Peroxisomal fatty-acid beta-oxidation (VLCFA, branched-chain, bile-acid intermediates)

Peroxisomal beta-oxidation chain-shortens the fatty acids that mitochondria cannot handle: very-long-chain fatty acids (VLCFAs, >=C22), 2-methyl-branched fatty acids (pristanic acid, from phytanic-acid alpha-oxidation), the C27 bile-acid intermediates di- and tri-hydroxycholestanoyl-CoA (DHCA/THCA, en route to cholic/chenodeoxycholic acid), and dicarboxylic acids from omega-oxidation. Each cycle removes two carbons as acetyl-CoA through the same four reactions, but with peroxisome-specific enzymes. Step 1 is an FAD-dependent acyl-CoA OXIDASE that passes electrons directly to O2 (making H2O2, not feeding the respiratory chain): ACOX1 acts on straight-chain (VLC) acyl-CoAs, and ACOX3 on 2-methyl-branched (pristanoyl) acyl-CoAs. Steps 2-3 (hydration then NAD+-dependent dehydrogenation) are performed by multifunctional proteins of opposite stereochemistry: the D-bifunctional protein HSD17B4 (the main enzyme for VLCFA, pristanic acid and bile-acid intermediates) and the L-bifunctional protein EHHADH (more important for medium-chain and dicarboxylic-acid substrates). Step 4, thiolytic cleavage to acetyl-CoA (or propionyl-CoA for branched substrates) plus a shortened acyl-CoA, is carried out by ACAA1 (straight-chain thiolase) and by the SCPx thiolase (encoded by SCP2, which also yields the sterol-carrier protein SCP2) for branched-chain and bile-acid substrates. The chain-shortened acyl-CoA re-enters the spiral. Inherited single-enzyme defects — ACOX1 deficiency (pseudo-neonatal adrenoleukodystrophy), D-bifunctional protein (HSD17B4) deficiency, EHHADH (renal Fanconi), and SCP2 deficiency — as well as the peroxisome-biogenesis Zellweger spectrum, cause VLCFA/pristanic-acid/bile-acid accumulation with severe neurological disease.

MODULE:peroxisomal_beta_oxidationDRAFTMetabolic Pathwaymodules/peroxisomal_beta_oxidation.yaml
fatty acid beta-oxidationGO:0006635 fatty acid beta-oxidation using acyl-CoA oxidaseGO:0033540
GO:0006635
fatty acid beta-oxidation
ACOX1/ACOX3, HSD17B4/EHHADH and ACAA1/SCP2 carry out fatty-acid beta-oxidation (GO:0006635).
GO:0033540
fatty acid beta-oxidation using acyl-CoA oxidase
The peroxisomal spiral is initiated by acyl-CoA oxidases, distinguishing it (GO:0033540).
file:human/ACOX1/ACOX1-ai-review.yaml
ACOX1 gene review (human)
The straight-chain acyl-CoA oxidation step (UniProtKB:Q15067, GO:0003997) matches the completed human ACOX1 review.
file:human/ACOX3/ACOX3-ai-review.yaml
ACOX3 gene review (human)
The branched (pristanoyl) acyl-CoA oxidation step (UniProtKB:O15254, GO:0016402) matches the completed human ACOX3 review.
file:human/HSD17B4/HSD17B4-ai-review.yaml
HSD17B4 gene review (human)
The D-bifunctional hydratase/dehydrogenase step (UniProtKB:P51659, GO:0080023/GO:0106386) matches the completed human HSD17B4 review.
file:human/EHHADH/EHHADH-ai-review.yaml
EHHADH gene review (human)
The L-bifunctional hydratase/dehydrogenase step (UniProtKB:Q08426, GO:0004300/GO:0003857) matches the completed human EHHADH review.
file:human/ACAA1/ACAA1-ai-review.yaml
ACAA1 gene review (human)
The straight-chain thiolytic cleavage step (UniProtKB:P09110, GO:0003988) matches the completed human ACAA1 review.
file:human/SCP2/SCP2-ai-review.yaml
SCP2 gene review (human)
The branched/bile-acid SCPx thiolase step (UniProtKB:P22307, GO:0050632) matches the completed human SCP2 review.
4Nodes
3Parts
0Variant Sets
0Variants
5Annotons
3Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:peroxisomal_beta_oxidation 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 (6/6 grounded genes reviewed)

5 complete review(s) · 0 with deep research · 0 missing review · 6 reviewed but lacking deep research

Gene Review Complete Deep research
ACAA1 P09110 ✓ ✓ ✗
ACOX1 Q15067 ✓ 48/49 ✗
ACOX3 O15254 ✓ ✓ ✗
EHHADH Q08426 ✓ ✓ ✗
HSD17B4 P51659 ✓ ✓ ✗
SCP2 P22307 ✓ ✓ ✗

