Glycolysis I — investment phase (glucose → glyceraldehyde-3-phosphate); GSD VII/XII, TPI/GPI deficiency

The investment (preparatory) phase of glycolysis is the first half of the cytosolic pathway that converts one molecule of glucose into two molecules of glyceraldehyde-3-phosphate, at the net cost of two ATP, priming the sugar for the energy-yielding payoff phase. Five steps: a hexokinase (HK1-3 or the glucose-sensor glucokinase GCK) phosphorylates glucose to glucose-6-phosphate; glucose-6-phosphate isomerase (GPI) isomerises it to fructose-6-phosphate; 6-phosphofructokinase-1 (the committed, rate-limiting, allosterically controlled step; muscle PFKM) phosphorylates fructose-6-phosphate to fructose-1,6-bisphosphate; class-I fructose-bisphosphate aldolase (muscle ALDOA) cleaves it to dihydroxyacetone phosphate (DHAP) + glyceraldehyde-3-phosphate; and triosephosphate isomerase (TPI1) interconverts DHAP and glyceraldehyde-3-phosphate so that both trioses continue into the payoff phase. Inherited defects across this phase mostly present as hereditary nonspherocytic hemolytic anemia and/or myopathy, with distinctive extras: HK1 deficiency (hemolytic anemia; other HK1 variants cause neuropathy/retinopathy); GCK mutations cause MODY2/neonatal diabetes or hyperinsulinism (glucose-sensing, not hemolysis); GPI deficiency (hemolytic anemia); PFKM deficiency = glycogen storage disease type VII (Tarui, exercise intolerance); ALDOA deficiency = GSD type XII; and TPI1 deficiency is a severe hemolytic anemia with progressive neurodegeneration.

MODULE:glycolysis_investment_phaseDRAFTMetabolic Pathwaymodules/glycolysis_investment_phase.yaml
glycolytic processGO:0006096
GO:0006096
glycolytic process
The module is grounded in the GO glycolytic process (GO:0006096); it covers the investment-phase steps from glucose to glyceraldehyde-3-phosphate.
Reactome:R-HSA-70171
Glycolysis
Step order and reaction stoichiometries follow the human Reactome "Glycolysis" reactions R-HSA-70420 (hexokinase), R-HSA-70471 (GPI), R-HSA-70467 (PFK), R-HSA-71496 (aldolase) and R-HSA-70454 (TPI1).
file:human/HK1/HK1-ai-review.yaml
HK1 gene review (human)
The hexokinase step (UniProtKB:P19367, GO:0004396) matches the completed human HK1 review.
file:human/GCK/GCK-ai-review.yaml
GCK gene review (human)
The glucose-sensor glucokinase isozyme of the hexokinase step (UniProtKB:P35557, GO:0004340) matches the completed human GCK review.
file:human/GPI/GPI-ai-review.yaml
GPI gene review (human)
The phosphoglucose-isomerase step (UniProtKB:P06744, GO:0004347) matches the completed human GPI review.
file:human/PFKM/PFKM-ai-review.yaml
PFKM gene review (human)
The rate-limiting phosphofructokinase step (UniProtKB:P08237, GO:0003872) matches the completed human PFKM review.
file:human/ALDOA/ALDOA-ai-review.yaml
ALDOA gene review (human)
The aldol-cleavage step (UniProtKB:P04075, GO:0004332) matches the completed human ALDOA review.
file:human/TPI1/TPI1-ai-review.yaml
TPI1 gene review (human)
The triose-phosphate-isomerase step (UniProtKB:P60174, GO:0004807) matches the completed human TPI1 review.
6Nodes
5Parts
0Variant Sets
0Variants
5Annotons
4Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:glycolysis_investment_phase deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Gene-review completeness (6/6 grounded genes reviewed)

5 complete review(s) · 0 with deep research · 0 missing review · 6 reviewed but lacking deep research

