Lysine catabolism (saccharopine pathway; AASS/ALDH7A1/AADAT/DHTKD1/GCDH)

The saccharopine pathway is the main route of L-lysine degradation in mammals, converting lysine to acetyl-CoA through 2-aminoadipate and glutaryl-CoA, predominantly in liver and brain mitochondria. The bifunctional enzyme AASS (2-aminoadipic-6-semialdehyde synthase) catalyses the first two steps: its lysine-ketoglutarate reductase domain condenses L-lysine with 2-oxoglutarate to saccharopine, and its saccharopine dehydrogenase domain then cleaves saccharopine to L-2-aminoadipate 6-semialdehyde (AASA) plus L-glutamate. AASA (in equilibrium with delta-1-piperideine-6-carboxylate, P6C) is oxidised to L-2-aminoadipate by the NAD-dependent aldehyde dehydrogenase ALDH7A1 (antiquitin); a block here causes accumulation of P6C, which inactivates pyridoxal-5'-phosphate and produces pyridoxine-dependent epilepsy. The PLP-dependent aminotransferase AADAT (KAT2) then transaminates 2-aminoadipate with 2-oxoglutarate to 2-oxoadipate (AADAT is also kynurenine aminotransferase II, linking to tryptophan metabolism). 2-oxoadipate is oxidatively decarboxylated to glutaryl-CoA by the 2-oxoadipate dehydrogenase DHTKD1 (with DLST and DLD), and glutaryl-CoA is dehydrogenated/decarboxylated to crotonyl-CoA by GCDH (glutaryl-CoA dehydrogenase), which continues to two acetyl-CoA. Inherited defects cause aminoadipic/oxoadipic aciduria (DHTKD1), pyridoxine-dependent epilepsy (ALDH7A1) and glutaric aciduria type 1 (GCDH).

MODULE:lysine_catabolism_saccharopineDRAFTMetabolic Pathwaymodules/lysine_catabolism_saccharopine.yaml
L-lysine catabolic processGO:0019477
GO:0019477
L-lysine catabolic process
The pathway carries out L-lysine catabolism (GO:0019477) via the saccharopine route to glutaryl-CoA.
file:human/AASS/AASS-ai-review.yaml
AASS gene review (human)
The bifunctional lysine->AASA saccharopine step (UniProtKB:Q9UDR5, GO:0047130) matches the completed human AASS review (on main).
file:human/ALDH7A1/ALDH7A1-ai-review.yaml
ALDH7A1 gene review (human)
The AASA->2-aminoadipate dehydrogenase step (UniProtKB:P49419, GO:0004043) matches the completed human ALDH7A1 review.
file:human/AADAT/AADAT-ai-review.yaml
AADAT gene review (human)
The 2-aminoadipate->2-oxoadipate transamination step (UniProtKB:Q8N5Z0, GO:0047536) matches the completed human AADAT review.
file:human/DHTKD1/DHTKD1-ai-review.yaml
DHTKD1 gene review (human)
The 2-oxoadipate->glutaryl-CoA step (UniProtKB:Q96HY7, GO:0160166) matches the completed human DHTKD1 review (on main).
file:human/GCDH/GCDH-ai-review.yaml
GCDH gene review (human)
The glutaryl-CoA->crotonyl-CoA step (UniProtKB:Q92947, GO:0004361) matches the completed human GCDH review (on main).
4Nodes
3Parts
0Variant Sets
0Variants
5Annotons
2Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:lysine_catabolism_saccharopine 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 (5/5 grounded genes reviewed)

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

Gene Review Complete Deep research
AADAT Q8N5Z0 ✓ ✓ ✗
AASS Q9UDR5 ✓ ✓ ✗
ALDH7A1 P49419 ✓ ✓ ✗
DHTKD1 Q96HY7 ✓ ✓ ✗
GCDH Q92947 ✓ ✓ ✗

Details

Context
mitochondrial matrixGO:0005759
Lysine catabolism (saccharopine pathway)Metabolic Pathwaylysine_catabolism_saccharopine
L-lysine catabolic processGO:0019477
Context
mitochondrial matrixGO:0005759

L-lysine catabolism (GO:0019477) via the saccharopine pathway, grounded to the completed human gene reviews: AASS (Q9UDR5, bifunctional, GO:0047130 saccharopine dehydrogenase — on main), ALDH7A1 (P49419, GO:0004043 aminoadipate-semialdehyde dehydrogenase — curated here), AADAT (Q8N5Z0, GO:0047536 2-aminoadipate transaminase + GO:0016212 kynurenine transaminase + PLP — curated here), DHTKD1 (Q96HY7, GO:0160166 2-oxoadipate dehydrogenase — on main) and GCDH (Q92947, GO:0004361 glutaryl-CoA dehydrogenase — on main). AADAT and DHTKD1 also connect this pathway to the mitochondrial 2-oxodicarboxylate carrier SLC25A21 and to tryptophan/kynurenine metabolism. GO term ids/labels verified against the local go.db (note GO:0006554 "lysine catabolic process" is obsolete → GO:0019477 used). Downstream, crotonyl-CoA is metabolised to two acetyl-CoA. Disorders: ALDH7A1 — pyridoxine-dependent epilepsy; DHTKD1 — 2-aminoadipic/2-oxoadipic aciduria; GCDH — glutaric aciduria type 1 (macrocephaly, striatal injury, encephalopathic crises).

