Pck1 (rat, P07379) - manual literature synthesis

No deep-research provider was run for this gene. This file collects the literature work
done by hand from the cached publications in publications/ and the UniProt record
(Pck1-uniprot.txt). Each assertion carries its source.

Identity

• Rat Pck1 encodes cytosolic phosphoenolpyruvate carboxykinase [GTP] (PEPCK-C), 622 aa,
  EC 4.1.1.32 [file:rat/Pck1/Pck1-uniprot.txt "Phosphoenolpyruvate carboxykinase, cytosolic [GTP]"].
• Vertebrates carry two PEPCK-GTP isozymes, cytosolic PCK1 and mitochondrial PCK2
  [file:rat/Pck1/Pck1-uniprot.txt "In eukaryotes there are two isozymes: a cytoplasmic one
  and a mitochondrial one."]. Ballard and Hanson purified the rat liver cytosolic enzyme and
  showed it is immunochemically distinct from the mitochondrial one [PMID:4186849, title].

Catalytic activity and mechanism

• Reaction: oxaloacetate + GTP = phosphoenolpyruvate + GDP + CO2 (RHEA:10388), reversible,
  with Mn2+ as the active-site metal [file:rat/Pck1/Pck1-uniprot.txt "Binds 1 Mn(2+) ion per subunit."].
• Rat PEPCK-C is the main structural model of the GTP-dependent PEPCKs. Structures with
  Mn2+, OAA, GDP and GTP show direct in-line phosphoryl transfer PMID:17685635.
• Holyoak lab kinetics on recombinant rat enzyme: active-site loop mutants (E89, H477R)
  [PMID:26709450; 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"]; inhibitors
  3-mercaptopicolinate at the substrate site and an allosteric site PMID:26322521 and CMP PMID:31461616.
• Monomer [file:rat/Pck1/Pck1-uniprot.txt "SUBUNIT: Monomer."].

Physiological roles

• Gluconeogenesis. PEPCK-C catalyses the committed step of gluconeogenesis from lactate,
  amino acids and TCA-cycle intermediates in liver and kidney. In rat liver, more than 90%
  of PEPCK activity is cytosolic and the cytosolic enzyme appears at birth with the onset
  of gluconeogenesis PMID:6049928. siRNA knockdown in H4IIEC3 rat hepatoma cells lowers glucose production
  PMID:18055057. Renal cortex gluconeogenesis develops with PEPCK PMID:4303362.
• Cataplerosis/anaplerosis. Mouse liver-specific knockout shows PEPCK-C removes TCA-cycle
  carbon PMID:15347677. Acetylation of rat PCK1 (Lys91 and others)
  switches the enzyme toward PEP carboxylation under high glucose; SIRT1 deacetylation
  restores the gluconeogenic direction PMID:30193097.
• Glyceroneogenesis. In adipose tissue PEPCK-C supplies PEP for glycerol-3-phosphate
  synthesis used to re-esterify fatty acids (mouse PPARE knock-in, PMID:11792850). Rat
  adipose Pck1 is induced together with other glyceroneogenic genes by methionine
  restriction PMID:23052097. The Holyoak lab describes PEPCK as operating in both
  gluconeogenesis and glyceroneogenesis PMID:26709450.
• Isozyme contrast in islets. Pancreatic beta cells (INS-1 832/13, rat and mouse islets)
  lack PEPCK-C; their PEPCK activity is entirely mitochondrial PEPCK-M (Pck2)
  PMID:19635791. This supports keeping the mitochondrial location on Pck2 only.

Regulation (expression)

• Transcription is induced by glucagon/cAMP and glucocorticoids and repressed by insulin
  [file:rat/Pck1/Pck1-uniprot.txt "Regulated by cAMP, dexamethasone, glucagon and by
  insulin."; PMID:18335579; PMID:21519922]. Many rat IEP annotations come from expression
  studies: osmotic stress in H4IIE cells PMID:9530152, cytokines [PMID:18335579,
  PMID:17805558], LPS PMID:19268478, hypoxia/HNF4A PMID:24177414, retinoids
  PMID:21519922, fructose PMID:21212096, exercise PMID:16458327, diet/programming
  [PMID:21486814, PMID:23307605, PMID:25943649, PMID:23052097].

Non-canonical activities (not shown in rat)

• Protein serine kinase (GTP donor): in human HCC cells AKT-phosphorylated PCK1 (Ser90)
  moves to the ER and phosphorylates INSIG1/2, activating SREBPs PMID:32322062. Rat annotations to this activity,
  ER location and lipid-biosynthesis regulation are all transfers of that one human study.
• Memory CD8+ T cells: mouse Pck1 is upregulated and channels gluconeogenic carbon to
  glycogen and the pentose phosphate pathway PMID:29230018. No rat data.
• Carbovir diphosphate phosphorylation: Reactome records rat PCK1 converting carbovir
  diphosphate to the triphosphate in vitro (PMID:1383219, R-RNO-2162084); the cached abstract
  does not mention PEPCK, and the full text was not available.