Gene Review Complete Deep research
ALDOA P04075 ✓ ✓ ✗
GCK P35557 ✓ ✓ ✗
GPI P06744 ✓ ✓ ✗
HK1 P19367 ✓ 66/67 ✗
PFKM P08237 ✓ ✓ ✗
TPI1 P60174 ✓ ✓ ✗

Details

Context
cytosolGO:0005829
Glycolysis (investment phase)Metabolic Pathwayglycolysis_investment_phase
glycolytic processGO:0006096
Context
cytosolGO:0005829

Five-step investment phase of glycolysis grounded to the human enzymes hexokinase HK1 (UniProtKB:P19367, GO:0004396) / glucokinase GCK (P35557, GO:0004340), GPI (P06744, GO:0004347), 6-phosphofructokinase PFKM (P08237, GO:0003872), aldolase ALDOA (P04075, GO:0004332) and triosephosphate isomerase TPI1 (P60174, GO:0004807). GO molecular-function terms were taken from the human GOA records; Reactome reaction ids and titles were verified against the local reactome cache. Each step uses a PANTHER family selector (generic over the tissue isozymes and orthologs): the hexokinase node carries HK1 and GCK as representatives (family also includes HK2/HK3/ HKDC1); PFK covers PFKM/PFKL/PFKP; aldolase covers ALDOA/ALDOB/ALDOC (ALDOB reviewed in the fructolysis module). Downstream, the two glyceraldehyde-3-phosphate molecules feed the glycolysis payoff phase (GAPDH -> PGK1 -> PGAM -> ENO -> pyruvate kinase; GAPDH/PKM already reviewed, remainder to follow), and pyruvate feeds the pyruvate- metabolism module (PDC/PC). Upstream, glucose-6-phosphate is shared with the glucose-6-phosphatase system, glycogen metabolism (via PGM1) and the pentose phosphate pathway; fructose-6-phosphate also receives dietary fructose carbon (fructolysis). Moonlighting roles (GPI = neuroleukin/AMF; ALDOA actin/RNA binding) are captured non-core in the gene reviews. Disorders: HK1 (hemolytic anemia); GCK (MODY2/PNDM/hyperinsulinism); GPI (hemolytic anemia); PFKM (GSD VII/Tarui); ALDOA (GSD XII); TPI1 (hemolytic anemia + neurodegeneration).

Connections

hexokinase_step -> gpi_step Provides Input For
Glucose-6-phosphate from hexokinase is isomerised by GPI.
gpi_step -> pfk_step Provides Input For
Fructose-6-phosphate from GPI is phosphorylated by PFK-1.
pfk_step -> aldolase_step Provides Input For
Fructose-1,6-bisphosphate from PFK-1 is cleaved by aldolase.
aldolase_step -> tpi_step Provides Input For
The DHAP arm from aldolase is isomerised by TPI1 to glyceraldehyde-3-phosphate (the glyceraldehyde-3-phosphate arm enters the payoff phase directly).
Part 1: phosphorylation of glucose (entry/commitment)
D-glucose + ATP to D-glucose-6-phosphate + ADPReactionhexokinase_step

Annotons

HK1-3/GCK: hexokinase / glucokinase
hexokinase_activity
Participant: Family: Hexokinase family (HK1/HK2/HK3/GCK/HKDC1)
Family:
Hexokinase family (HK1/HK2/HK3/GCK/HKDC1)PANTHER:PTHR19443
Representative Members: HK1 (human, ubiquitous hexokinase-1)UniProtKB:P19367 GCK (human, liver/beta-cell glucokinase)UniProtKB:P35557

Function

hexokinase activityGO:0004396
Substrates: D-glucose ATP
Products: D-glucose 6-phosphate ADP

Locations

cytosolGO:0005829

Phosphorylates glucose to glucose-6-phosphate (also feeding the pentose phosphate pathway and glycogen synthesis). HK1-3 are high-affinity, G6P-product-inhibited hexokinases (HK1 ubiquitous); GCK is the high-Km, non-inhibited liver/beta-cell glucose sensor (MODY2, hyperinsulinism).

