Fructolysis (hepatic dietary fructose catabolism; hereditary fructose intolerance)

Fructolysis is the liver (and kidney/intestine) pathway that catabolises dietary fructose, feeding its carbon into glycolysis/gluconeogenesis while bypassing the main phosphofructokinase regulatory step of glycolysis. Three cytosolic steps: ketohexokinase (KHK, fructokinase) phosphorylates fructose to fructose-1-phosphate at the expense of ATP; the liver-type fructose-bisphosphate aldolase (ALDOB) cleaves fructose-1-phosphate to dihydroxyacetone phosphate (DHAP) + D-glyceraldehyde; and triokinase (TKFC) phosphorylates the D-glyceraldehyde to D-glyceraldehyde-3- phosphate. The DHAP and glyceraldehyde-3-phosphate then enter the glycolytic / gluconeogenic triose-phosphate pool. Because KHK is not feedback-regulated, hepatic fructose uptake and phosphorylation are rapid and unregulated, transiently trapping phosphate as fructose-1-phosphate. Inherited defects: KHK deficiency causes benign essential fructosuria; ALDOB deficiency causes hereditary fructose intolerance (HFI) — toxic accumulation of fructose-1-phosphate with ATP/phosphate depletion, hypoglycemia and hepatic/renal injury on fructose or sucrose ingestion; and TKFC deficiency causes a rare multisystem disorder (cataracts, developmental problems). ALDOB (like the other aldolases) also participates in the aldol cleavage of fructose-1,6-bisphosphate in glycolysis/gluconeogenesis, and TKFC additionally has an FMN-cyclase (FAD-AMP lyase) activity in riboflavin metabolism.

MODULE:fructolysisDRAFTMetabolic Pathwaymodules/fructolysis.yaml
fructose catabolic process to hydroxyacetone phosphate and glyceraldehyde-3-phosphateGO:0006001
GO:0006001
fructose catabolic process
The module is grounded in GO:0006001. The route-specific term GO:0061624 (fructose catabolic process to hydroxyacetone phosphate and glyceraldehyde-3-phosphate) was obsoleted in GO release 2026-05-19 with replaced_by GO:0006001; the conversion of fructose to DHAP + glyceraldehyde-3-phosphate is carried by the module structure.
Reactome:R-HSA-70350
Fructose catabolism
Step order and reaction stoichiometries follow the human Reactome "Fructose catabolism" reactions R-HSA-70333 (KHK), R-HSA-70342 (ALDOB) and R-HSA-70349 (TKFC).
file:human/KHK/KHK-ai-review.yaml
KHK gene review (human)
The fructose-phosphorylation step (UniProtKB:P50053, GO:0004454 ketohexokinase activity) matches the completed human KHK review.
file:human/ALDOB/ALDOB-ai-review.yaml
ALDOB gene review (human)
The fructose-1-phosphate cleavage step (UniProtKB:P05062, GO:0061609 fructose-1-phosphate aldolase activity, GO:0004332) matches the completed human ALDOB review.
file:human/TKFC/TKFC-ai-review.yaml
TKFC gene review (human)
The triose-phosphorylation step (UniProtKB:Q3LXA3, GO:0050354 triokinase activity) matches the completed human TKFC review.
4Nodes
3Parts
0Variant Sets
0Variants
3Annotons
2Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:fructolysis 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.

Function consistency and core coverage

3 gene-function check(s) reflected in core functions · 0 conflict(s) · 2 evidence or coverage gap(s) (6 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
khk_activity KHK (human)
UniProtKB:P50053
Family Representative 		ketohexokinase activity
GO:0004454 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
aldob_activity ALDOB (human, liver/kidney/intestine)
UniProtKB:P05062
Family Representative 		fructose-1-phosphate aldolase activity
GO:0061609 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
tkfc_activity TKFC (human)
UniProtKB:Q3LXA3
Family Representative 		triokinase activity
GO:0050354 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
khk_activity Ketohexokinase / carbohydrate kinase (PfkB/ribokinase-like) family (KHK)
Family 		ketohexokinase activity
GO:0004454 		Family Id Missing
The family has no identifier linking it to a curated family review.
aldob_activity Class I fructose-bisphosphate aldolase family (ALDOA/B/C)
PANTHER:PTHR11627
Family 		fructose-1-phosphate aldolase activity
GO:0061609 		Family Scope Restricted
GO:0061609 is SUBFAMILY_ONLY; this family grounding does not establish the allowed subfamily scope. Module fructolysis (aldob_activity) assigns fructose-1-phosphate aldolase activity to PTHR11627 with ALDOB as the representative. All class I aldolases can cleave fructose 1-phosphate to some degree, but the physiologically significant activity is the aldolase B property that PAINT places at the vertebrate ALDOB node (PTN002614886). Granting the term family-wide would assign the fructolysis step to aldolase A and C and to the invertebrate and plant enzymes, which is not supported. Safe for SF2 only.
tkfc_activity Triokinase / FMN cyclase (DAK) family (TKFC)
PANTHER:PTHR28629
Family 		triokinase activity
GO:0050354 		Family Supported
Family review supports GO:0050354 FAMILY_WIDE. Triokinase (D-glyceraldehyde kinase) activity is established for TKFC (SF4), and S. pombe dak1 (SF14) also keeps it; fructolysis asserts it on the base family.

