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.

Function consistency and core coverage

5 gene-function check(s) reflected in core functions · 0 conflict(s) · 5 evidence or coverage gap(s) (10 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
aass_activity AASS (human)
UniProtKB:Q9UDR5
Family Representative 		saccharopine dehydrogenase (NADP+, L-lysine-forming) activity
GO:0047130 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
aldh7a1_activity ALDH7A1 (human)
UniProtKB:P49419
Family Representative 		L-aminoadipate-semialdehyde dehydrogenase [NAD(P)+] activity
GO:0004043 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
aadat_activity AADAT (human)
UniProtKB:Q8N5Z0
Family Representative 		L-2-aminoadipate:2-oxoglutarate transaminase activity
GO:0047536 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dhtkd1_activity DHTKD1 (human)
UniProtKB:Q96HY7
Family Representative 		2-oxoadipate dehydrogenase activity
GO:0160166 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
gcdh_activity GCDH (human)
UniProtKB:Q92947
Family Representative 		glutaryl-CoA dehydrogenase activity
GO:0004361 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
aass_activity AASS / 2-aminoadipic-6-semialdehyde synthase family
PANTHER:PTHR11133
Family 		saccharopine dehydrogenase (NADP+, L-lysine-forming) activity
GO:0047130 		Family Scope Restricted
GO:0047130 is SUBFAMILY_ONLY; this family grounding does not establish the allowed subfamily scope. The animal AASS lysine-ketoglutarate reductase domain (SF22). lysine_catabolism and lysine_catabolism_saccharopine select the base family.
aldh7a1_activity ALDH7A1 / antiquitin (aminoadipate-semialdehyde dehydrogenase) family
PANTHER:PTHR43521
Family 		L-aminoadipate-semialdehyde dehydrogenase [NAD(P)+] activity
GO:0004043 		Family Function Unreviewed
Family review leaves GO:0004043 UNRESOLVED. Recombinant human ALDH7A1 metabolizes aminoadipic semialdehyde and additional aldehydes (PMID:20207735), supporting the aminoadipate-semialdehyde reaction in its branch. ALDH4/P5C-related members act on a different semialdehyde in proline metabolism. The complete substrate-specific boundary is unresolved across these branches; lysine catabolism, proline catabolism, cofactor preferences and stress responses are not interchangeable universal functions.
aadat_activity AADAT / 2-aminoadipate (kynurenine) aminotransferase family
PANTHER:PTHR42790
Family 		L-2-aminoadipate:2-oxoglutarate transaminase activity
GO:0047536 		Family Scope Restricted
GO:0008483 is SUBFAMILY_ONLY; this family grounding does not establish the allowed subfamily scope. Safe for the enzyme subfamilies (aromatic aminotransferases SF1, SF2, SF21 and SF23, AvtA SF4) and for SF19, whose AADAT, LysN and archaeal members are aminotransferases. Even within SF19 the PtsJ and NorG regulators should not be assumed to have the activity. Not safe for the MocR regulator subfamilies (SF6, SF7, SF8, SF9, SF17, SF20, SF22). Both yeast gene reviews accept the IBA.
dhtkd1_activity DHTKD1 / 2-oxoadipate dehydrogenase (E1) family
PANTHER:PTHR23152
Family 		2-oxoadipate dehydrogenase activity
GO:0160166 		Family Scope Restricted
GO:0160166 is SUBFAMILY_ONLY; this family grounding does not establish the allowed subfamily scope. DHTKD1 (in SF4), as lysine_catabolism and lysine_catabolism_saccharopine assert on the base family.
gcdh_activity GCDH / glutaryl-CoA dehydrogenase family
PANTHER:PTHR42807
Family 		glutaryl-CoA dehydrogenase activity
GO:0004361 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR42807.

Gene-review completeness (5/5 grounded genes reviewed)

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

Gene Review Complete Deep research
AADAT Q8N5Z0 ✓ ✓ ✗
AASS Q9UDR5 ✓ 18/23 ✓
ALDH7A1 P49419 ✓ ✓ ✓
DHTKD1 Q96HY7 ✓ ✓ ✗
GCDH Q92947 ✓ 24/25 ✗

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.