Mammalian GABA shunt (glutamate to GABA to succinate)

The mammalian GABA shunt couples cytosolic neurotransmitter synthesis to mitochondrial catabolism. PLP-dependent GAD1/2 decarboxylate L-glutamate to GABA and carbon dioxide in the cytosol. After GABA enters the mitochondrial matrix, PLP-dependent ABAT transfers its amino group to 2-oxoglutarate, producing succinate semialdehyde and regenerating L-glutamate; ALDH5A1 then uses NAD+ to oxidize the semialdehyde to succinate and NADH. The shunt feeds the TCA cycle while bypassing its 2-oxoglutarate-to-succinate segment. GAD1, ABAT, and ALDH5A1 deficiencies cause inherited neurological or metabolic disorders, including GABA-transaminase and succinate-semialdehyde-dehydrogenase deficiencies.

MODULE:gaba_shuntDRAFTCONCRETEMetabolic Pathwaymodules/gaba_shunt.yaml

GABA shuntGO:0006540

GO:0006540

GABA shunt

The module is grounded in the GO GABA shunt (GO:0006540): glutamate -> GABA -> succinate semialdehyde -> succinate.

Reactome:R-HSA-888572

PXLP-K405-GAD1 decarboxylates L-Glu to form GABA

Reactions follow the human Reactome GABA-metabolism reactions R-HSA-888572 (GAD1), R-HSA-916855 (ABAT) and R-HSA-888548 (ALDH5A1).

file:human/GAD1/GAD1-ai-review.yaml

GAD1 gene review (human)

The glutamate-decarboxylation (GABA synthesis) step (UniProtKB:Q99259, GO:0004351) matches the completed human GAD1 review.

file:human/ABAT/ABAT-ai-review.yaml

ABAT gene review (human)

The GABA-transamination step (UniProtKB:P80404, GO:0034386) matches the completed human ABAT review.

file:human/ALDH5A1/ALDH5A1-ai-review.yaml

ALDH5A1 gene review (human)

The succinate-semialdehyde-dehydrogenase step (UniProtKB:P51649, GO:0004777) matches the completed human ALDH5A1 review.

4Nodes

3Parts

0Variant Sets

0Variants

3Annotons

2Connections

Derived QC

Recommended-field compliance

80.0% recommended fields populated

module.knowledge_gaps[0] · provenance (0/1)

Module deep research

✗ none found

No MODULE:gaba_shunt 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 (3/4 grounded genes reviewed)

3 complete review(s) · 0 with deep research · 1 missing review · 3 reviewed but lacking deep research

Gene	Review	Complete	Deep research
ABAT P80404	✓	✓	✗
ALDH5A1 P51649	✓	✓	✗
GAD1 Q99259	✓	✓	✗
GAD2 (human, GAD65) Q05329	✗	—	—

Tree

Mammalian GABA shunt (glutamate to GABA to succinate)Metabolic Pathwaygaba_shunt

Parts
1. 1. GABA synthesis (glutamate decarboxylation)
2. L-glutamate to GABA + CO2Reactiongad_step
  
  Annotons
  - GAD1/GAD2: glutamate decarboxylase Family: Glutamate decarboxylase family (GAD1/GAD2)
3. 2. GABA transamination (first catabolic step)
4. GABA + 2-oxoglutarate to succinate semialdehyde + L-glutamateReactionabat_step
  
  Annotons
  - ABAT: 4-aminobutyrate aminotransferase (GABA-T) Family: 4-aminobutyrate aminotransferase family (ABAT)
5. 3. oxidation to succinate (feeds TCA cycle)
6. succinate semialdehyde + NAD+ to succinate + NADHReactionaldh5a1_step
  
  Annotons
  - ALDH5A1: succinate-semialdehyde dehydrogenase (SSADH) Family: Succinate-semialdehyde dehydrogenase family (ALDH5A1)

