L-lysine catabolism (saccharopine pathway to glutaryl-CoA; glutaric aciduria type 1)

The main (saccharopine) pathway of L-lysine degradation in humans, a mitochondrial route that also handles L-hydroxylysine and the final steps of L-tryptophan catabolism, converging on glutaryl-CoA and ultimately acetyl-CoA. The bifunctional alpha-aminoadipic semialdehyde synthase (AASS) catalyses the first two committed steps: its lysine-2-oxoglutarate reductase (saccharopine dehydrogenase, NADP+) activity condenses L-lysine with 2-oxoglutarate to saccharopine, and its saccharopine dehydrogenase (NAD+) activity then oxidises saccharopine to L-2-aminoadipate-6-semialdehyde + L-glutamate. Downstream (semialdehyde -> L-2-aminoadipate by ALDH7A1; L-2-aminoadipate -> 2-oxoadipate by the aminotransferase AADAT — not modelled here) yields 2-oxoadipate, which the 2-oxoadipate dehydrogenase complex (OADHC) oxidatively decarboxylates to glutaryl-CoA. The OADHC is a paralogous sibling of the 2-oxoglutarate dehydrogenase complex: a dedicated E1 (DHTKD1, TPP-dependent) plus the shared E2 succinyltransferase core (DLST, acting as a glutaryltransferase here) and the shared E3 (DLD). Finally the FAD-dependent glutaryl-CoA dehydrogenase (GCDH) oxidatively decarboxylates glutaryl-CoA to crotonyl-CoA + CO2, passing electrons to the electron-transfer flavoprotein system (ETF -> ETFDH -> respiratory chain). Inherited defects: AASS deficiency causes (largely benign) hyperlysinemia / saccharopinuria; DHTKD1 deficiency causes 2-aminoadipic/2-oxoadipic aciduria (and is linked to Charcot-Marie-Tooth 2Q); and GCDH deficiency causes glutaric aciduria type 1 (GA1), a serious encephalopathy with striatal injury.

MODULE:lysine_catabolismDRAFTMetabolic Pathwaymodules/lysine_catabolism.yaml
L-lysine catabolic processGO:0019477
GO:0019477
L-lysine catabolic process
The module is grounded in the GO L-lysine catabolic process (GO:0019477); each step is annotated within it (converging on glutaryl-CoA).
Reactome:R-HSA-71064
Lysine catabolism
Step order follows the human Reactome "Lysine catabolism" pathway; the glutaryl-CoA-forming (R-HSA-9858590, DLST) and glutaryl-CoA dehydrogenase (R-HSA-71046, GCDH) reactions were verified against the local cache.
file:human/AASS/AASS-ai-review.yaml
AASS gene review (human)
The bifunctional entry step (UniProtKB:Q9UDR5, GO:0047130 + GO:0047131) matches the completed human AASS review.
file:human/DHTKD1/DHTKD1-ai-review.yaml
DHTKD1 gene review (human)
The 2-oxoadipate dehydrogenase E1 grounding (UniProtKB:Q96HY7, GO:0160166, GO:0160167 complex) matches the completed human DHTKD1 review.
file:human/DLST/DLST-ai-review.yaml
DLST gene review (human)
The shared E2 core grounding (UniProtKB:P36957, GO:0120571 dihydrolipoyllysine- residue glutaryltransferase activity for the OADHC) matches the completed human DLST review.
file:human/DLD/DLD-ai-review.yaml
DLD gene review (human)
The shared E3 grounding (UniProtKB:P09622, GO:0004148) matches the completed human DLD review.
file:human/GCDH/GCDH-ai-review.yaml
GCDH gene review (human)
The glutaryl-CoA dehydrogenase step (UniProtKB:Q92947, GO:0004361) matches the completed human GCDH review (glutaric aciduria type 1).
4Nodes
3Parts
0Variant Sets
0Variants
6Annotons
2Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:lysine_catabolism 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

