PCK1 (human, P35558) curation notes

Deep research status

• 2026-10-16: just deep-research human PCK1 --provider falcon was run and FAILED.
  The Edison/falcon client could not authenticate: HTTPStatusError: Client error '403 Forbidden' for url 'https://api.platform.edisonscientific.com/auth/login'
  (a direct probe of the endpoint also returned HTTP 403 from the upstream server,
  not from the local proxy). No deep-research file was generated, and none has been
  written by hand. The review below is based on the UniProt record, the cached
  publications (mostly abstract-only), the cached Reactome entries, and the GO-CAM
  models that include PCK1.

Identity and core biochemistry

• PCK1 = cytosolic phosphoenolpyruvate carboxykinase [GTP] (PEPCK-C), EC 4.1.1.32;
  catalyses GTP + oxaloacetate = PEP + GDP + CO2 (Rhea:10388). The mitochondrial
  paralog is PCK2 (PEPCK-M).
  [file:human/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"]
• First crystal structure of a GTP-dependent PEPCK (human PCK1); novel GTP-binding site
  with a phenylalanine-walled guanine pocket; Mn2+ cofactor (1 per subunit; monomer).
  PMID:11851336
  [file:human/PCK1/PCK1-uniprot.txt "Binds 1 Mn(2+) ion per subunit"]
• Reactome: PCK1 converts OA to PEP in the cytosol as part of gluconeogenesis.
  [Reactome:R-HSA-70241 "The transfer of a high-energy phosphate bond from GTP to oxaloacetate (OA), to form phosphoenolpyruvate (PEP), GDP, and CO2, is catalyzed by cytosolic phosphoenolpyruvate carboxykinase PCK1"]

Cataplerosis / anaplerosis and regulation by acetylation

• Latorre-Muro et al. 2018: acetylation (p300; K91) toggles PCK1 from gluconeogenic
  (OAA->PEP) to anaplerotic (PEP->OAA) direction; SIRT1 deacetylation restores
  gluconeogenic direction; GSK3B-mediated phosphorylation affects acetylation and
  ubiquitination.
  PMID:30193097
  PMID:30193097
• GO:0072350 "tricarboxylic acid metabolic process" (IDA, this paper) is defined as
  metabolism of acids with three carboxyl groups; PCK1 substrates (OAA, a dicarboxylic
  acid; PEP) are not tricarboxylic acids. The curator's intent (TCA-cycle intermediate
  flux / cataplerosis-anaplerosis) is better captured by GO:0006107 oxaloacetate
  metabolic process, which PCK1 already carries.

Human genetics

• Cytosolic PEPCK deficiency (PCKDC, MIM 261680): hypoglycemia, liver dysfunction,
  lactic acidosis, urinary TCA intermediates (fumarate).
  PMID:26971250
  PMID:28216384
  PMID:24863970
• Promoter SNP -232C>G associated with T2D; reporter insensitive to insulin
  down-regulation. This is a cis-regulatory (promoter) observation, not a property of
  the protein.
  PMID:14764811

Moonlighting protein kinase activity (the key issue)

• Xu et al. 2020 (Nature), human HCC cells: AKT phosphorylates PCK1 Ser90; pS90-PCK1
  translocates to ER and uses GTP to phosphorylate INSIG1 Ser207 / INSIG2 Ser151; this
  reduces sterol binding by INSIGs and disrupts INSIG-SCAP interaction, releasing
  SCAP-SREBP to the Golgi and activating SREBPs and lipogenesis.
  PMID:32322062
  PMID:32322062
• Cached copy is abstract-only (content_type: abstract_only). The GOA IDA rows
  (GO:0106264, GO:0018105, GO:0046889, GO:0046890, GO:0005783, GO:0005829, GO:0004613,
  GO:0032869) were made by a curator who read the full text, so they are not removed.
• Only independent follow-up found: Ma et al. 2024, PRRSV infection of MARC-145 (monkey
  kidney) cells; AKT->PCK1->INSIG->SREBP axis invoked, INSIG phosphorylation reported to
  cause INSIG degradation. Not an independent biochemical reconstitution with purified
  PCK1.
  PMID:39433189
• Assessment: the protein-kinase activity is a single-lab, cancer-cell-line finding, not
  reconstituted independently and not separated from PEPCK catalysis by a kinase-dead /
  PEPCK-competent mutant pair in another lab. It is kept, but as non-core.
• Direction of effect: PCK1 opposes SREBP-SCAP retention in the ER. GO-CAM
  gomodel:6205c24300000880 models PCK1 GO:0106264 part_of GO:0046889 with a negative
  causal edge onto INSIG activities that are part_of GO:0036316 (SREBP-SCAP complex
  retention in ER). The export produced acts_upstream_of_or_within GO:0036316 for PCK1,
  which was ISO-transferred to mouse Pck1 (genes/mouse/Pck1, GO_REF:0000119, with
  UniProtKB:P35558). That is an over-annotation (PCK1 is not part of the retention
  machinery; its reported effect is the opposite sign). Human PCK1 has no GO:0036316
  row and none is proposed here.

Other localisation / process notes

• PCK1 is the cytosolic isozyme; no mitochondrial targeting. The IBA "is_active_in
  mitochondrion" (PTN000169230, donors PCK2 human/mouse) reflects the PCK2 branch.
• Glyceroneogenesis in adipose/liver (rat Pck1 evidence) generates glycerol-3-phosphate
  rather than free glycerol. GO nevertheless made GO:0006114 glycerol biosynthetic process
  the replacement for the obsolete GO:0046327 (exact synonym "glyceroneogenesis"), so
  GO:0006114 is accepted, not re-termed to GO:0046167. GO:0046166
  glyceraldehyde-3-phosphate biosynthetic process is also accepted, matching the mouse
  Pck1 review (IMP row, plus GO-CAM gomodel:6494e2e900002018). Reconciled 2026-10-16 when
  both species were reviewed together.
• Memory CD8+ T cell role (mouse, By similarity in UniProt): PCK1-derived PEP feeds
  glycogen and the pentose phosphate pathway. This is a metabolic requirement rather
  than a regulatory role in differentiation.
  [file:human/PCK1/PCK1-uniprot.txt "The resultant phosphoenolpyruvate flows to glycogen and pentose phosphate pathway, which is essential for memory CD8(+) T-cells homeostasis"]

2026-11-05 ORGANELLES ER batch 3 (endoplasmic reticulum rows)

Rows: GO:0005783 IDA (PMID:32322062) and GO:0005783 IEA (GO_REF:0000120, from mouse Q9Z2V4). Both already KEEP_AS_NON_CORE.

Checks:
- Mouse Q9Z2V4 (UniProt REST, 2026-11-05) lists the ER by similarity to human P35558 (ECO:0000250), and the human line is curated from PMID:32322062 (ECO:0000269): one source.
- PMID:32322062 is abstract-only in the cache: "Phosphorylated PCK1 translocates to the endoplasmic reticulum" PMID:32322062. The ER marker and fractionation controls cannot be checked.
- PCK1 is soluble and cytosolic (no signal peptide, no TM); the pSer90 pool is recruited to the ER surface.

Outcome: actions unchanged (KEEP_AS_NON_CORE on curator deference); a dated sentence added to each reason. Stays at the root. Marker-controlled fractionation of endogenous pSer90-PCK1 would settle the location.