Pck1-uniprot.txt Phosphorylation at Ser-90 promotes translocation to the endoplasmic reticulum. |
| GO:0005783 endoplasmic reticulum | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Endoplasmic reticulum, ISO from human PCK1 (P35558) / mouse Pck1. Reason: The ER location rests on human PCK1 in HCC cells, where AKT phosphorylation at Ser90 drives translocation of a fraction of PCK1 to the ER (PMID:32322062); UniProt carries it for rat "By similarity". The organelle claim is the observed one (no sub-compartment can be resolved from it). It is a conditional, signalling-dependent pool, not the location of the enzyme's metabolic activity (cytosol), so it is kept as non-core. Checked source: human IDA (PMID:32322062). Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: MGI:MGI:97501 SUPPORTS TRANSFER Source location from the human HCC study PMID:32322062; Ser90 conserved in rat. Supporting Evidence: PMID:32322062 Phosphorylated PCK1 translocates to the endoplasmic reticulum, where it uses GTP as a phosphate donor to phosphorylate INSIG1 at Ser207 and INSIG2 at Ser151. file:rat/Pck1/Pck1-uniprot.txt Phosphorylation at Ser-90 promotes translocation to the endoplasmic reticulum. |
| GO:0005783 endoplasmic reticulum | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Endoplasmic reticulum, ISO from human PCK1 (P35558) / mouse Pck1. Reason: The ER location rests on human PCK1 in HCC cells, where AKT phosphorylation at Ser90 drives translocation of a fraction of PCK1 to the ER (PMID:32322062); UniProt carries it for rat "By similarity". The organelle claim is the observed one (no sub-compartment can be resolved from it). It is a conditional, signalling-dependent pool, not the location of the enzyme's metabolic activity (cytosol), so it is kept as non-core. Checked source: human IDA (PMID:32322062). Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:P35558 SUPPORTS TRANSFER Source location from the human HCC study PMID:32322062; Ser90 conserved in rat. Supporting Evidence: PMID:32322062 Phosphorylated PCK1 translocates to the endoplasmic reticulum, where it uses GTP as a phosphate donor to phosphorylate INSIG1 at Ser207 and INSIG2 at Ser151. file:rat/Pck1/Pck1-uniprot.txt Phosphorylation at Ser-90 promotes translocation to the endoplasmic reticulum. |
| GO:0005783 endoplasmic reticulum | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Endoplasmic reticulum, ISS from human PCK1 (P35558) / mouse Pck1. Reason: The ER location rests on human PCK1 in HCC cells, where AKT phosphorylation at Ser90 drives translocation of a fraction of PCK1 to the ER (PMID:32322062); UniProt carries it for rat "By similarity". The organelle claim is the observed one (no sub-compartment can be resolved from it). It is a conditional, signalling-dependent pool, not the location of the enzyme's metabolic activity (cytosol), so it is kept as non-core. Checked source: human IDA (PMID:32322062). Supporting Evidence: PMID:32322062 Phosphorylated PCK1 translocates to the endoplasmic reticulum, where it uses GTP as a phosphate donor to phosphorylate INSIG1 at Ser207 and INSIG2 at Ser151. file:rat/Pck1/Pck1-uniprot.txt Phosphorylation at Ser-90 promotes translocation to the endoplasmic reticulum. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Cytosol, IBA. Reason: Rat PEPCK-C is the cytosolic isozyme: purified from the liver cytosol fraction (PMID:4186849), >90% of liver PEPCK activity is cytoplasmic (PMID:6049928), and it lacks a mitochondrial targeting sequence. Cytosol is where the core activity acts. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol PMID:6049928 Similar studies of the intracellular distribution of phosphoenolpyruvate carboxykinase show that more than 90% of the activity is in the cytoplasm. PMID:4186849 Purification of phosphoenolpyruvate carboxykinase from the cytosol fraction of rat liver |
| GO:0005829 cytosol | IEA GO_REF:0000120 | ACCEPT | Summary: Cytosol, IEA. Reason: Rat PEPCK-C is the cytosolic isozyme: purified from the liver cytosol fraction (PMID:4186849), >90% of liver PEPCK activity is cytoplasmic (PMID:6049928), and it lacks a mitochondrial targeting sequence. Cytosol is where the core activity acts. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol PMID:6049928 Similar studies of the intracellular distribution of phosphoenolpyruvate carboxykinase show that more than 90% of the activity is in the cytoplasm. PMID:4186849 Purification of phosphoenolpyruvate carboxykinase from the cytosol fraction of rat liver |
| GO:0005829 cytosol | ISO GO_REF:0000121 | ACCEPT | Summary: Cytosol, ISO. Reason: Rat PEPCK-C is the cytosolic isozyme: purified from the liver cytosol fraction (PMID:4186849), >90% of liver PEPCK activity is cytoplasmic (PMID:6049928), and it lacks a mitochondrial targeting sequence. Cytosol is where the core activity acts. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol PMID:6049928 Similar studies of the intracellular distribution of phosphoenolpyruvate carboxykinase show that more than 90% of the activity is in the cytoplasm. PMID:4186849 Purification of phosphoenolpyruvate carboxykinase from the cytosol fraction of rat liver |
| GO:0005829 cytosol | ISO GO_REF:0000121 | ACCEPT | Summary: Cytosol, ISO. Reason: Rat PEPCK-C is the cytosolic isozyme: purified from the liver cytosol fraction (PMID:4186849), >90% of liver PEPCK activity is cytoplasmic (PMID:6049928), and it lacks a mitochondrial targeting sequence. Cytosol is where the core activity acts. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol PMID:6049928 Similar studies of the intracellular distribution of phosphoenolpyruvate carboxykinase show that more than 90% of the activity is in the cytoplasm. PMID:4186849 Purification of phosphoenolpyruvate carboxykinase from the cytosol fraction of rat liver |
| GO:0005829 cytosol | ISO GO_REF:0000121 | ACCEPT | Summary: Cytosol, ISO. Reason: Rat PEPCK-C is the cytosolic isozyme: purified from the liver cytosol fraction (PMID:4186849), >90% of liver PEPCK activity is cytoplasmic (PMID:6049928), and it lacks a mitochondrial targeting sequence. Cytosol is where the core activity acts. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol PMID:6049928 Similar studies of the intracellular distribution of phosphoenolpyruvate carboxykinase show that more than 90% of the activity is in the cytoplasm. PMID:4186849 Purification of phosphoenolpyruvate carboxykinase from the cytosol fraction of rat liver |
| GO:0005829 cytosol | ISS GO_REF:0000024 | ACCEPT | Summary: Cytosol, ISS. Reason: Rat PEPCK-C is the cytosolic isozyme: purified from the liver cytosol fraction (PMID:4186849), >90% of liver PEPCK activity is cytoplasmic (PMID:6049928), and it lacks a mitochondrial targeting sequence. Cytosol is where the core activity acts. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol PMID:6049928 Similar studies of the intracellular distribution of phosphoenolpyruvate carboxykinase show that more than 90% of the activity is in the cytoplasm. PMID:4186849 Purification of phosphoenolpyruvate carboxykinase from the cytosol fraction of rat liver |
| GO:0005829 cytosol | TAS Reactome:R-RNO-2162084 | ACCEPT | Summary: Cytosol, TAS. Reason: Rat PEPCK-C is the cytosolic isozyme: purified from the liver cytosol fraction (PMID:4186849), >90% of liver PEPCK activity is cytoplasmic (PMID:6049928), and it lacks a mitochondrial targeting sequence. Cytosol is where the core activity acts. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol PMID:6049928 Similar studies of the intracellular distribution of phosphoenolpyruvate carboxykinase show that more than 90% of the activity is in the cytoplasm. PMID:4186849 Purification of phosphoenolpyruvate carboxykinase from the cytosol fraction of rat liver |
| GO:0006006 glucose metabolic process | IMP PMID:18055057 Efficient delivery of siRNA using dendritic poly(L-lysine) f... | MODIFY | Summary: Glucose metabolic process, IMP from siRNA knockdown in H4IIEC3 rat hepatoma cells (PMID:18055057). Reason: Knockdown of PEPCK reduced glucose production by the hepatoma cells, i.e. the defect is in glucose synthesis. Glucose metabolic process is correct but general; gluconeogenesis (GO:0006094, an is_a child), which the gene already carries, is the specific process. Proposed replacements: gluconeogenesis Supporting Evidence: PMID:18055057 the knockdown of PEPCK, which is the rate-limiting enzyme for gluconeogenesis, led to a reduction in glucose production in rat hepatoma H4IIEC3 cells. |
| GO:0006006 glucose metabolic process | ISO GO_REF:0000121 | MODIFY | Summary: Glucose metabolic process, ISO from human PCK1 (source IMP, PMID:14764811 promoter SNP study). Reason: True but general: PCK1's role in glucose metabolism is the gluconeogenic step, captured by the child term GO:0006094 which the gene already carries. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P35558 · PCK1 (human) SOURCE WEAK OR INFERRED Human source is a promoter-polymorphism association/reporter study (PMID:14764811), weak for a process claim but the general claim holds. Proposed replacements: gluconeogenesis Supporting Evidence: PMID:18055057 the knockdown of PEPCK, which is the rate-limiting enzyme for gluconeogenesis, led to a reduction in glucose production in rat hepatoma H4IIEC3 cells. file:rat/Pck1/Pck1-uniprot.txt Cytosolic phosphoenolpyruvate carboxykinase that catalyzes the reversible decarboxylation and phosphorylation of oxaloacetate (OAA) and acts as the rate-limiting enzyme in gluconeogenesis |
| GO:0006094 gluconeogenesis | IBA GO_REF:0000033 | ACCEPT | Summary: Gluconeogenesis, IBA (GO_REF:0000033). Reason: PEPCK-C catalyses the committed, rate-limiting step of gluconeogenesis from lactate, amino acids and TCA-cycle intermediates in liver and kidney cortex. The rat enzyme appears at birth with the onset of hepatic gluconeogenesis (PMID:6049928), and knockdown in rat hepatoma cells lowers glucose output (PMID:18055057). Core process. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Cytosolic phosphoenolpyruvate carboxykinase that catalyzes the reversible decarboxylation and phosphorylation of oxaloacetate (OAA) and acts as the rate-limiting enzyme in gluconeogenesis PMID:18055057 the knockdown of PEPCK, which is the rate-limiting enzyme for gluconeogenesis, led to a reduction in glucose production in rat hepatoma H4IIEC3 cells. |
