Human gluconeogenesis: the synthesis of free glucose from non-carbohydrate precursors (lactate, glucogenic amino acids such as alanine, and glycerol). Unlike the taxon-neutral gluconeogenesis template, this module is grounded to specific human isozymes and is organised around the fact that in a metazoan the pathway is not uniformly active: every cell carries the genes, but free-glucose output is restricted to a few tissues. Three control points are encoded as variant sets over human isozymes that differ by tissue and subcellular compartment: the phosphoenolpyruvate-forming step (cytosolic PCK1 vs mitochondrial PCK2), the fructose-1,6-bisphosphatase step (gluconeogenic FBP1 vs muscle FBP2), and the terminal glucose-releasing step, which is a two-component endoplasmic-reticulum system requiring both a catalytic subunit and the glucose-6-phosphate antiporter SLC37A4. The terminal step is the physiological gate: only tissues expressing the gluconeogenic catalytic subunit G6PC1 together with SLC37A4 can release free glucose, which is why liver, kidney cortex, and intestine are gluconeogenic while skeletal muscle and brain are not. This module is designed to be evaluated against tissue expression data: each isozyme atom is an expressed/not-expressed predicate per context, so the realised route through the pathway can be resolved per tissue.
All recommended fields populated.
✗ none found
No MODULE:gluconeogenesis_human deep-research report alongside the module YAML.
1 leaf node(s) with no concrete protein grounding:
✓ every declared conforms_to bundle matches its template motif.
0 complete review(s) · 0 with deep research · 7 missing review · 0 reviewed but lacking deep research
| Gene | Review | Complete | Deep research |
|---|---|---|---|
| FBP2 (muscle fructose-1,6-bisphosphatase) O00757 | ✗ | — | — |
| SLC37A4 (glucose-6-phosphate transporter / G6PT) O43826 | ✗ | — | — |
| FBP1 (liver fructose-1,6-bisphosphatase) P09467 | ✗ | — | — |
| PC (pyruvate carboxylase) P11498 | ✗ | — | — |
| PCK1 (cytosolic PEPCK) P35558 | ✗ | — | — |
| G6PC1 (glucose-6-phosphatase catalytic subunit 1) P35575 | ✗ | — | — |
| PCK2 (mitochondrial PEPCK) Q16822 | ✗ | — | — |
Tissue-/compartment-resolved human specialisation of the generic gluconeogenesis template (modules/gluconeogenesis.yaml). Human isozyme accessions were verified against UniProt; GO molecular-function, location, and transporter terms were verified via QuickGO. The module is built for expression-grounded satisfiability: see modules/experimental/gluconeogenesis-context/ for the logic compiler and the GTEx oracle that resolve the active route per tissue and identify the terminal G6PC1+SLC37A4 step as the gluconeogenic gate.
Anaplerotic carboxylation of pyruvate; the entry point for lactate- and alanine-derived carbon into gluconeogenesis.
PEPCK exists as cytosolic (PCK1) and mitochondrial (PCK2) isozymes; many gluconeogenic tissues express both, and the cytosolic/mitochondrial flux split varies by tissue and metabolic state.
The near-equilibrium reactions (enolase, phosphoglycerate mutase, PGK, GAPDH, aldolase, triosephosphate isomerase, phosphoglucose isomerase) run in the gluconeogenic direction. These are broadly expressed housekeeping enzymes and are not tissue-restricted, so the trunk is treated as constitutively satisfiable and is not a gate; the tissue-restricting control points are the bypass reactions.
The gluconeogenic isozyme; carries gluconeogenic flux in liver and kidney.
Muscle isozyme; provides the phosphatase activity but its physiological role is linked to regulation of glycolysis/glycogen rather than free-glucose-releasing gluconeogenesis.
Free-glucose output requires a two-component endoplasmic-reticulum system: glucose 6-phosphate must be imported into the ER lumen by the SLC37A4 antiporter AND hydrolysed by a catalytic subunit whose active site faces the ER lumen. Both components are required (logical AND), making this the gate that distinguishes gluconeogenic tissues. The gluconeogenic catalytic subunit is G6PC1; G6PC2 (islet) and G6PC3 (ubiquitous, "G6Pase-beta") are paralogs that do not confer gluconeogenic free-glucose release and are recorded as a paralog trap, not as satisfying variants of the gluconeogenic route.
Paralog trap: G6PC2 (UniProtKB:Q9NQR9, pancreatic-islet, largely catalytically inactive autoantigen) and G6PC3 (UniProtKB:Q9BUM1, ubiquitous G6Pase-beta with a neutrophil role) are paralogs of G6PC1. Their expression must NOT be read as gluconeogenic free-glucose-release capacity; only G6PC1 satisfies the gluconeogenic route.
Gluconeogenic catalytic subunit; expressed in liver, kidney cortex, and intestine. Required for free-glucose release.
Imports cytosolic glucose 6-phosphate into the ER lumen for hydrolysis; obligately required alongside the catalytic subunit.