Gene-review completeness (3/3 grounded genes reviewed)

2 complete review(s) · 0 with deep research · 0 missing review · 3 reviewed but lacking deep research

Gene Review Complete Deep research
ALDOB P05062 ✓ 52/53 ✗
KHK P50053 ✓ ✓ ✗
TKFC Q3LXA3 ✓ ✓ ✗

Details

Context
cytosolGO:0005829
Fructolysis (dietary fructose catabolism)Metabolic Pathwayfructolysis
fructose catabolic process to hydroxyacetone phosphate and glyceraldehyde-3-phosphateGO:0006001
Context
cytosolGO:0005829

Three-step hepatic fructolysis grounded to the human enzymes KHK (UniProtKB:P50053, GO:0004454, EC 2.7.1.3), ALDOB (P05062, GO:0061609 / GO:0004332, EC 4.1.2.13) and TKFC (Q3LXA3, GO:0050354, EC 2.7.1.28). 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 paralogs and orthologs) plus a concrete human representative member; the ALDOB family also includes the glycolytic aldolases ALDOA (muscle) and ALDOC (brain). Downstream, DHAP and glyceraldehyde-3-phosphate feed glycolysis / gluconeogenesis (existing gluconeogenesis modules). ALDOB's glycolytic fructose-1,6-bisphosphate aldol activity and TKFC's FMN-cyclase / MDA5-regulatory moonlighting roles are noted but out of scope for this dietary-fructose-catabolism module. Disorders: KHK → essential fructosuria (benign); ALDOB → hereditary fructose intolerance; TKFC → TKFC deficiency.

Connections

khk_step -> aldob_step Provides Input For
Fructose-1-phosphate from KHK is cleaved by ALDOB.
aldob_step -> tkfc_step Provides Input For
The D-glyceraldehyde arm from ALDOB is phosphorylated by TKFC (the DHAP arm enters glycolysis directly).
Part 1: committed fructose phosphorylation
D-fructose + ATP to D-fructose-1-phosphate + ADPReactionkhk_step

Annotons

KHK: ketohexokinase (fructokinase)
khk_activity
Participant: Family: Ketohexokinase / carbohydrate kinase (PfkB/ribokinase-like) family (KHK)
Family:
Ketohexokinase / carbohydrate kinase (PfkB/ribokinase-like) family (KHK)
Representative Members: KHK (human)UniProtKB:P50053

Function

ketohexokinase activityGO:0004454
Substrates: D-fructose ATP
Products: D-fructose 1-phosphate ADP

Locations

cytosolGO:0005829

Committed, unregulated first step of fructolysis (KHK-C is the high-affinity hepatic isoform; KHK-A a wider-tissue splice form). Deficiency causes benign essential fructosuria.

Part 2: aldol cleavage of fructose-1-phosphate
D-fructose-1-phosphate to DHAP + D-glyceraldehydeReactionaldob_step

Annotons

ALDOB: fructose-bisphosphate aldolase B
aldob_activity
Participant: Family: Class I fructose-bisphosphate aldolase family (ALDOA/B/C)
Family:
Class I fructose-bisphosphate aldolase family (ALDOA/B/C)PANTHER:PTHR11627
Representative Members: ALDOB (human, liver/kidney/intestine)UniProtKB:P05062

Function

fructose-1-phosphate aldolase activityGO:0061609
Substrates: D-fructose 1-phosphate
Products: dihydroxyacetone phosphate (DHAP) D-glyceraldehyde

Locations

cytosolGO:0005829

Class-I (Schiff-base) homotetrameric aldolase; the liver isoform with high fructose-1-phosphate cleaving activity (it also cleaves fructose-1,6-bisphosphate in glycolysis/gluconeogenesis). Deficiency causes hereditary fructose intolerance (HFI).

Part 3: phosphorylation of glyceraldehyde into the triose-phosphate pool
D-glyceraldehyde + ATP to D-glyceraldehyde-3-phosphate + ADPReactiontkfc_step

Annotons

TKFC: triokinase
tkfc_activity
Participant: Family: Triokinase / FMN cyclase (DAK) family (TKFC)
Family:
Triokinase / FMN cyclase (DAK) family (TKFC)PANTHER:PTHR28629
Representative Members: TKFC (human)UniProtKB:Q3LXA3

Function

triokinase activityGO:0050354
Substrates: D-glyceraldehyde ATP
Products: D-glyceraldehyde 3-phosphate ADP

Locations

cytosolGO:0005829

Phosphorylates the ALDOB-derived D-glyceraldehyde to glyceraldehyde-3-phosphate, returning fructose carbon to the glycolytic triose-phosphate pool. Bifunctional (also an FMN-cyclase / FAD-AMP lyase in riboflavin metabolism); deficiency is a rare multisystem disorder.