| GO:0006094 gluconeogenesis | IDA PMID:11440903 Mechanism of fat-induced hepatic gluconeogenesis: effect of ... | ACCEPT | Summary: Gluconeogenesis, IDA (PMID:11440903). Reason: PEPCK-C catalyses the committed, rate-limiting step of gluconeogenesis from lactate, amino acids and TCA-cycle intermediates in liver and kidney cortex. The rat enzyme appears at birth with the onset of hepatic gluconeogenesis (PMID:6049928), and knockdown in rat hepatoma cells lowers glucose output (PMID:18055057). Core process. Supporting Evidence: PMID:11440903 Gluconeogenic enzyme activity and, where appropriate, protein and mRNA levels were measured in liver tissues. file:rat/Pck1/Pck1-uniprot.txt Cytosolic phosphoenolpyruvate carboxykinase that catalyzes the reversible decarboxylation and phosphorylation of oxaloacetate (OAA) and acts as the rate-limiting enzyme in gluconeogenesis PMID:18055057 the knockdown of PEPCK, which is the rate-limiting enzyme for gluconeogenesis, led to a reduction in glucose production in rat hepatoma H4IIEC3 cells. |
| GO:0006094 gluconeogenesis | IDA PMID:4186849 Purification of phosphoenolpyruvate carboxykinase from the c... | ACCEPT | Summary: Gluconeogenesis, IDA (PMID:4186849). Reason: PEPCK-C catalyses the committed, rate-limiting step of gluconeogenesis from lactate, amino acids and TCA-cycle intermediates in liver and kidney cortex. The rat enzyme appears at birth with the onset of hepatic gluconeogenesis (PMID:6049928), and knockdown in rat hepatoma cells lowers glucose output (PMID:18055057). Core process. Supporting Evidence: PMID:4186849 Purification of phosphoenolpyruvate carboxykinase from the cytosol fraction of rat liver file:rat/Pck1/Pck1-uniprot.txt Cytosolic phosphoenolpyruvate carboxykinase that catalyzes the reversible decarboxylation and phosphorylation of oxaloacetate (OAA) and acts as the rate-limiting enzyme in gluconeogenesis PMID:18055057 the knockdown of PEPCK, which is the rate-limiting enzyme for gluconeogenesis, led to a reduction in glucose production in rat hepatoma H4IIEC3 cells. |
| GO:0006094 gluconeogenesis | IDA PMID:4303362 Gluconeogenesis in developing rat kidney cortex. | ACCEPT | Summary: Gluconeogenesis, IDA (PMID:4303362). Reason: PEPCK-C catalyses the committed, rate-limiting step of gluconeogenesis from lactate, amino acids and TCA-cycle intermediates in liver and kidney cortex. The rat enzyme appears at birth with the onset of hepatic gluconeogenesis (PMID:6049928), and knockdown in rat hepatoma cells lowers glucose output (PMID:18055057). Core process. Supporting Evidence: PMID:4303362 Glucose 6-phosphatase and phosphoenolpyruvate carboxykinase are present in late foetal (21-22-day-old) tissue and increase rapidly postnatally. file:rat/Pck1/Pck1-uniprot.txt Cytosolic phosphoenolpyruvate carboxykinase that catalyzes the reversible decarboxylation and phosphorylation of oxaloacetate (OAA) and acts as the rate-limiting enzyme in gluconeogenesis PMID:18055057 the knockdown of PEPCK, which is the rate-limiting enzyme for gluconeogenesis, led to a reduction in glucose production in rat hepatoma H4IIEC3 cells. |
| GO:0006094 gluconeogenesis | IDA PMID:4353083 Induction and suppression of the key enzymes of glycolysis a... | ACCEPT | Summary: Gluconeogenesis, IDA (PMID:4353083). Reason: PEPCK-C catalyses the committed, rate-limiting step of gluconeogenesis from lactate, amino acids and TCA-cycle intermediates in liver and kidney cortex. The rat enzyme appears at birth with the onset of hepatic gluconeogenesis (PMID:6049928), and knockdown in rat hepatoma cells lowers glucose output (PMID:18055057). Core process. Supporting Evidence: PMID:4353083 Measurements were made of the activities of the four key enzymes involved in gluconeogenesis file:rat/Pck1/Pck1-uniprot.txt Cytosolic phosphoenolpyruvate carboxykinase that catalyzes the reversible decarboxylation and phosphorylation of oxaloacetate (OAA) and acts as the rate-limiting enzyme in gluconeogenesis PMID:18055057 the knockdown of PEPCK, which is the rate-limiting enzyme for gluconeogenesis, led to a reduction in glucose production in rat hepatoma H4IIEC3 cells. |
| GO:0006094 gluconeogenesis | IDA PMID:6049928 Phosphoenolpyruvate carboxykinase and pyruvate carboxylase i... | ACCEPT | Summary: Gluconeogenesis, IDA (PMID:6049928). Reason: PEPCK-C catalyses the committed, rate-limiting step of gluconeogenesis from lactate, amino acids and TCA-cycle intermediates in liver and kidney cortex. The rat enzyme appears at birth with the onset of hepatic gluconeogenesis (PMID:6049928), and knockdown in rat hepatoma cells lowers glucose output (PMID:18055057). Core process. Supporting Evidence: PMID:6049928 It is suggested that the appearance of the soluble phosphoenolpyruvate carboxykinase at birth initiates the rapid increase in overall gluconeogenesis at this stage. file:rat/Pck1/Pck1-uniprot.txt Cytosolic phosphoenolpyruvate carboxykinase that catalyzes the reversible decarboxylation and phosphorylation of oxaloacetate (OAA) and acts as the rate-limiting enzyme in gluconeogenesis PMID:18055057 the knockdown of PEPCK, which is the rate-limiting enzyme for gluconeogenesis, led to a reduction in glucose production in rat hepatoma H4IIEC3 cells. |
| GO:0006094 gluconeogenesis | IEA GO_REF:0000120 | ACCEPT | Summary: Gluconeogenesis, IEA (GO_REF:0000120). Reason: PEPCK-C catalyses the committed, rate-limiting step of gluconeogenesis from lactate, amino acids and TCA-cycle intermediates in liver and kidney cortex. The rat enzyme appears at birth with the onset of hepatic gluconeogenesis (PMID:6049928), and knockdown in rat hepatoma cells lowers glucose output (PMID:18055057). Core process. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Cytosolic phosphoenolpyruvate carboxykinase that catalyzes the reversible decarboxylation and phosphorylation of oxaloacetate (OAA) and acts as the rate-limiting enzyme in gluconeogenesis PMID:18055057 the knockdown of PEPCK, which is the rate-limiting enzyme for gluconeogenesis, led to a reduction in glucose production in rat hepatoma H4IIEC3 cells. |
| GO:0006094 gluconeogenesis | ISO GO_REF:0000121 | ACCEPT | Summary: Gluconeogenesis, ISO (GO_REF:0000121). Reason: PEPCK-C catalyses the committed, rate-limiting step of gluconeogenesis from lactate, amino acids and TCA-cycle intermediates in liver and kidney cortex. The rat enzyme appears at birth with the onset of hepatic gluconeogenesis (PMID:6049928), and knockdown in rat hepatoma cells lowers glucose output (PMID:18055057). Core process. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Cytosolic phosphoenolpyruvate carboxykinase that catalyzes the reversible decarboxylation and phosphorylation of oxaloacetate (OAA) and acts as the rate-limiting enzyme in gluconeogenesis PMID:18055057 the knockdown of PEPCK, which is the rate-limiting enzyme for gluconeogenesis, led to a reduction in glucose production in rat hepatoma H4IIEC3 cells. |
| GO:0006094 gluconeogenesis | ISO GO_REF:0000121 | ACCEPT | Summary: Gluconeogenesis, ISO (GO_REF:0000121). Reason: PEPCK-C catalyses the committed, rate-limiting step of gluconeogenesis from lactate, amino acids and TCA-cycle intermediates in liver and kidney cortex. The rat enzyme appears at birth with the onset of hepatic gluconeogenesis (PMID:6049928), and knockdown in rat hepatoma cells lowers glucose output (PMID:18055057). Core process. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Cytosolic phosphoenolpyruvate carboxykinase that catalyzes the reversible decarboxylation and phosphorylation of oxaloacetate (OAA) and acts as the rate-limiting enzyme in gluconeogenesis PMID:18055057 the knockdown of PEPCK, which is the rate-limiting enzyme for gluconeogenesis, led to a reduction in glucose production in rat hepatoma H4IIEC3 cells. |
| GO:0006094 gluconeogenesis | ISO GO_REF:0000121 | ACCEPT | Summary: Gluconeogenesis, ISO (GO_REF:0000121). Reason: PEPCK-C catalyses the committed, rate-limiting step of gluconeogenesis from lactate, amino acids and TCA-cycle intermediates in liver and kidney cortex. The rat enzyme appears at birth with the onset of hepatic gluconeogenesis (PMID:6049928), and knockdown in rat hepatoma cells lowers glucose output (PMID:18055057). Core process. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Cytosolic phosphoenolpyruvate carboxykinase that catalyzes the reversible decarboxylation and phosphorylation of oxaloacetate (OAA) and acts as the rate-limiting enzyme in gluconeogenesis PMID:18055057 the knockdown of PEPCK, which is the rate-limiting enzyme for gluconeogenesis, led to a reduction in glucose production in rat hepatoma H4IIEC3 cells. |
| GO:0006094 gluconeogenesis | TAS PMID:11820793 Phosphoenolpyruvate carboxykinase is induced in growth-arres... | ACCEPT | Summary: Gluconeogenesis, TAS (PMID:11820793). Reason: PEPCK-C catalyses the committed, rate-limiting step of gluconeogenesis from lactate, amino acids and TCA-cycle intermediates in liver and kidney cortex. The rat enzyme appears at birth with the onset of hepatic gluconeogenesis (PMID:6049928), and knockdown in rat hepatoma cells lowers glucose output (PMID:18055057). Core process. Supporting Evidence: PMID:11820793 Induction of growth arrest either by contact inhibition (high culture density) or by serum deprivation correlated with significant increases in PEPCK protein and its mRNA. file:rat/Pck1/Pck1-uniprot.txt Cytosolic phosphoenolpyruvate carboxykinase that catalyzes the reversible decarboxylation and phosphorylation of oxaloacetate (OAA) and acts as the rate-limiting enzyme in gluconeogenesis PMID:18055057 the knockdown of PEPCK, which is the rate-limiting enzyme for gluconeogenesis, led to a reduction in glucose production in rat hepatoma H4IIEC3 cells. |
| GO:0006107 oxaloacetate metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Oxaloacetate metabolic process, IBA (GO_REF:0000033). Reason: PEPCK-C converts oxaloacetate to PEP (cataplerosis) and, when acetylated under high glucose, PEP back to oxaloacetate (anaplerosis, PMID:30193097). Oxaloacetate is its direct substrate/product, so this process term describes the reaction's metabolic role. Core. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 PMID:30193097 dynamic acetylation of PCK1 interconverts the enzyme between gluconeogenic and anaplerotic activities |