Part 2: aldose-ketose isomerisation
D-glucose-6-phosphate to D-fructose-6-phosphateReactiongpi_step

Annotons

GPI: glucose-6-phosphate isomerase
gpi_activity
Participant: Family: Glucose-6-phosphate isomerase family (GPI)
Family:
Glucose-6-phosphate isomerase family (GPI)PANTHER:PTHR11469
Representative Members: GPI (human)UniProtKB:P06744

Function

glucose-6-phosphate isomerase activityGO:0004347
Substrates: D-glucose 6-phosphate
Products: D-fructose 6-phosphate

Locations

cytosolGO:0005829

Reversibly isomerises glucose-6-phosphate and fructose-6-phosphate. The same protein moonlights extracellularly as neuroleukin / autocrine motility factor (non-core). Deficiency causes hemolytic anemia.

Part 3: committed, rate-limiting phosphorylation
D-fructose-6-phosphate + ATP to D-fructose-1,6-bisphosphate + ADPReactionpfk_step

Annotons

PFKM/PFKL/PFKP: 6-phosphofructokinase-1
pfk_activity
Participant: Family: 6-phosphofructokinase-1 family (PFKM/PFKL/PFKP)
Family:
6-phosphofructokinase-1 family (PFKM/PFKL/PFKP)PANTHER:PTHR13697
Representative Members: PFKM (human, muscle isozyme)UniProtKB:P08237

Function

6-phosphofructokinase activityGO:0003872
Substrates: D-fructose 6-phosphate ATP
Products: D-fructose 1,6-bisphosphate ADP

Locations

cytosolGO:0005829

The committed, rate-limiting glycolytic step and principal allosteric control point. Active as a tetramer of the PFKM/PFKL/PFKP isozymes (muscle = PFKM homotetramer). PFKM deficiency = GSD VII (Tarui disease).

Part 4: aldol cleavage to two trioses
D-fructose-1,6-bisphosphate to DHAP + D-glyceraldehyde-3-phosphateReactionaldolase_step

Annotons

ALDOA/B/C: fructose-bisphosphate aldolase
aldolase_activity
Participant: Family: Class I fructose-bisphosphate aldolase family (ALDOA/ALDOB/ALDOC)
Family:
Class I fructose-bisphosphate aldolase family (ALDOA/ALDOB/ALDOC)PANTHER:PTHR11627
Representative Members: ALDOA (human, muscle/red-cell isozyme)UniProtKB:P04075

Function

fructose-bisphosphate aldolase activityGO:0004332
Substrates: D-fructose 1,6-bisphosphate
Products: dihydroxyacetone phosphate (DHAP) D-glyceraldehyde 3-phosphate

Locations

cytosolGO:0005829

Homotetrameric Schiff-base aldolase cleaving fructose-1,6-bisphosphate into DHAP and glyceraldehyde-3-phosphate. ALDOA (muscle) deficiency = GSD XII (hemolytic anemia + myopathy); the ALDOB liver isozyme handles dietary fructose (fructolysis module; HFI).

Part 5: interconversion of the triose phosphates
dihydroxyacetone phosphate to D-glyceraldehyde-3-phosphateReactiontpi_step

Annotons

TPI1: triosephosphate isomerase
tpi_activity
Participant: Family: Triosephosphate isomerase family (TPI1)
Family:
Triosephosphate isomerase family (TPI1)PANTHER:PTHR21139
Representative Members: TPI1 (human)UniProtKB:P60174

Function

triose-phosphate isomerase activityGO:0004807
Substrates: dihydroxyacetone phosphate (DHAP)
Products: D-glyceraldehyde 3-phosphate

Locations

cytosolGO:0005829

Interconverts DHAP and glyceraldehyde-3-phosphate so that both aldolase products enter the payoff phase (doubling the yield). Deficiency causes a severe hemolytic anemia with progressive neurodegeneration.