FBP1 (Fructose-1,6-bisphosphatase 1) - review notes

UniProt P09467 (F16P1_HUMAN); HGNC:3606; EC 3.1.3.11; 338 aa; FBPase class 1 family
(PANTHER PTHR11556:SF11).

Literature work (2026-10-09)

just deep-research-falcon human FBP1 reported a timeout ("Provider falcon timed out after 600s"), so the
review below was written from UniProt, GOA, cached Reactome entries and cached PubMed abstracts/full texts
(fetched with just fetch-pmid). The falcon report (FBP1-deep-research-falcon.md) was written afterwards.
Checked against the review: it gives the same primary annotation (cytosolic, metal-dependent
fructose-1,6-bisphosphate 1-phosphohydrolase for hepatic and renal gluconeogenesis, restrained by AMP and
fructose-2,6-bisphosphate) and treats nuclear HIF repression in ccRCC as secondary, as the review does
(PMID:25043030 rows), so it changes no curation decision.

Core biology

• Catalytic activity: fructose 1,6-bisphosphate + H2O -> fructose 6-phosphate + Pi, Mg2+
  dependent [file:human/FBP1/FBP1-uniprot.txt "Catalyzes the hydrolysis of fructose
  1,6-bisphosphate to fructose 6-phosphate in the presence of divalent cations, acting as a
  rate-limiting enzyme in gluconeogenesis."]
• Recombinant human liver enzyme is active; Asp118/Asp121 metal-pocket residues are catalytic
  PMID:8387495.
• Allosteric inhibition by AMP, competitive inhibition by fructose 2,6-bisphosphate
  PMID:8387495; homotetramer PMID:18650089.
• Cytosolic; gluconeogenesis step [Reactome:R-HSA-70479 "Cytosolic FBP
  (fructose-1,6-bisphosphatase) tetramers catalyze the physiologically irreversible
  hydrolysis of F1,6PP"].
• Hepatic FBP1 required for fructose tolerance PMID:36964915.
• Moonlighting: nuclear FBP1 represses HIF via the HIF inhibitory domain in ccRCC,
  independent of catalysis PMID:25043030. Kept as
  non-core.

Disease

• FBPase deficiency (MIM:229700; MONDO:0009251), autosomal recessive; ClinGen Definitive (AR,
  2025-11-14). PMID:25601412; patient missense proteins inactive [PMID:9382095; PMID:20096900];
  misfolding class of variants PMID:37507476.

Annotation decisions (summary)

• ACCEPT: FBPase activity (all lines), gluconeogenesis (all lines), cytosol/cytoplasm.
• MODIFY: phosphatase activity / phosphoric ester hydrolase activity -> GO:0042132;
  carbohydrate metabolic process -> GO:0006094.
• KEEP_AS_NON_CORE: identical protein binding (homotetramer), AMP binding, metal ion binding,
  fructose and fructose 6-phosphate metabolic process, HIF-related nucleus / negative
  regulation of Pol II transcription / TF binding, negative regulation of glycolysis,
  exosome (HDA).
• REMOVE: all bare protein binding IPIs (uninformative; HIF content captured by GO:0061629);
  cellular response to xenobiotic stimulus (in vitro inhibitor chemistry); rodent-expression
  IEA responses to raffinose, salinity, phorbol ester.
• MARK_AS_OVER_ANNOTATED: regulation of gluconeogenesis (enzyme, not regulator), negative
  regulation of cell growth and of Ras signalling (FBP1 is downstream of/repressed by Ras),
  response to Mg2+ (cofactor), monosaccharide binding, extracellular region, response to
  insulin/cAMP/nutrient levels (transcriptional regulation of FBP1, not participation).
• Caveat: PMID:17350621 (EXP for activity) abstract concerns the muscle isozyme; accepted,
  deferring to curator (full text not cached).

Alignment with dismech

dismech Fructose-1,6-Bisphosphatase_Deficiency binds the trigger node to FBP1 (hgnc:3606)
with fructose 1,6-bisphosphate 1-phosphatase activity (GO:0042132) and gluconeogenesis
(GO:0006094) DECREASED in the cytosol (GO:0005829) of hepatocytes. This matches the single
core function here exactly (MF, BP, location). The gluconeogenesis_human and
gluconeogenesis_human_substrates modules carry FBP1 with the same MF and cytosol location.