| GO:0006107 oxaloacetate metabolic process | IDA PMID:16125296 Response of glucose metabolism enzymes in an acute porphyria... | ACCEPT | Summary: Oxaloacetate metabolic process, IDA (PMID:16125296). Reason: PEPCK-C converts oxaloacetate to PEP (cataplerosis) and, when acetylated under high glucose, PEP back to oxaloacetate (anaplerosis, PMID:30193097). Oxaloacetate is its direct substrate/product, so this process term describes the reaction's metabolic role. Core. Supporting Evidence: PMID:16125296 PEPCK activity decreased about 30% in group H with respect to groups C and L file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 PMID:30193097 dynamic acetylation of PCK1 interconverts the enzyme between gluconeogenic and anaplerotic activities |
| GO:0006107 oxaloacetate metabolic process | IDA PMID:26322521 Inhibition and Allosteric Regulation of Monomeric Phosphoeno... | ACCEPT | Summary: Oxaloacetate metabolic process, IDA (PMID:26322521). Reason: PEPCK-C converts oxaloacetate to PEP (cataplerosis) and, when acetylated under high glucose, PEP back to oxaloacetate (anaplerosis, PMID:30193097). Oxaloacetate is its direct substrate/product, so this process term describes the reaction's metabolic role. Core. Supporting Evidence: PMID:26322521 PEPCK is inhibited by the binding of MPA at two discrete binding sites file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 PMID:30193097 dynamic acetylation of PCK1 interconverts the enzyme between gluconeogenic and anaplerotic activities |
| GO:0006107 oxaloacetate metabolic process | IDA PMID:26709450 Utilization of Substrate Intrinsic Binding Energy for Confor... | ACCEPT | Summary: Oxaloacetate metabolic process, IDA (PMID:26709450). Reason: PEPCK-C converts oxaloacetate to PEP (cataplerosis) and, when acetylated under high glucose, PEP back to oxaloacetate (anaplerosis, PMID:30193097). Oxaloacetate is its direct substrate/product, so this process term describes the reaction's metabolic role. Core. Supporting Evidence: PMID:26709450 Phosphoenolpyruvate carboxykinase (PEPCK) is an essential metabolic enzyme operating in the gluconeogenesis and glyceroneogenesis pathways. file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 PMID:30193097 dynamic acetylation of PCK1 interconverts the enzyme between gluconeogenic and anaplerotic activities |
| GO:0006107 oxaloacetate metabolic process | IDA PMID:30193097 Dynamic Acetylation of Phosphoenolpyruvate Carboxykinase Tog... | ACCEPT | Summary: Oxaloacetate metabolic process, IDA (PMID:30193097). Reason: PEPCK-C converts oxaloacetate to PEP (cataplerosis) and, when acetylated under high glucose, PEP back to oxaloacetate (anaplerosis, PMID:30193097). Oxaloacetate is its direct substrate/product, so this process term describes the reaction's metabolic role. Core. Supporting Evidence: PMID:30193097 dynamic acetylation of PCK1 interconverts the enzyme between gluconeogenic and anaplerotic activities file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 PMID:30193097 dynamic acetylation of PCK1 interconverts the enzyme between gluconeogenic and anaplerotic activities |
| GO:0006107 oxaloacetate metabolic process | IDA PMID:31461616 Characterization of 3-[(Carboxymethyl)thio]picolinic Acid: A... | ACCEPT | Summary: Oxaloacetate metabolic process, IDA (PMID:31461616). Reason: PEPCK-C converts oxaloacetate to PEP (cataplerosis) and, when acetylated under high glucose, PEP back to oxaloacetate (anaplerosis, PMID:30193097). Oxaloacetate is its direct substrate/product, so this process term describes the reaction's metabolic role. Core. Supporting Evidence: PMID:31461616 These data demonstrate that CMP acts as a competitive inhibitor at the OAA/PEP binding site file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 PMID:30193097 dynamic acetylation of PCK1 interconverts the enzyme between gluconeogenic and anaplerotic activities |
| GO:0006107 oxaloacetate metabolic process | IDA PMID:4303362 Gluconeogenesis in developing rat kidney cortex. | ACCEPT | Summary: Oxaloacetate metabolic process, IDA (PMID:4303362). Reason: PEPCK-C converts oxaloacetate to PEP (cataplerosis) and, when acetylated under high glucose, PEP back to oxaloacetate (anaplerosis, PMID:30193097). Oxaloacetate is its direct substrate/product, so this process term describes the reaction's metabolic role. Core. Supporting Evidence: PMID:4303362 Glucose 6-phosphatase and phosphoenolpyruvate carboxykinase are present in late foetal (21-22-day-old) tissue and increase rapidly postnatally. file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 PMID:30193097 dynamic acetylation of PCK1 interconverts the enzyme between gluconeogenic and anaplerotic activities |
| GO:0006107 oxaloacetate metabolic process | IDA PMID:6049928 Phosphoenolpyruvate carboxykinase and pyruvate carboxylase i... | ACCEPT | Summary: Oxaloacetate metabolic process, IDA (PMID:6049928). Reason: PEPCK-C converts oxaloacetate to PEP (cataplerosis) and, when acetylated under high glucose, PEP back to oxaloacetate (anaplerosis, PMID:30193097). Oxaloacetate is its direct substrate/product, so this process term describes the reaction's metabolic role. Core. Supporting Evidence: PMID:6049928 Similar studies of the intracellular distribution of phosphoenolpyruvate carboxykinase show that more than 90% of the activity is in the cytoplasm. file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 PMID:30193097 dynamic acetylation of PCK1 interconverts the enzyme between gluconeogenic and anaplerotic activities |
| GO:0006107 oxaloacetate metabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: Oxaloacetate metabolic process, IEA (GO_REF:0000107). Reason: PEPCK-C converts oxaloacetate to PEP (cataplerosis) and, when acetylated under high glucose, PEP back to oxaloacetate (anaplerosis, PMID:30193097). Oxaloacetate is its direct substrate/product, so this process term describes the reaction's metabolic role. Core. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 PMID:30193097 dynamic acetylation of PCK1 interconverts the enzyme between gluconeogenic and anaplerotic activities |
| GO:0006107 oxaloacetate metabolic process | ISO GO_REF:0000121 | ACCEPT | Summary: Oxaloacetate metabolic process, ISO (GO_REF:0000121). Reason: PEPCK-C converts oxaloacetate to PEP (cataplerosis) and, when acetylated under high glucose, PEP back to oxaloacetate (anaplerosis, PMID:30193097). Oxaloacetate is its direct substrate/product, so this process term describes the reaction's metabolic role. Core. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 PMID:30193097 dynamic acetylation of PCK1 interconverts the enzyme between gluconeogenic and anaplerotic activities |
| GO:0006107 oxaloacetate metabolic process | ISO GO_REF:0000121 | ACCEPT | Summary: Oxaloacetate metabolic process, ISO (GO_REF:0000121). Reason: PEPCK-C converts oxaloacetate to PEP (cataplerosis) and, when acetylated under high glucose, PEP back to oxaloacetate (anaplerosis, PMID:30193097). Oxaloacetate is its direct substrate/product, so this process term describes the reaction's metabolic role. Core. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 PMID:30193097 dynamic acetylation of PCK1 interconverts the enzyme between gluconeogenic and anaplerotic activities |
| GO:0006107 oxaloacetate metabolic process | ISO GO_REF:0000121 | ACCEPT | Summary: Oxaloacetate metabolic process, ISO (GO_REF:0000121). Reason: PEPCK-C converts oxaloacetate to PEP (cataplerosis) and, when acetylated under high glucose, PEP back to oxaloacetate (anaplerosis, PMID:30193097). Oxaloacetate is its direct substrate/product, so this process term describes the reaction's metabolic role. Core. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Reaction=oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 PMID:30193097 dynamic acetylation of PCK1 interconverts the enzyme between gluconeogenic and anaplerotic activities |
| GO:0006114 glycerol biosynthetic process | IDA PMID:4186849 Purification of phosphoenolpyruvate carboxykinase from the c... | MODIFY | Summary: Glycerol biosynthetic process, IDA (BHF-UCL) citing PMID:4186849. Reason: PEPCK-C's role in glycerol-lipid metabolism is glyceroneogenesis: PEP made by PEPCK-C is converted to dihydroxyacetone phosphate and then glycerol 3-phosphate, which is used to re-esterify fatty acids (PMID:11792850; PMID:26709450). The product is glycerol 3-phosphate, not free glycerol, so GO:0046167 glycerol-3-phosphate biosynthetic process is the accurate term (a lateral correction; GO:0046167 is not a descendant of GO:0006114). The cited 1969 purification paper is abstract-unavailable, so the assay behind this row could not be checked; the glyceroneogenic role itself is independently established. Proposed replacements: glycerol-3-phosphate biosynthetic process Supporting Evidence: PMID:26709450 Phosphoenolpyruvate carboxykinase (PEPCK) is an essential metabolic enzyme operating in the gluconeogenesis and glyceroneogenesis pathways. PMID:11792850 The importance of glyceroneogenesis in adipose tissue was assessed in mice by specifically eliminating the expression of the cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK-C), an enzyme that plays a pivotal role in the pathway. PMID:23052097 MR not only caused the transcriptional upregulation of genes associated with fatty acid synthesis but also of Lpin1, Pc, Pck1 and Pdk1, genes that are associated with glyceroneogenesis. |
| GO:0006114 glycerol biosynthetic process | ISO GO_REF:0000121 | MODIFY | Summary: Glycerol biosynthetic process, ISO from mouse Pck1 (MGI IMP, PMID:11792850, adipose PPARE mutant). Reason: The mouse adipose-specific loss of PEPCK-C reduces glyceroneogenesis and triglyceride deposition (PMID:11792850). Glyceroneogenesis makes glycerol 3-phosphate, so GO:0046167 is the accurate term (lateral correction; not a descendant of GO:0006114). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:97501 · Pck1 (mouse) SUPPORTS TRANSFER Mouse IMP supports glyceroneogenesis; only the term choice (glycerol vs glycerol 3-phosphate) is off. Proposed replacements: glycerol-3-phosphate biosynthetic process Supporting Evidence: PMID:11792850 The importance of glyceroneogenesis in adipose tissue was assessed in mice by specifically eliminating the expression of the cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK-C), an enzyme that plays a pivotal role in the pathway. PMID:11792850 Epididymal white adipose tissue from these mice had a reduced triglyceride deposition, with 25% of the animals displaying lipodystrophy. |