6 gene-function check(s) reflected in core functions · 0 conflict(s) · 6 evidence or coverage gap(s) (12 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_lkr AASS (human, bifunctional)
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).
aass_sdh AASS (human, bifunctional)
UniProtKB:Q9UDR5
Family Representative 		saccharopine dehydrogenase (NAD+, L-glutamate-forming) activity
GO:0047131 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dhtkd1_e1 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).
dlst_e2 DLST (human)
UniProtKB:P36957
Family Representative 		dihydrolipoyllysine-residue glutaryltransferase activity
GO:0120571 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dld_e3 DLD (human)
UniProtKB:P09622
Family Representative 		dihydrolipoyl dehydrogenase (NADH) activity
GO:0004148 		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_lkr Alpha-aminoadipic semialdehyde synthase / saccharopine dehydrogenase family (AASS)
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.
aass_sdh Alpha-aminoadipic semialdehyde synthase / saccharopine dehydrogenase family (AASS)
PANTHER:PTHR11133
Family 		saccharopine dehydrogenase (NAD+, L-glutamate-forming) activity
GO:0047131 		Family Scope Restricted
GO:0047131 is SUBFAMILY_ONLY; this family grounding does not establish the allowed subfamily scope. The animal AASS saccharopine dehydrogenase domain (SF22).
dhtkd1_e1 2-oxoglutarate/2-oxoadipate dehydrogenase E1 family (DHTKD1/OGDH)
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.
dlst_e2 Dihydrolipoyllysine-residue succinyl/glutaryl-transferase E2 family (DLST)
PANTHER:PTHR43416
Family 		dihydrolipoyllysine-residue glutaryltransferase activity
GO:0120571 		Family Scope Restricted
GO:0120571 is SUBFAMILY_ONLY; this family grounding does not establish the allowed subfamily scope. Glutaryltransferase for human DLST in the 2-oxoadipate dehydrogenase complex, as lysine_catabolism selects.
dld_e3 Dihydrolipoyl dehydrogenase family (DLD)
PANTHER:PTHR22912
Family 		dihydrolipoyl dehydrogenase (NADH) activity
GO:0004148 		Family Scope Restricted
GO:0004148 is SUBFAMILY_ONLY; this family grounding does not establish the allowed subfamily scope. The E3 subfamilies, not the divergent SthA transhydrogenase. SF219 is included on the basis of its independently mapped AcoL representative, the native sequence-based E3 assignment in PMID:10368162 and the conserved catalytic architecture. This extends chemistry scope, not a requirement that all E3 paralogs serve the same physiological complexes. No new PAINT node is inferred.
gcdh_activity Acyl-CoA dehydrogenase family, glutaryl-CoA subfamily (GCDH)
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
AASS Q9UDR5 ✓ 18/23 ✓
DHTKD1 Q96HY7 ✓ ✓ ✗
DLD P09622 ✓ ✓ ✓
DLST P36957 ✓ ✓ ✗
GCDH Q92947 ✓ 24/25 ✗

Details

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

L-lysine (and L-tryptophan) degradation converging on glutaryl-CoA, grounded to the human enzymes AASS (UniProtKB:Q9UDR5; bifunctional GO:0047130 LKR + GO:0047131 SDH), the 2-oxoadipate dehydrogenase complex — DHTKD1 E1 (Q96HY7, GO:0160166), the shared E2 DLST (P36957, GO:0120571 glutaryltransferase / GO:0004149 succinyltransferase in the TCA OGDHC) and the shared E3 DLD (P09622, GO:0004148), assembled as GO:0160167 — and glutaryl-CoA dehydrogenase GCDH (Q92947, GO:0004361, EC 1.3.8.6). 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 concrete human representative members; the OADHC is modelled as a PROTEIN_COMPLEX node whose E2 (DLST) and E3 (DLD) are shared with the TCA-cycle 2-oxoglutarate dehydrogenase complex. The intermediate ALDH7A1 (antiquitin; pyridoxine-dependent epilepsy) and AADAT steps between AASS and the OADHC are noted but not yet modelled. Downstream, GCDH-derived crotonyl-CoA is further catabolised to acetyl-CoA and its electrons feed the ETF system (see MODULE:electron_transfer_flavoprotein_system).

Connections

aass_step -> oadhc_step Provides Input For
AASS begins lysine degradation; after the (unmodelled) ALDH7A1 and AADAT steps, the resulting 2-oxoadipate is oxidatively decarboxylated by the OADHC.
oadhc_step -> gcdh_step Provides Input For
Glutaryl-CoA made by the OADHC is dehydrogenated/decarboxylated by GCDH.
Part 1: bifunctional entry (saccharopine pathway, first two steps)
L-lysine + 2-oxoglutarate to L-2-aminoadipate-6-semialdehyde (via saccharopine)Reactionaass_step

Annotons

AASS: lysine-2-oxoglutarate reductase (saccharopine-forming)
aass_lkr
Participant: Family: Alpha-aminoadipic semialdehyde synthase / saccharopine dehydrogenase family (AASS)
Family:
Alpha-aminoadipic semialdehyde synthase / saccharopine dehydrogenase family (AASS)PANTHER:PTHR11133
Representative Members: AASS (human, bifunctional)UniProtKB:Q9UDR5

Function

saccharopine dehydrogenase (NADP+, L-lysine-forming) activityGO:0047130
Substrates: L-lysine 2-oxoglutarate NADPH
Products: saccharopine

Locations

mitochondrial matrixGO:0005759

N-terminal lysine-2-oxoglutarate reductase (LKR) domain; condenses lysine and 2-oxoglutarate to saccharopine (NADPH-dependent), the committed first step of lysine degradation.