Details

Mammalian GABA shunt (glutamate to GABA to succinate)Metabolic Pathwaygaba_shunt

GABA shuntGO:0006540

The mammalian GABA shunt is grounded to the human enzymes glutamate decarboxylase GAD1 (UniProtKB:Q99259, GO:0004351, EC 4.1.1.15), 4-aminobutyrate aminotransferase ABAT (P80404, GO:0034386, EC 2.6.1.19) and succinate-semialdehyde dehydrogenase ALDH5A1 (P51649, GO:0004777, EC 1.2.1.24). GO molecular-function terms were taken from the human GOA records; Reactome reaction ids and titles were verified against the local reactome cache. The GAD node uses a PANTHER family selector (PTHR45677) with both isoforms as representatives — GAD1/GAD67 (constitutive, cytosolic) and GAD2/GAD65 (synaptic-vesicle-associated); ABAT and ALDH5A1 use their own family selectors. The pathway is compartment-split: GABA synthesis (GAD) is cytosolic while GABA catabolism (ABAT, ALDH5A1) is in the mitochondrial matrix (GABA is transported in). Both GAD and ABAT are PLP-dependent; ABAT regenerates the glutamate consumed by GAD. The terminal succinate enters the TCA cycle, so the shunt bypasses the 2-oxoglutarate -> succinyl-CoA -> succinate segment. Disorders: GAD1 -> spastic paraplegia / cerebral palsy / DEE; ABAT -> GABA-transaminase deficiency; ALDH5A1 -> succinic semialdehyde dehydrogenase deficiency (GHB/4-hydroxybutyric aciduria). ABAT's secondary beta-amino-acid transaminase activity links to pyrimidine (thymine) catabolism. This concrete mammalian realization should not be broadened to cover the P. putida GabT/GabD pathway; bacterial GABA transport, regulation, and enzyme implementations belong in a separate bacterial module, with a future abstract GABA-shunt motif available to link the two realizations through `conforms_to`.

Connections

gad_step -> abat_step Provides Input For

abat_step -> aldh5a1_step Provides Input For

Part 1: GABA synthesis (glutamate decarboxylation)

L-glutamate to GABA + CO2Reactiongad_step

Annotons

GAD1/GAD2: glutamate decarboxylase

gad_activity

Participant: Family: Glutamate decarboxylase family (GAD1/GAD2)

Family:

Glutamate decarboxylase family (GAD1/GAD2)PANTHER:PTHR45677

Representative Members: GAD1 (human, GAD67)UniProtKB:Q99259 GAD2 (human, GAD65)UniProtKB:Q05329

Function

glutamate decarboxylase activityGO:0004351

Substrates: L-glutamate

Products: gamma-aminobutyric acid (GABA) CO2

Locations

cytosolGO:0005829

PLP-dependent decarboxylation of glutamate to the inhibitory neurotransmitter GABA. GAD1 (GAD67) is the constitutive cytosolic isoform; GAD2 (GAD65) is membrane-associated at synaptic vesicles. GAD1 deficiency -> spastic paraplegia / cerebral palsy / epileptic encephalopathy.

Part 2: GABA transamination (first catabolic step)

GABA + 2-oxoglutarate to succinate semialdehyde + L-glutamateReactionabat_step

Annotons

ABAT: 4-aminobutyrate aminotransferase (GABA-T)

abat_activity

Participant: Family: 4-aminobutyrate aminotransferase family (ABAT)

Family:

4-aminobutyrate aminotransferase family (ABAT)PANTHER:PTHR43206

Representative Members: ABAT (human)UniProtKB:P80404

Function

4-aminobutyrate:2-oxoglutarate transaminase activityGO:0034386

Substrates: gamma-aminobutyric acid (GABA) 2-oxoglutarate

Products: succinate semialdehyde L-glutamate

Locations

mitochondrial matrixGO:0005759

PLP-dependent mitochondrial GABA transaminase: transfers GABA's amino group to 2-oxoglutarate, yielding succinate semialdehyde and regenerating glutamate. First step of GABA degradation; deficiency = GABA-transaminase deficiency.

Part 3: oxidation to succinate (feeds TCA cycle)

succinate semialdehyde + NAD+ to succinate + NADHReactionaldh5a1_step

Annotons

ALDH5A1: succinate-semialdehyde dehydrogenase (SSADH)

aldh5a1_activity

Participant: Family: Succinate-semialdehyde dehydrogenase family (ALDH5A1)

Family:

Succinate-semialdehyde dehydrogenase family (ALDH5A1)PANTHER:PTHR43353

Representative Members: ALDH5A1 (human)UniProtKB:P51649

Function

succinate-semialdehyde dehydrogenase (NAD+) activityGO:0004777

Substrates: succinate semialdehyde NAD+

Products: succinate NADH

Locations

mitochondrial matrixGO:0005759

NAD+-dependent oxidation of succinate semialdehyde to succinate, which enters the TCA cycle — completing the GABA shunt. Deficiency = SSADH deficiency (4-hydroxybutyric / GHB aciduria).