| GO:0006629 lipid metabolic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Lipid metabolic process, ISO from mouse Pck1 (acts_upstream_of_or_within; MGI IMP PMID:11792850). Reason: The mouse adipose PEPCK-C mutant has reduced triglyceride deposition. Pck1's direct contribution is the glycerol-3-phosphate backbone via glyceroneogenesis (captured by GO:0046167 in core functions), which is not a descendant of lipid metabolic process; this lipid-level consequence is as precise as the phenotype allows and is kept as non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: MGI:MGI:97501 · Pck1 (mouse) SUPPORTS TRANSFER Mouse IMP phenotype; acts_upstream_of_or_within qualifier appropriate. Supporting Evidence: PMID:11792850 Epididymal white adipose tissue from these mice had a reduced triglyceride deposition, with 25% of the animals displaying lipodystrophy. |
| GO:0009617 response to bacterium | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Response to bacterium, ISO from a mouse IEP (intestinal expression profiling). Reason: The mouse source is an expression change in a whole-genome profile of infected gnotobiotic mouse intestine. A transcript change does not show that Pck1 does any of the work of a response to bacteria, and nothing links PEPCK-C activity to host defence in rat. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK CONTEXT OR TISSUE MISMATCH Sources checked: MGI:MGI:97501 · Pck1 (mouse) SOURCE WEAK OR INFERRED Source is IEP from expression profiling (PMID:23012479). Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Cytosolic phosphoenolpyruvate carboxykinase that catalyzes the reversible decarboxylation and phosphorylation of oxaloacetate (OAA) and acts as the rate-limiting enzyme in gluconeogenesis |
| GO:0014823 response to activity | IEP PMID:16458327 Merit of physical exercise to reverse the higher gene expres... | MARK AS OVER ANNOTATED | Summary: response to activity, IEP (PMID:16458327). Reason: Endurance training reduced the elevated hepatic PEPCK mRNA and protein of obese Zucker rats (PMID:16458327). Pck1 is a heavily regulated metabolic gene whose mRNA or activity changes under many treatments; the change is a readout, and the enzyme itself does none of the work of sensing or responding to the stimulus. Supporting Evidence: PMID:16458327 the diabetes-related elevation in mRNA level and protein content of hepatic PEPCK were observed in non-exercise obese groups but they were markedly reduced by exercise training. |
| GO:0017076 purine nucleotide binding | IEA GO_REF:0000002 | TOO GENERAL | Summary: Purine nucleotide binding, IEA from InterPro. Reason: True (GTP and GDP are substrates), but entailed by the more specific GTP binding (GO:0005525) and GDP binding (GO:0019003) asserted elsewhere in this review. Supporting Evidence: PMID:17685635 In the PEPCK-Mn2+-GTP structure, the same water molecule displaced by the C1 carboxylate of OAA is displaced by one of the gamma-phosphate oxygens of the triphosphate nucleotide. |
| GO:0018105 peptidyl-serine phosphorylation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Peptidyl-serine phosphorylation, ISS from human PCK1 (PMID:32322062). Reason: All rat rows for the GTP-dependent protein kinase function (GO:0106264, GO:0018105, the ER location and the lipid-biosynthesis regulation terms) are transfers of one human study, PMID:32322062: in human hepatocellular carcinoma cells AKT phosphorylates PCK1 at Ser90, and PCK1 then moves to the ER and uses GTP to phosphorylate INSIG1 Ser207 and INSIG2 Ser151, releasing SCAP-SREBP. Ser90 is conserved in rat Pck1 (UniProt records the S90 mutagenesis in PMID:30193097), so the transfer is plausible, but no rat experiment on Pck1 protein kinase activity or INSIG phosphorylation exists and the human finding has not been reproduced in a normal gluconeogenic tissue. The term is kept as non-core: it describes a context-dependent moonlighting activity, not the enzyme's metabolic role. Supporting Evidence: PMID:32322062 Phosphorylated PCK1 translocates to the endoplasmic reticulum, where it uses GTP as a phosphate donor to phosphorylate INSIG1 at Ser207 and INSIG2 at Ser151. file:rat/Pck1/Pck1-uniprot.txt In addition to the phosphoenolpyruvate carboxykinase activity, also acts as a protein kinase when phosphorylated at Ser-90 |
| GO:0019003 GDP binding | IDA PMID:16125296 Response of glucose metabolism enzymes in an acute porphyria... | KEEP AS NON CORE | Summary: GDP binding, IDA (RGD, PMID:16125296). Reason: GDP is the product of the forward reaction and a substrate of the reverse reaction; rat PEPCK-C structures with Mn2+-OAA-Mn2+GDP show its binding. The cited porphyria study measured PEPCK activity, which involves the nucleotide; the binding itself is established structurally. Entailed by GO:0004613; non-core. Supporting Evidence: PMID:17685635 illustrate inner-sphere coordination of OAA to the manganese ion PMID:16125296 PEPCK activity decreased about 30% in group H with respect to groups C and L |
| GO:0030145 manganese ion binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Manganese ion binding, IBA (PTN000169226). Reason: Mn2+ is the active-site metal of GTP-dependent PEPCKs (one Mn2+ per subunit in all rat structures). Essential cofactor binding, entailed by the core activity; non-core. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Binds 1 Mn(2+) ion per subunit. PMID:17685635 illustrate inner-sphere coordination of OAA to the manganese ion |
| GO:0030145 manganese ion binding | IDA PMID:17685635 Structures of rat cytosolic PEPCK: insight into the mechanis... | KEEP AS NON CORE | Summary: Manganese ion binding, IDA from rat PEPCK-C structures (PMID:17685635). Reason: Rat structures show inner-sphere coordination of OAA to the active-site Mn2+. Cofactor binding entailed by the core activity; non-core. Supporting Evidence: PMID:17685635 illustrate inner-sphere coordination of OAA to the manganese ion file:rat/Pck1/Pck1-uniprot.txt Binds 1 Mn(2+) ion per subunit. |
| GO:0030145 manganese ion binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manganese ion binding, ISO from human PCK1. Reason: Consistent with direct rat structural evidence (PMID:17685635). Non-core cofactor binding. Supporting Evidence: PMID:17685635 illustrate inner-sphere coordination of OAA to the manganese ion file:rat/Pck1/Pck1-uniprot.txt Binds 1 Mn(2+) ion per subunit. |
| GO:0031406 carboxylic acid binding | IDA PMID:17685635 Structures of rat cytosolic PEPCK: insight into the mechanis... | KEEP AS NON CORE | Summary: Carboxylic acid binding, IDA from rat PEPCK-C structures with OAA (PMID:17685635). Reason: Oxaloacetate and phosphoenolpyruvate are carboxylic-acid substrates; the structures show OAA bound to the active-site metal. Substrate binding entailed by GO:0004613; non-core. Supporting Evidence: PMID:17685635 OAA is observed to bind in a number of different orientations coordinating directly to the active site metal. |
| GO:0031406 carboxylic acid binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Carboxylic acid binding, ISO from human PCK1. Reason: Accurate substrate binding (rat structures, PMID:17685635), entailed by GO:0004613; non-core. Supporting Evidence: PMID:17685635 OAA is observed to bind in a number of different orientations coordinating directly to the active site metal. |
| GO:0031667 response to nutrient levels | IEP PMID:23307605 Nutrigenomic effects of germinated brown rice and its bioact... | MARK AS OVER ANNOTATED | Summary: response to nutrient levels, IEP (PMID:23307605). Reason: Germinated brown rice down-regulated Pck1 mRNA in diabetic rats (PMID:23307605); this is a diet effect on a gluconeogenic marker gene, not nutrient sensing by Pck1. Pck1 is a heavily regulated metabolic gene whose mRNA or activity changes under many treatments; the change is a readout, and the enzyme itself does none of the work of sensing or responding to the stimulus. Supporting Evidence: PMID:23307605 GBR downregulated gluconeogenic genes (Fbp1 and Pck1) in a manner similar to, but more potently than, metformin |
| GO:0031667 response to nutrient levels | IEP PMID:25943649 Fasting for 3 days during the suckling-weaning transient per... | MARK AS OVER ANNOTATED | Summary: response to nutrient levels, IEP (PMID:25943649). Reason: Neonatal fasting raised adult hepatic PEPCK1 protein on a low-fat diet (PMID:25943649), a long-term programming effect. Pck1 is a heavily regulated metabolic gene whose mRNA or activity changes under many treatments; the change is a readout, and the enzyme itself does none of the work of sensing or responding to the stimulus. Supporting Evidence: PMID:25943649 PEPCK1 protein expression levels in rats fed the LF diet were higher in rats fasted for 3 days during the suckling-weaning transient period than in non-fasted rats. |
| GO:0032496 response to lipopolysaccharide | IEP PMID:19268478 Endotoxin induced hyperlactatemia and hypoglycemia is linked... | MARK AS OVER ANNOTATED | Summary: response to lipopolysaccharide, IEP (PMID:19268478). Reason: In LPS-treated rats hepatic PCK1 mRNA rose 44% while PEPCK-C activity was unchanged; the paper attributes the endotoxaemic hypoglycaemia to PEPCK-M (PMID:19268478). Pck1 is a heavily regulated metabolic gene whose mRNA or activity changes under many treatments; the change is a readout, and the enzyme itself does none of the work of sensing or responding to the stimulus. Supporting Evidence: PMID:19268478 Hepatic PCK1 mRNA levels increased by 44%, but PEPCK-C enzyme activity remained unchanged. |
| GO:0032868 response to insulin | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Response to insulin, ISO from human PCK1. Reason: Insulin represses PCK1 transcription (UniProt induction; PMID:14764811 promoter reporter). The enzyme does not transduce insulin signals; this is regulation of the gene, kept as non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P35558 · PCK1 (human) SUPPORTS TRANSFER Insulin repression of PCK1 transcription is conserved. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Regulated by cAMP, dexamethasone, glucagon and by insulin. PMID:14764811 The expression of a luciferase reporter construct containing -232G in three different cell lines showed significantly increased basal expression with no down-regulation by insulin compared with a construct containing -232C. |