AASS: saccharopine dehydrogenase (glutamate-forming)
aass_sdh
Participant: Family: Alpha-aminoadipic semialdehyde synthase / saccharopine dehydrogenase family (AASS)
Family:
Alpha-aminoadipic semialdehyde synthase / saccharopine dehydrogenase family (AASS)PANTHER:PTHR11133
Representative Members: AASS (human, bifunctional)UniProtKB:Q9UDR5

Function

saccharopine dehydrogenase (NAD+, L-glutamate-forming) activityGO:0047131
Substrates: saccharopine NAD+
Products: L-2-aminoadipate-6-semialdehyde L-glutamate

Locations

mitochondrial matrixGO:0005759

C-terminal saccharopine dehydrogenase (SDH) domain; oxidises saccharopine to L-2-aminoadipate-6-semialdehyde + glutamate. (Downstream ALDH7A1 and AADAT steps to 2-oxoadipate are not modelled here.)

Part 2: oxidative decarboxylation of 2-oxoadipate (multienzyme complex)
2-oxoadipate + CoA + NAD+ to glutaryl-CoA + CO2 + NADHProtein Complexoadhc_step

Annotons

DHTKD1: 2-oxoadipate dehydrogenase E1
dhtkd1_e1
Participant: Family: 2-oxoglutarate/2-oxoadipate dehydrogenase E1 family (DHTKD1/OGDH)
Family:
2-oxoglutarate/2-oxoadipate dehydrogenase E1 family (DHTKD1/OGDH)PANTHER:PTHR23152
Representative Members: DHTKD1 (human)UniProtKB:Q96HY7

Function

2-oxoadipate dehydrogenase activityGO:0160166
Substrates: 2-oxoadipate thiamine diphosphate (cofactor)
Products: (decarboxylated glutaryl-lipoyl intermediate) carbon dioxide

Locations

mitochondrial matrixGO:0005759

TPP-dependent E1 that decarboxylates 2-oxoadipate; the substrate- specific subunit of the 2-oxoadipate dehydrogenase complex (OADHC), paralogous to OGDH. Deficiency causes 2-aminoadipic/2-oxoadipic aciduria.

DLST: shared E2 (glutaryltransferase core)
dlst_e2
Participant: Family: Dihydrolipoyllysine-residue succinyl/glutaryl-transferase E2 family (DLST)
Family:
Dihydrolipoyllysine-residue succinyl/glutaryl-transferase E2 family (DLST)PANTHER:PTHR43416
Representative Members: DLST (human)UniProtKB:P36957

Function

dihydrolipoyllysine-residue glutaryltransferase activityGO:0120571
Substrates: S-glutaryl-dihydrolipoyl intermediate coenzyme A
Products: glutaryl-CoA

Locations

mitochondrial matrixGO:0005759

The E2 core, shared with the TCA-cycle 2-oxoglutarate dehydrogenase complex (where it acts as a succinyltransferase); in the OADHC it transfers the glutaryl group to CoA forming glutaryl-CoA.

DLD: shared E3 (dihydrolipoyl dehydrogenase)
dld_e3
Participant: Family: Dihydrolipoyl dehydrogenase family (DLD)
Family:
Dihydrolipoyl dehydrogenase family (DLD)PANTHER:PTHR22912
Representative Members: DLD (human)UniProtKB:P09622

Function

dihydrolipoyl dehydrogenase (NADH) activityGO:0004148
Substrates: dihydrolipoyl-E2 NAD+
Products: lipoyl-E2 (reoxidised) NADH

Locations

mitochondrial matrixGO:0005759

FAD-dependent E3 that reoxidises the dihydrolipoyl arm; the common E3 shared across the 2-oxoacid dehydrogenase complexes.

Part 3: FAD-dependent oxidative decarboxylation of glutaryl-CoA
glutaryl-CoA + FAD to crotonyl-CoA + CO2 + FADH2Reactiongcdh_step

Annotons

GCDH: glutaryl-CoA dehydrogenase
gcdh_activity
Participant: Family: Acyl-CoA dehydrogenase family, glutaryl-CoA subfamily (GCDH)
Family:
Acyl-CoA dehydrogenase family, glutaryl-CoA subfamily (GCDH)PANTHER:PTHR42807
Representative Members: GCDH (human)UniProtKB:Q92947

Function

glutaryl-CoA dehydrogenase activityGO:0004361
Substrates: glutaryl-CoA FAD
Products: crotonyl-CoA carbon dioxide FADH2

Locations

mitochondrial matrixGO:0005759

FAD-dependent acyl-CoA dehydrogenase performing a combined dehydrogenation and decarboxylation of glutaryl-CoA to crotonyl-CoA; electrons pass to the ETF system (see the ETF module). Deficiency causes glutaric aciduria type 1.