Connections

lys_to_aasa -> aasa_to_oxoadipate Provides Input For
AASS-derived 2-aminoadipate 6-semialdehyde is oxidised (ALDH7A1) and transaminated (AADAT) to 2-oxoadipate.
2-oxoadipate is decarboxylated to glutaryl-CoA (DHTKD1) and dehydrogenated to crotonyl-CoA (GCDH), continuing to acetyl-CoA.
Part 1: lysine -> 2-aminoadipate semialdehyde (saccharopine)
Saccharopine formation and cleavage (AASS)Reactionlys_to_aasa

Annotons

AASS: bifunctional 2-aminoadipic-6-semialdehyde synthase
aass_activity
Participant: Family: AASS / 2-aminoadipic-6-semialdehyde synthase family
Family:
AASS / 2-aminoadipic-6-semialdehyde synthase familyPANTHER:PTHR11133
Representative Members: AASS (human)UniProtKB:Q9UDR5

Function

saccharopine dehydrogenase (NADP+, L-lysine-forming) activityGO:0047130
Substrates: L-lysine 2-oxoglutarate / saccharopine
Products: L-2-aminoadipate 6-semialdehyde (AASA) L-glutamate

Locations

mitochondrial matrixGO:0005759

Bifunctional; converts L-lysine to 2-aminoadipate semialdehyde via saccharopine.

Part 2: 2-aminoadipate semialdehyde -> 2-oxoadipate
Aminoadipate formation and transamination (ALDH7A1, AADAT)Reactionaasa_to_oxoadipate

Annotons

ALDH7A1 (antiquitin): AASA dehydrogenase
aldh7a1_activity
Participant: Family: ALDH7A1 / antiquitin (aminoadipate-semialdehyde dehydrogenase) family
Family:
ALDH7A1 / antiquitin (aminoadipate-semialdehyde dehydrogenase) familyPANTHER:PTHR43521
Representative Members: ALDH7A1 (human)UniProtKB:P49419

Function

L-aminoadipate-semialdehyde dehydrogenase [NAD(P)+] activityGO:0004043
Substrates: L-2-aminoadipate 6-semialdehyde (AASA) NAD+
Products: L-2-aminoadipate

Locations

mitochondrial matrixGO:0005759

Oxidises AASA to L-2-aminoadipate.

AADAT (KAT2): 2-aminoadipate aminotransferase
aadat_activity
Participant: Family: AADAT / 2-aminoadipate (kynurenine) aminotransferase family
Family:
AADAT / 2-aminoadipate (kynurenine) aminotransferase familyPANTHER:PTHR42790
Representative Members: AADAT (human)UniProtKB:Q8N5Z0

Function

L-2-aminoadipate:2-oxoglutarate transaminase activityGO:0047536
Substrates: L-2-aminoadipate 2-oxoglutarate
Products: 2-oxoadipate L-glutamate

Locations

mitochondrial matrixGO:0005759

Transaminates L-2-aminoadipate to 2-oxoadipate.

Part 3: 2-oxoadipate -> glutaryl-CoA -> crotonyl-CoA
2-oxoadipate decarboxylation and glutaryl-CoA dehydrogenation (DHTKD1, GCDH)Reactionoxoadipate_to_crotonyl

Annotons

DHTKD1: 2-oxoadipate dehydrogenase (E1)
dhtkd1_activity
Participant: Family: DHTKD1 / 2-oxoadipate dehydrogenase (E1) family
Family:
DHTKD1 / 2-oxoadipate dehydrogenase (E1) familyPANTHER:PTHR23152
Representative Members: DHTKD1 (human)UniProtKB:Q96HY7

Function

2-oxoadipate dehydrogenase activityGO:0160166
Substrates: 2-oxoadipate thiamine pyrophosphate / CoA (with DLST, DLD)
Products: glutaryl-CoA CO2

Locations

mitochondrial matrixGO:0005759

Oxidatively decarboxylates 2-oxoadipate to glutaryl-CoA.

GCDH: glutaryl-CoA dehydrogenase
gcdh_activity
Participant: Family: GCDH / glutaryl-CoA dehydrogenase family
Family:
GCDH / glutaryl-CoA dehydrogenase familyPANTHER:PTHR42807
Representative Members: GCDH (human)UniProtKB:Q92947

Function

glutaryl-CoA dehydrogenase activityGO:0004361
Substrates: glutaryl-CoA FAD (electrons to ETF)
Products: crotonyl-CoA CO2

Locations

mitochondrial matrixGO:0005759

Dehydrogenates/decarboxylates glutaryl-CoA to crotonyl-CoA.