| GO:0032868 response to insulin | ISS PMID:14764811 Promoter polymorphism in PCK1 (phosphoenolpyruvate carboxyki... | KEEP AS NON CORE | Summary: Response to insulin, ISS (PMID:14764811). Reason: Insulin represses Pck1 transcription; the human promoter study shows an insulin-resistant promoter allele. Regulation of the gene, non-core. Supporting Evidence: PMID:14764811 The expression of a luciferase reporter construct containing -232G in three different cell lines showed significantly increased basal expression with no down-regulation by insulin compared with a construct containing -232C. file:rat/Pck1/Pck1-uniprot.txt Regulated by cAMP, dexamethasone, glucagon and by insulin. |
| GO:0032869 cellular response to insulin stimulus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Cellular response to insulin stimulus, IBA (GO_REF:0000033). Reason: Insulin repression of cytosolic PEPCK transcription is shared by vertebrate PCK1 genes (PTN000169232; rat Pck1 is among the sources). Insulin suppresses Pck1 transcription in rat hepatocytes (PMID:21519922; PMID:9530152). This hormonal/nutritional control of Pck1 transcription is a physiologically central part of the hepatic fasting-feeding switch, but it describes how the gene is regulated rather than what the enzyme does, so it is kept as non-core. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Regulated by cAMP, dexamethasone, glucagon and by insulin. PMID:21519922 retinoid treatment attenuated insulin-mediated suppression of Pck1 expression in primary rat hepatocytes |
| GO:0032869 cellular response to insulin stimulus | IEP PMID:21519922 Retinoids induced Pck1 expression and attenuated insulin-med... | KEEP AS NON CORE | Summary: Cellular response to insulin stimulus, IEP (PMID:21519922). Reason: Insulin suppresses Pck1 transcription in rat hepatocytes (PMID:21519922; PMID:9530152). This hormonal/nutritional control of Pck1 transcription is a physiologically central part of the hepatic fasting-feeding switch, but it describes how the gene is regulated rather than what the enzyme does, so it is kept as non-core. Supporting Evidence: PMID:21519922 retinoid treatment attenuated insulin-mediated suppression of Pck1 expression in primary rat hepatocytes |
| GO:0032869 cellular response to insulin stimulus | IEP PMID:9530152 Cell volume regulates liver phosphoenolpyruvate carboxykinas... | KEEP AS NON CORE | Summary: Cellular response to insulin stimulus, IEP (PMID:9530152). Reason: Insulin suppresses Pck1 transcription in rat hepatocytes (PMID:21519922; PMID:9530152). This hormonal/nutritional control of Pck1 transcription is a physiologically central part of the hepatic fasting-feeding switch, but it describes how the gene is regulated rather than what the enzyme does, so it is kept as non-core. Supporting Evidence: PMID:9530152 The antagonistic effects of hyper- and hypotonicity mimic the counteracting effects of adenosine 3',5'-cyclic monophosphate (cAMP) and insulin on PCK and FBP mRNA levels. |
| GO:0032869 cellular response to insulin stimulus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Cellular response to insulin stimulus, ISO (GO_REF:0000121). Reason: Insulin suppresses Pck1 transcription in rat hepatocytes (PMID:21519922; PMID:9530152). This hormonal/nutritional control of Pck1 transcription is a physiologically central part of the hepatic fasting-feeding switch, but it describes how the gene is regulated rather than what the enzyme does, so it is kept as non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P35558 · PCK1 (human) SUPPORTS TRANSFER Conserved insulin repression of PCK1. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Regulated by cAMP, dexamethasone, glucagon and by insulin. PMID:21519922 retinoid treatment attenuated insulin-mediated suppression of Pck1 expression in primary rat hepatocytes |
| GO:0032869 cellular response to insulin stimulus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cellular response to insulin stimulus, ISS (GO_REF:0000024). Reason: Insulin suppresses Pck1 transcription in rat hepatocytes (PMID:21519922; PMID:9530152). This hormonal/nutritional control of Pck1 transcription is a physiologically central part of the hepatic fasting-feeding switch, but it describes how the gene is regulated rather than what the enzyme does, so it is kept as non-core. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Regulated by cAMP, dexamethasone, glucagon and by insulin. PMID:21519922 retinoid treatment attenuated insulin-mediated suppression of Pck1 expression in primary rat hepatocytes |
| GO:0033993 response to lipid | IEP PMID:21486814 Gestational high fat diet programs hepatic phosphoenolpyruva... | MARK AS OVER ANNOTATED | Summary: response to lipid, IEP (PMID:21486814). Reason: A gestational high-fat diet raised hepatic Pck1 expression and altered its histone marks in neonatal offspring (PMID:21486814); this is developmental programming of the gene, not a response by the enzyme to lipid. Pck1 is a heavily regulated metabolic gene whose mRNA or activity changes under many treatments; the change is a readout, and the enzyme itself does none of the work of sensing or responding to the stimulus. Supporting Evidence: PMID:21486814 Our results demonstrate that in utero exposure to HF diet has the potential to program the gluconeogenic capacity of offspring through epigenetic modifications |
| GO:0042593 glucose homeostasis | IDA PMID:4186849 Purification of phosphoenolpyruvate carboxykinase from the c... | KEEP AS NON CORE | Summary: Glucose homeostasis, IDA (BHF-UCL, PMID:4186849). Reason: PEPCK-C-driven gluconeogenesis contributes to maintenance of blood glucose, so the term is true, but it is an organism-level consequence of the core gluconeogenic activity (GO:0006094). The cited purification paper could not be read beyond its title. Kept as non-core. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Cytosolic phosphoenolpyruvate carboxykinase that catalyzes the reversible decarboxylation and phosphorylation of oxaloacetate (OAA) and acts as the rate-limiting enzyme in gluconeogenesis PMID:6049928 It is suggested that the appearance of the soluble phosphoenolpyruvate carboxykinase at birth initiates the rapid increase in overall gluconeogenesis at this stage. |
| GO:0042594 response to starvation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Response to starvation, IBA (PTN000169226). Reason: Fasting induces PEPCK-C and gluconeogenesis across vertebrates; the gene is induced, the enzyme does not sense starvation. Non-core. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Regulated by cAMP, dexamethasone, glucagon and by insulin. PMID:4303362 Glucose 6-phosphatase and phosphoenolpyruvate carboxykinase are present in late foetal (21-22-day-old) tissue and increase rapidly postnatally. |
| GO:0043382 positive regulation of memory T cell differentiation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Positive regulation of memory T cell differentiation, IEA from mouse Pck1 (source IMP PMID:29230018). Reason: In mouse CD8+ memory T cells, Pck1 is upregulated and supplies gluconeogenic carbon to glycogen and then the pentose phosphate pathway, sustaining NADPH and glutathione; abrogating the pathway impairs memory-cell formation (PMID:29230018). That is necessity evidence for a metabolic enzyme whose product the cells need; Pck1 does not itself regulate a differentiation programme. No rat T-cell data exist. The metabolic activity is captured by GO:0004613/GO:0006094; the regulatory process term over-states its role. Supporting Evidence: PMID:29230018 CD8+ Tm cells markedly upregulate cytosolic phosphoenolpyruvate carboxykinase (Pck1), the hub molecule regulating glycolysis, tricarboxylic acid cycle and gluconeogenesis, to increase glycogenesis via gluconeogenesis. file:rat/Pck1/Pck1-uniprot.txt Acts as a regulator of formation and maintenance of memory CD8(+) T-cells |
| GO:0043382 positive regulation of memory T cell differentiation | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Positive regulation of memory T cell differentiation, ISO from mouse Pck1 (source IMP PMID:29230018). Reason: In mouse CD8+ memory T cells, Pck1 is upregulated and supplies gluconeogenic carbon to glycogen and then the pentose phosphate pathway, sustaining NADPH and glutathione; abrogating the pathway impairs memory-cell formation (PMID:29230018). That is necessity evidence for a metabolic enzyme whose product the cells need; Pck1 does not itself regulate a differentiation programme. No rat T-cell data exist. The metabolic activity is captured by GO:0004613/GO:0006094; the regulatory process term over-states its role. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION CONTEXT OR TISSUE MISMATCH Sources checked: MGI:MGI:97501 · Pck1 (mouse) SUPPORTS SOURCE BUT NOT TARGET Mouse IMP shows a metabolic requirement in memory T cells; regulatory term over-states the role and is not tested in rat. Supporting Evidence: PMID:29230018 CD8+ Tm cells markedly upregulate cytosolic phosphoenolpyruvate carboxykinase (Pck1), the hub molecule regulating glycolysis, tricarboxylic acid cycle and gluconeogenesis, to increase glycogenesis via gluconeogenesis. file:rat/Pck1/Pck1-uniprot.txt Acts as a regulator of formation and maintenance of memory CD8(+) T-cells |
| GO:0043382 positive regulation of memory T cell differentiation | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Positive regulation of memory T cell differentiation, ISS from mouse Pck1 (source IMP PMID:29230018). Reason: In mouse CD8+ memory T cells, Pck1 is upregulated and supplies gluconeogenic carbon to glycogen and then the pentose phosphate pathway, sustaining NADPH and glutathione; abrogating the pathway impairs memory-cell formation (PMID:29230018). That is necessity evidence for a metabolic enzyme whose product the cells need; Pck1 does not itself regulate a differentiation programme. No rat T-cell data exist. The metabolic activity is captured by GO:0004613/GO:0006094; the regulatory process term over-states its role. Supporting Evidence: PMID:29230018 CD8+ Tm cells markedly upregulate cytosolic phosphoenolpyruvate carboxykinase (Pck1), the hub molecule regulating glycolysis, tricarboxylic acid cycle and gluconeogenesis, to increase glycogenesis via gluconeogenesis. file:rat/Pck1/Pck1-uniprot.txt Acts as a regulator of formation and maintenance of memory CD8(+) T-cells |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Positive regulation of transcription by RNA polymerase II, ISO from mouse Pck1 (MGI IDA PMID:19458124, acts_upstream_of_or_within). Reason: Nothing in Pck1 biology indicates a role in RNA polymerase II transcription. The mouse source study measured renal PEPCK mRNA as a readout of metabolic acidosis and K+ restriction (PMID:19458124); the abstract reports no experiment in which Pck1 controls another gene's transcription. This looks like an expression readout coded as a regulatory function. The source full text could not be read, so the source is flagged for checking rather than removed. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:97501 · Pck1 (mouse) SOURCE BAD Mouse IDA appears to encode PEPCK mRNA induction as transcriptional regulation by PEPCK. Supporting Evidence: PMID:19458124 SNAT3, PDG, and PEPCK mRNA abundance were elevated during MA and after 14-day K(+) restriction but not during high protein intake. |
| GO:0046166 glyceraldehyde-3-phosphate biosynthetic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Glyceraldehyde-3-phosphate biosynthetic process, IEA (Ensembl Compara from mouse). Reason: PEP made by PEPCK-C is converted by the reversed glycolytic enzymes to glyceraldehyde 3-phosphate, an intermediate on the way to both glucose and glycerol 3-phosphate; PEPCK-C supplies the first committed step. The term is defensible but the specific products are captured by gluconeogenesis and glycerol-3-phosphate biosynthesis, so non-core. Supporting Evidence: PMID:11792850 The importance of glyceroneogenesis in adipose tissue was assessed in mice by specifically eliminating the expression of the cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK-C), an enzyme that plays a pivotal role in the pathway. PMID:26709450 Phosphoenolpyruvate carboxykinase (PEPCK) is an essential metabolic enzyme operating in the gluconeogenesis and glyceroneogenesis pathways. |
| GO:0046166 glyceraldehyde-3-phosphate biosynthetic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Glyceraldehyde-3-phosphate biosynthetic process, ISO from mouse Pck1 (MGI IMP PMID:11792850). Reason: PEP made by PEPCK-C is converted by the reversed glycolytic enzymes to glyceraldehyde 3-phosphate, an intermediate on the way to both glucose and glycerol 3-phosphate; PEPCK-C supplies the first committed step. The term is defensible but the specific products are captured by gluconeogenesis and glycerol-3-phosphate biosynthesis, so non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: MGI:MGI:97501 · Pck1 (mouse) SUPPORTS TRANSFER Mouse adipose PEPCK-C mutant (glyceroneogenesis). Supporting Evidence: PMID:11792850 The importance of glyceroneogenesis in adipose tissue was assessed in mice by specifically eliminating the expression of the cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK-C), an enzyme that plays a pivotal role in the pathway. PMID:26709450 Phosphoenolpyruvate carboxykinase (PEPCK) is an essential metabolic enzyme operating in the gluconeogenesis and glyceroneogenesis pathways. |
| GO:0046889 positive regulation of lipid biosynthetic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of lipid biosynthetic process, ISO from human PCK1 (PMID:32322062). Reason: All rat rows for the GTP-dependent protein kinase function (GO:0106264, GO:0018105, the ER location and the lipid-biosynthesis regulation terms) are transfers of one human study, PMID:32322062: in human hepatocellular carcinoma cells AKT phosphorylates PCK1 at Ser90, and PCK1 then moves to the ER and uses GTP to phosphorylate INSIG1 Ser207 and INSIG2 Ser151, releasing SCAP-SREBP. Ser90 is conserved in rat Pck1 (UniProt records the S90 mutagenesis in PMID:30193097), so the transfer is plausible, but no rat experiment on Pck1 protein kinase activity or INSIG phosphorylation exists and the human finding has not been reproduced in a normal gluconeogenic tissue. The term is kept as non-core: it describes a context-dependent moonlighting activity, not the enzyme's metabolic role. Phosphorylation of INSIG1/2 by PCK1 releases SCAP-SREBP and promotes lipogenic gene expression, which is the positive regulation this term names. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:P35558 · PCK1 (human) SUPPORTS TRANSFER Single human HCC study; Ser90 conserved in rat. Supporting Evidence: PMID:32322062 disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus, the activation of SREBP proteins (SREBP1 or SREBP2) and the transcription of downstream lipogenesis-related genes |
| GO:0046890 regulation of lipid biosynthetic process | ISO GO_REF:0000121 | MODIFY | Summary: Regulation of lipid biosynthetic process, ISO from human PCK1 (PMID:32322062). Reason: The human study shows that PCK1 promotes SREBP activation and lipogenesis, so the direction is known. Regulation of lipid biosynthetic process is correct but general; its is_a child GO:0046889 positive regulation of lipid biosynthetic process, which the gene already carries (kept as non-core), is the specific term. All rat rows for the GTP-dependent protein kinase function (GO:0106264, GO:0018105, the ER location and the lipid-biosynthesis regulation terms) are transfers of one human study, PMID:32322062: in human hepatocellular carcinoma cells AKT phosphorylates PCK1 at Ser90, and PCK1 then moves to the ER and uses GTP to phosphorylate INSIG1 Ser207 and INSIG2 Ser151, releasing SCAP-SREBP. Ser90 is conserved in rat Pck1 (UniProt records the S90 mutagenesis in PMID:30193097), so the transfer is plausible, but no rat experiment on Pck1 protein kinase activity or INSIG phosphorylation exists and the human finding has not been reproduced in a normal gluconeogenic tissue. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P35558 · PCK1 (human) SUPPORTS TRANSFER Human source supports the positive direction. Proposed replacements: positive regulation of lipid biosynthetic process Supporting Evidence: PMID:32322062 disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus, the activation of SREBP proteins (SREBP1 or SREBP2) and the transcription of downstream lipogenesis-related genes |
| GO:0046890 regulation of lipid biosynthetic process | ISS GO_REF:0000024 | MODIFY | Summary: Regulation of lipid biosynthetic process, ISS from human PCK1 (PMID:32322062). Reason: The human study shows that PCK1 promotes SREBP activation and lipogenesis, so the direction is known. Regulation of lipid biosynthetic process is correct but general; its is_a child GO:0046889 positive regulation of lipid biosynthetic process, which the gene already carries (kept as non-core), is the specific term. All rat rows for the GTP-dependent protein kinase function (GO:0106264, GO:0018105, the ER location and the lipid-biosynthesis regulation terms) are transfers of one human study, PMID:32322062: in human hepatocellular carcinoma cells AKT phosphorylates PCK1 at Ser90, and PCK1 then moves to the ER and uses GTP to phosphorylate INSIG1 Ser207 and INSIG2 Ser151, releasing SCAP-SREBP. Ser90 is conserved in rat Pck1 (UniProt records the S90 mutagenesis in PMID:30193097), so the transfer is plausible, but no rat experiment on Pck1 protein kinase activity or INSIG phosphorylation exists and the human finding has not been reproduced in a normal gluconeogenic tissue. Proposed replacements: positive regulation of lipid biosynthetic process Supporting Evidence: PMID:32322062 disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus, the activation of SREBP proteins (SREBP1 or SREBP2) and the transcription of downstream lipogenesis-related genes |
| GO:0051365 cellular response to potassium ion starvation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Cellular response to potassium ion starvation, ISO from mouse Pck1 (MGI IDA PMID:19458124). Reason: Renal PEPCK mRNA rises after 14 days of dietary K+ restriction together with increased ammoniagenesis (PMID:19458124). Renal PEPCK-C removes the carbon skeleton of glutamine-derived alpha-ketoglutarate as part of ammoniagenesis, so the induction is physiologically meaningful, but it is an expression response and is kept as non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: MGI:MGI:97501 · Pck1 (mouse) SUPPORTS TRANSFER Mouse renal expression response. Supporting Evidence: PMID:19458124 SNAT3, PDG, and PEPCK mRNA abundance were elevated during MA and after 14-day K(+) restriction but not during high protein intake. |
| GO:0070365 hepatocyte differentiation | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Hepatocyte differentiation, IBA (PTN000169232; donors chicken PCK1 P05153 and PCK2 P21642). Reason: PEPCK-C is a classic marker of differentiated hepatocytes, and its induction around birth accompanies hepatocyte maturation (PMID:6049928). Being a marker is not participation: PEPCK-C performs a metabolic step and does not drive the differentiation programme. The term over-states the role inherited from the chicken donors. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN000169232 SOURCE WEAK OR INFERRED Node seeded by chicken PCK1/PCK2 annotations for hepatocyte differentiation; marker gene, not effector. UniProtKB:P05153 · PCK1 (chicken) SOURCE WEAK OR INFERRED Chicken PCK1. UniProtKB:P21642 · PCK2 (chicken) SOURCE WEAK OR INFERRED Chicken PCK2. Supporting Evidence: PMID:6049928 It is suggested that the appearance of the soluble phosphoenolpyruvate carboxykinase at birth initiates the rapid increase in overall gluconeogenesis at this stage. |
| GO:0070741 response to interleukin-6 | IEP PMID:17805558 Impact of interleukin-6 on the glucose metabolic capacity in... | MARK AS OVER ANNOTATED | Summary: response to interleukin-6, IEP (PMID:17805558). Reason: IL-6 injection halved periportal PCK1 mRNA in rat liver while PCK1 enzyme activity was unchanged (PMID:17805558). Pck1 is a heavily regulated metabolic gene whose mRNA or activity changes under many treatments; the change is a readout, and the enzyme itself does none of the work of sensing or responding to the stimulus. Supporting Evidence: PMID:17805558 PCK1 enzyme activity was not affected by IL6. |
| GO:0071300 cellular response to retinoic acid | IEP PMID:21519922 Retinoids induced Pck1 expression and attenuated insulin-med... | MARK AS OVER ANNOTATED | Summary: cellular response to retinoic acid, IEP (PMID:21519922). Reason: Retinoids, including retinoic acid, induced Pck1 mRNA in primary rat hepatocytes through a promoter RARE (PMID:21519922). Pck1 is a heavily regulated metabolic gene whose mRNA or activity changes under many treatments; the change is a readout, and the enzyme itself does none of the work of sensing or responding to the stimulus. Supporting Evidence: PMID:21519922 Retinol, retinal, and retinoic acid (RA) induced Pck1 expression dose-dependently in primary hepatocytes. |
| GO:0071320 cellular response to cAMP | IEP PMID:18335579 Inhibition of glucagon-signaling and downstream actions by i... | KEEP AS NON CORE | Summary: cellular response to cAMP, IEP (PMID:18335579). Reason: Glucagon raises PCK1 mRNA in cultured rat hepatocytes by raising cAMP, and the cAMP analogue CPT-cAMP has the same effect (PMID:18335579). This hormonal/nutritional control of Pck1 transcription is a physiologically central part of the hepatic fasting-feeding switch, but it describes how the gene is regulated rather than what the enzyme does, so it is kept as non-core. Supporting Evidence: PMID:18335579 In cultured rat hepatocytes, glucagon increased the phosphoenolpyruvate carboxykinase (PCK1) mRNA by increasing cellular cAMP concentrations. |
| GO:0071320 cellular response to cAMP | IEP PMID:9530152 Cell volume regulates liver phosphoenolpyruvate carboxykinas... | KEEP AS NON CORE | Summary: cellular response to cAMP, IEP (PMID:9530152). Reason: cAMP induces PCK mRNA in H4IIE cells, the effect that hypertonicity mimics (PMID:9530152). This hormonal/nutritional control of Pck1 transcription is a physiologically central part of the hepatic fasting-feeding switch, but it describes how the gene is regulated rather than what the enzyme does, so it is kept as non-core. Supporting Evidence: PMID:9530152 The antagonistic effects of hyper- and hypotonicity mimic the counteracting effects of adenosine 3',5'-cyclic monophosphate (cAMP) and insulin on PCK and FBP mRNA levels. |
| GO:0071332 cellular response to fructose stimulus | IEP PMID:21212096 Fructose induces gluconeogenesis and lipogenesis through a S... | MARK AS OVER ANNOTATED | Summary: cellular response to fructose stimulus, IEP (PMID:21212096). Reason: Fructose increased PEPCK activity and glucose output of rat hepatocytes via SIRT1 (PMID:21212096). Pck1 is a heavily regulated metabolic gene whose mRNA or activity changes under many treatments; the change is a readout, and the enzyme itself does none of the work of sensing or responding to the stimulus. Supporting Evidence: PMID:21212096 Fructose also induced gluconeogenesis, with increases in peroxisome proliferator-activated receptor coactivator 1-alpha (PGC1α) and phosphoenolpyruvate carboxykinase (PEPCK; gene code Pck1) gene expression, PEPCK activity, and hepatocyte glucose production. |
| GO:0071333 cellular response to glucose stimulus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Cellular response to glucose stimulus, IBA (GO_REF:0000033). Reason: High glucose triggers p300-dependent acetylation of rat PCK1 (Lys91 and others), shifting the enzyme from the gluconeogenic to the anaplerotic direction; low glucose allows SIRT1 deacetylation (PMID:30193097). Glucose also represses Pck1 transcription. This is how the enzyme is regulated by glucose rather than an activity of its own in a glucose-response pathway, so non-core. Supporting Evidence: PMID:30193097 Under high glucose, p300-dependent hyperacetylation of PCK1 did not lead to protein degradation but instead increased the ability of PCK1 to perform the anaplerotic reaction, converting phosphoenolpyruvate to oxaloacetate. file:rat/Pck1/Pck1-uniprot.txt At high glucose levels, it catalyzes the anaplerotic conversion of phosphoenolpyruvate to oxaloacetate |
| GO:0071333 cellular response to glucose stimulus | IDA PMID:30193097 Dynamic Acetylation of Phosphoenolpyruvate Carboxykinase Tog... | KEEP AS NON CORE | Summary: Cellular response to glucose stimulus, IDA (PMID:30193097). Reason: High glucose triggers p300-dependent acetylation of rat PCK1 (Lys91 and others), shifting the enzyme from the gluconeogenic to the anaplerotic direction; low glucose allows SIRT1 deacetylation (PMID:30193097). Glucose also represses Pck1 transcription. This is how the enzyme is regulated by glucose rather than an activity of its own in a glucose-response pathway, so non-core. Supporting Evidence: PMID:30193097 Under high glucose, p300-dependent hyperacetylation of PCK1 did not lead to protein degradation but instead increased the ability of PCK1 to perform the anaplerotic reaction, converting phosphoenolpyruvate to oxaloacetate. file:rat/Pck1/Pck1-uniprot.txt At high glucose levels, it catalyzes the anaplerotic conversion of phosphoenolpyruvate to oxaloacetate |
| GO:0071333 cellular response to glucose stimulus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Cellular response to glucose stimulus, ISO (GO_REF:0000121). Reason: High glucose triggers p300-dependent acetylation of rat PCK1 (Lys91 and others), shifting the enzyme from the gluconeogenic to the anaplerotic direction; low glucose allows SIRT1 deacetylation (PMID:30193097). Glucose also represses Pck1 transcription. This is how the enzyme is regulated by glucose rather than an activity of its own in a glucose-response pathway, so non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P35558 · PCK1 (human) SUPPORTS TRANSFER Conserved acetylation-based glucose control. Supporting Evidence: PMID:30193097 Under high glucose, p300-dependent hyperacetylation of PCK1 did not lead to protein degradation but instead increased the ability of PCK1 to perform the anaplerotic reaction, converting phosphoenolpyruvate to oxaloacetate. file:rat/Pck1/Pck1-uniprot.txt At high glucose levels, it catalyzes the anaplerotic conversion of phosphoenolpyruvate to oxaloacetate |
| GO:0071347 cellular response to interleukin-1 | IEP PMID:18335579 Inhibition of glucagon-signaling and downstream actions by i... | MARK AS OVER ANNOTATED | Summary: cellular response to interleukin-1, IEP (PMID:18335579). Reason: IL-1beta attenuated the glucagon-induced increase in PCK1 mRNA in rat hepatocytes (PMID:18335579). Pck1 is a heavily regulated metabolic gene whose mRNA or activity changes under many treatments; the change is a readout, and the enzyme itself does none of the work of sensing or responding to the stimulus. Supporting Evidence: PMID:18335579 The proinflammatory cytokines rhIL1beta and rhTNF alpha impaired the increase both in cAMP and PCK1 mRNA. |
| GO:0071356 cellular response to tumor necrosis factor | IEP PMID:18335579 Inhibition of glucagon-signaling and downstream actions by i... | MARK AS OVER ANNOTATED | Summary: cellular response to tumor necrosis factor, IEP (PMID:18335579). Reason: TNF-alpha attenuated the glucagon-induced increase in PCK1 mRNA in rat hepatocytes (PMID:18335579). Pck1 is a heavily regulated metabolic gene whose mRNA or activity changes under many treatments; the change is a readout, and the enzyme itself does none of the work of sensing or responding to the stimulus. Supporting Evidence: PMID:18335579 The proinflammatory cytokines rhIL1beta and rhTNF alpha impaired the increase both in cAMP and PCK1 mRNA. |
| GO:0071377 cellular response to glucagon stimulus | IEP PMID:18335579 Inhibition of glucagon-signaling and downstream actions by i... | KEEP AS NON CORE | Summary: cellular response to glucagon stimulus, IEP (PMID:18335579). Reason: Glucagon increases PCK1 mRNA in cultured rat hepatocytes via cAMP (PMID:18335579). This hormonal/nutritional control of Pck1 transcription is a physiologically central part of the hepatic fasting-feeding switch, but it describes how the gene is regulated rather than what the enzyme does, so it is kept as non-core. Supporting Evidence: PMID:18335579 In cultured rat hepatocytes, glucagon increased the phosphoenolpyruvate carboxykinase (PCK1) mRNA by increasing cellular cAMP concentrations. file:rat/Pck1/Pck1-uniprot.txt Regulated by cAMP, dexamethasone, glucagon and by insulin. |
| GO:0071456 cellular response to hypoxia | IEP PMID:24177414 HNF4α contributes to glucose formation in aged rat hepatocyt... | MARK AS OVER ANNOTATED | Summary: cellular response to hypoxia, IEP (PMID:24177414). Reason: Hypoxia raised PEPCK mRNA and protein in rat hepatocytes via stabilised HNF4A (PMID:24177414). Pck1 is a heavily regulated metabolic gene whose mRNA or activity changes under many treatments; the change is a readout, and the enzyme itself does none of the work of sensing or responding to the stimulus. Supporting Evidence: PMID:24177414 Hypoxia increased the PEPCK mRNA and protein expression levels in accordance with the HIF1α expression. |
| GO:0071474 cellular hyperosmotic response | IEP PMID:9530152 Cell volume regulates liver phosphoenolpyruvate carboxykinas... | MARK AS OVER ANNOTATED | Summary: cellular hyperosmotic response, IEP (PMID:9530152). Reason: Hypertonic shrinkage increased and hypotonic swelling transiently decreased PCK mRNA in H4IIE rat hepatoma cells (PMID:9530152). Pck1 is a heavily regulated metabolic gene whose mRNA or activity changes under many treatments; the change is a readout, and the enzyme itself does none of the work of sensing or responding to the stimulus. Supporting Evidence: PMID:9530152 Hypertonic-induced cell shrinkage increases glucose release in H-4-II-E rat hepatoma cells. |
| GO:0071475 cellular hyperosmotic salinity response | IEP PMID:9530152 Cell volume regulates liver phosphoenolpyruvate carboxykinas... | MARK AS OVER ANNOTATED | Summary: cellular hyperosmotic salinity response, IEP (PMID:9530152). Reason: Hypertonic shrinkage increased and hypotonic swelling transiently decreased PCK mRNA in H4IIE rat hepatoma cells (PMID:9530152). Pck1 is a heavily regulated metabolic gene whose mRNA or activity changes under many treatments; the change is a readout, and the enzyme itself does none of the work of sensing or responding to the stimulus. Supporting Evidence: PMID:9530152 Hypertonic-induced cell shrinkage increases glucose release in H-4-II-E rat hepatoma cells. |
| GO:0071476 cellular hypotonic response | IEP PMID:9530152 Cell volume regulates liver phosphoenolpyruvate carboxykinas... | MARK AS OVER ANNOTATED | Summary: cellular hypotonic response, IEP (PMID:9530152). Reason: Hypertonic shrinkage increased and hypotonic swelling transiently decreased PCK mRNA in H4IIE rat hepatoma cells (PMID:9530152). Pck1 is a heavily regulated metabolic gene whose mRNA or activity changes under many treatments; the change is a readout, and the enzyme itself does none of the work of sensing or responding to the stimulus. Supporting Evidence: PMID:9530152 Hypertonic-induced cell shrinkage increases glucose release in H-4-II-E rat hepatoma cells. |
| GO:0071477 cellular hypotonic salinity response | IEP PMID:9530152 Cell volume regulates liver phosphoenolpyruvate carboxykinas... | MARK AS OVER ANNOTATED | Summary: cellular hypotonic salinity response, IEP (PMID:9530152). Reason: Hypertonic shrinkage increased and hypotonic swelling transiently decreased PCK mRNA in H4IIE rat hepatoma cells (PMID:9530152). Pck1 is a heavily regulated metabolic gene whose mRNA or activity changes under many treatments; the change is a readout, and the enzyme itself does none of the work of sensing or responding to the stimulus. Supporting Evidence: PMID:9530152 Hypertonic-induced cell shrinkage increases glucose release in H-4-II-E rat hepatoma cells. |
| GO:0071549 cellular response to dexamethasone stimulus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Cellular response to dexamethasone stimulus, IBA (PTN000169232). Reason: Glucocorticoids (dexamethasone) induce Pck1 transcription in rat liver and hepatoma cells (UniProt induction, PMID:6096365 cited there). Regulation of the gene during fasting; non-core. Supporting Evidence: file:rat/Pck1/Pck1-uniprot.txt Regulated by cAMP, dexamethasone, glucagon and by insulin. |
| GO:0072350 tricarboxylic acid metabolic process | ISO GO_REF:0000121 | MODIFY | Summary: Tricarboxylic acid metabolic process, ISO from human PCK1 (UniProt IDA, PMID:30193097). Reason: The source study concerns PCK1 cataplerosis/anaplerosis, i.e. interconversion of oxaloacetate and PEP. Oxaloacetate is a dicarboxylic acid and PEP is a monocarboxylic acid; no tricarboxylic acid (citrate, isocitrate, cis-aconitate) is a substrate or product. The intended claim is captured by GO:0006107 oxaloacetate metabolic process, which the gene already carries. GO:0006107 is not a descendant of GO:0072350, so this is a lateral correction of the source term (presumably chosen for "TCA-cycle" flux). Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P35558 · PCK1 (human) SOURCE BAD Human IDA to GO:0072350 appears to conflate "TCA cycle intermediates" with tricarboxylic acids. Proposed replacements: oxaloacetate metabolic process Supporting Evidence: PMID:30193097 dynamic acetylation of PCK1 interconverts the enzyme between gluconeogenic and anaplerotic activities file:rat/Pck1/Pck1-uniprot.txt At high glucose levels, it catalyzes the anaplerotic conversion of phosphoenolpyruvate to oxaloacetate |
| GO:0097403 cellular response to raffinose | IEP PMID:9530152 Cell volume regulates liver phosphoenolpyruvate carboxykinas... | MARK AS OVER ANNOTATED | Summary: cellular response to raffinose, IEP (PMID:9530152). Reason: Hypertonic shrinkage increased and hypotonic swelling transiently decreased PCK mRNA in H4IIE rat hepatoma cells (PMID:9530152). Raffinose was used as an impermeant osmolyte to make the medium hypertonic, so "response to raffinose" is a reagent artefact of the osmotic experiment. Pck1 is a heavily regulated metabolic gene whose mRNA or activity changes under many treatments; the change is a readout, and the enzyme itself does none of the work of sensing or responding to the stimulus. Supporting Evidence: PMID:9530152 Hypertonic-induced cell shrinkage increases glucose release in H-4-II-E rat hepatoma cells. |
| GO:0106264 protein serine kinase activity (using GTP as donor) | IEA GO_REF:0000116 | KEEP AS NON CORE | Summary: Protein serine kinase activity (using GTP as donor), IEA from Rhea (RHEA:64020). Reason: All rat rows for the GTP-dependent protein kinase function (GO:0106264, GO:0018105, the ER location and the lipid-biosynthesis regulation terms) are transfers of one human study, PMID:32322062: in human hepatocellular carcinoma cells AKT phosphorylates PCK1 at Ser90, and PCK1 then moves to the ER and uses GTP to phosphorylate INSIG1 Ser207 and INSIG2 Ser151, releasing SCAP-SREBP. Ser90 is conserved in rat Pck1 (UniProt records the S90 mutagenesis in PMID:30193097), so the transfer is plausible, but no rat experiment on Pck1 protein kinase activity or INSIG phosphorylation exists and the human finding has not been reproduced in a normal gluconeogenic tissue. The term is kept as non-core: it describes a context-dependent moonlighting activity, not the enzyme's metabolic role. Supporting Evidence: PMID:32322062 Phosphorylated PCK1 translocates to the endoplasmic reticulum, where it uses GTP as a phosphate donor to phosphorylate INSIG1 at Ser207 and INSIG2 at Ser151. file:rat/Pck1/Pck1-uniprot.txt In addition to the phosphoenolpyruvate carboxykinase activity, also acts as a protein kinase when phosphorylated at Ser-90 |
| GO:0106264 protein serine kinase activity (using GTP as donor) | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Protein serine kinase activity (using GTP as donor), ISO from human PCK1. Reason: All rat rows for the GTP-dependent protein kinase function (GO:0106264, GO:0018105, the ER location and the lipid-biosynthesis regulation terms) are transfers of one human study, PMID:32322062: in human hepatocellular carcinoma cells AKT phosphorylates PCK1 at Ser90, and PCK1 then moves to the ER and uses GTP to phosphorylate INSIG1 Ser207 and INSIG2 Ser151, releasing SCAP-SREBP. Ser90 is conserved in rat Pck1 (UniProt records the S90 mutagenesis in PMID:30193097), so the transfer is plausible, but no rat experiment on Pck1 protein kinase activity or INSIG phosphorylation exists and the human finding has not been reproduced in a normal gluconeogenic tissue. The term is kept as non-core: it describes a context-dependent moonlighting activity, not the enzyme's metabolic role. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:P35558 · PCK1 (human) SUPPORTS TRANSFER Single human HCC study (PMID:32322062); Ser90 conserved in rat. Supporting Evidence: PMID:32322062 Phosphorylated PCK1 translocates to the endoplasmic reticulum, where it uses GTP as a phosphate donor to phosphorylate INSIG1 at Ser207 and INSIG2 at Ser151. PMID:32322062 Here we show that activated AKT in human hepatocellular carcinoma (HCC) cells phosphorylates cytosolic phosphoenolpyruvate carboxykinase 1 (PCK1), the rate-limiting enzyme in gluconeogenesis, at Ser90. |
| GO:0106264 protein serine kinase activity (using GTP as donor) | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Protein serine kinase activity (using GTP as donor), ISS from human PCK1. Reason: All rat rows for the GTP-dependent protein kinase function (GO:0106264, GO:0018105, the ER location and the lipid-biosynthesis regulation terms) are transfers of one human study, PMID:32322062: in human hepatocellular carcinoma cells AKT phosphorylates PCK1 at Ser90, and PCK1 then moves to the ER and uses GTP to phosphorylate INSIG1 Ser207 and INSIG2 Ser151, releasing SCAP-SREBP. Ser90 is conserved in rat Pck1 (UniProt records the S90 mutagenesis in PMID:30193097), so the transfer is plausible, but no rat experiment on Pck1 protein kinase activity or INSIG phosphorylation exists and the human finding has not been reproduced in a normal gluconeogenic tissue. The term is kept as non-core: it describes a context-dependent moonlighting activity, not the enzyme's metabolic role. Supporting Evidence: PMID:32322062 Phosphorylated PCK1 translocates to the endoplasmic reticulum, where it uses GTP as a phosphate donor to phosphorylate INSIG1 at Ser207 and INSIG2 at Ser151. file:rat/Pck1/Pck1-uniprot.txt In addition to the phosphoenolpyruvate carboxykinase activity, also acts as a protein kinase when phosphorylated at Ser-90 |
| GO:1904628 cellular response to phorbol 13-acetate 12-myristate | IEP PMID:9530152 Cell volume regulates liver phosphoenolpyruvate carboxykinas... | MARK AS OVER ANNOTATED | Summary: cellular response to phorbol 13-acetate 12-myristate, IEP (PMID:9530152). Reason: Hypertonic shrinkage increased and hypotonic swelling transiently decreased PCK mRNA in H4IIE rat hepatoma cells (PMID:9530152). PMA was used to probe the protein kinase C pathway, which the paper found was not required for the hypertonic induction. Pck1 is a heavily regulated metabolic gene whose mRNA or activity changes under many treatments; the change is a readout, and the enzyme itself does none of the work of sensing or responding to the stimulus. Supporting Evidence: PMID:9530152 Hypertonic-induced cell shrinkage increases glucose release in H-4-II-E rat hepatoma cells. PMID:9530152 The inductive effect of hypertonicity does not require ongoing protein synthesis and acts independently of the cAMP-dependent protein kinase and protein kinase C pathways. |
| GO:1904640 response to methionine | IEP PMID:23052097 Genomic and metabolic responses to methionine-restricted and... | MARK AS OVER ANNOTATED | Summary: response to methionine, IEP (PMID:23052097). Reason: Methionine restriction up-regulated Pck1 with other glyceroneogenic genes in rat inguinal adipose tissue (PMID:23052097); this is a diet effect, not a response to methionine itself. Pck1 is a heavily regulated metabolic gene whose mRNA or activity changes under many treatments; the change is a readout, and the enzyme itself does none of the work of sensing or responding to the stimulus. Supporting Evidence: PMID:23052097 MR not only caused the transcriptional upregulation of genes associated with fatty acid synthesis but also of Lpin1, Pc, Pck1 and Pdk1, genes that are associated with glyceroneogenesis. |
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Download this section (compressed HTML)Q: Is rat Pck1 phosphorylated at Ser90 by AKT in liver or adipose tissue, and does a Pck1 pool reach the ER and phosphorylate INSIG1/2 outside the cancer-cell context reported for human PCK1?
Q: Did PMID:1383219 measure carbovir diphosphate phosphorylation by PEPCK with ATP or with PEP as donor? If PEP, the GO:0004550 NDP kinase mapping in Reactome R-RNO-2162084 is wrong.
Q: Should the PAINT mitochondrion IBA (PTN000169230) be blocked on the PCK1 clade, given that all characterised PCK1 orthologs are cytosolic?
Experiment: Express rat Pck1 S90A and S90D in primary rat hepatocytes and measure INSIG1/2 phosphorylation, SREBP processing and de novo lipogenesis under insulin stimulation, to test whether the human protein-kinase mechanism operates in normal rat liver.
Experiment: Assay purified rat PEPCK-C with carbovir diphosphate using ATP or PEP as phosphoryl donor (with and without CO2/HCO3-) to establish whether the analogue phosphorylation is the PEPCK reverse reaction.
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