Details

Context
peroxisomal matrixGO:0005782
Peroxisomal fatty-acid beta-oxidationMetabolic Pathwayperoxisomal_beta_oxidation
fatty acid beta-oxidationGO:0006635 fatty acid beta-oxidation using acyl-CoA oxidaseGO:0033540
Context
peroxisomal matrixGO:0005782

Peroxisomal fatty-acid beta-oxidation (GO:0006635 + GO:0033540), grounded to six completed human gene reviews, all peroxisomal-matrix enzymes. STEP 1 (FAD oxidase, O2->H2O2): ACOX1 (Q15067, straight/VLCFA, GO:0003997; pseudo-neonatal ALD) + ACOX3 (O15254, 2-methyl-branched/pristanoyl, GO:0016402 — NB GO:0033812 is a THIOLASE not the oxidase) share PTHR10909. STEPS 2-3 (hydration+NAD+ dehydrogenation), opposite stereochemistry: D-bifunctional HSD17B4 (P51659 PTHR45024, GO:0080023 hydratase-2 + GO:0106386 (3R)-HAD; main enzyme for VLCFA/pristanic/bile-acid; D-BP deficiency + Perrault) and L-bifunctional EHHADH (Q08426 PTHR23309, GO:0004300 hydratase + GO:0003857 (3S)-HAD; medium-chain/dicarboxylic; PPARa-induced; renal Fanconi on mistargeting). STEP 4 (thiolysis): straight-chain ACAA1 (P09110 PTHR43853, GO:0003988) + branched/bile-acid SCPx (SCP2 gene, P22307 PTHR42870, GO:0050632 thiolase + GO:0120020 sterol transfer; SCP2 deficiency). The spiral iterates; acetyl-CoA/propionyl-CoA products and chain-shortened acyl-CoAs exit (via carnitine) to mitochondria. GO term ids/labels verified against the local go.db. This complements the mitochondrial FAO/ETF modules; the bile-acid branch feeds bile-acid synthesis (curated separately). Disorders: ACOX1, HSD17B4 (D-BP), EHHADH, SCP2 deficiencies; Zellweger spectrum (peroxisome biogenesis).

Connections

The 2-trans-enoyl-CoA made by the oxidases is hydrated + dehydrogenated by HSD17B4/EHHADH.
The 3-oxoacyl-CoA is thiolytically cleaved by ACAA1 (straight) or SCPx/SCP2 (branched/bile-acid).
thiolytic_cleavage -> acyl_coa_oxidation Provides Input For
The chain-shortened acyl-CoA (minus two carbons) re-enters the oxidase step, iterating the beta-oxidation spiral until the substrate is fully shortened.
Part 1: acyl-CoA oxidation (O2 -> H2O2)
Acyl-CoA oxidases (ACOX1/ACOX3)Reactionacyl_coa_oxidation

Annotons

ACOX1/ACOX3: FAD acyl-CoA oxidase
acox_activity
Participant: Family: ACOX / peroxisomal acyl-CoA oxidase family
Family:
ACOX / peroxisomal acyl-CoA oxidase familyPANTHER:PTHR10909
Representative Members: ACOX1 (human, straight-chain/VLCFA)UniProtKB:Q15067 ACOX3 (human, branched/pristanoyl)UniProtKB:O15254

Function

acyl-CoA oxidase activityGO:0003997
Substrates: acyl-CoA (ACOX1 straight-chain/VLC; ACOX3 2-methyl-branched/pristanoyl) O2 (FAD)
Products: 2-trans-enoyl-CoA H2O2

Locations

peroxisomal matrixGO:0005782

Dehydrogenate acyl-CoA to 2-trans-enoyl-CoA, reducing O2 to H2O2.

Part 2: hydration + dehydrogenation (bifunctional proteins)
Bifunctional proteins (HSD17B4 D / EHHADH L)Reactionhydration_dehydrogenation

Annotons

HSD17B4: D-bifunctional protein (hydratase 2 + (3R)-HAD)
hsd17b4_activity
Participant: Family: HSD17B4 / D-bifunctional protein family
Family:
HSD17B4 / D-bifunctional protein familyPANTHER:PTHR45024
Representative Members: HSD17B4 (human)UniProtKB:P51659

Function

(2E)-enoyl-CoA hydratase 2 activity (D-specific)GO:0080023
Substrates: 2-trans-enoyl-CoA (VLC / branched / bile-acid; H2O) NAD+ (for the (3R)-HAD dehydrogenase domain, GO:0106386)
Products: (R)-3-hydroxyacyl-CoA then 3-oxoacyl-CoA NADH

Locations

peroxisomal matrixGO:0005782

D-specific hydration + (3R)-dehydrogenation (main enzyme).

EHHADH: L-bifunctional protein (hydratase + (3S)-HAD)
ehhadh_activity
Participant: Family: EHHADH / L-bifunctional protein family
Family:
EHHADH / L-bifunctional protein familyPANTHER:PTHR23309
Representative Members: EHHADH (human)UniProtKB:Q08426

Function

enoyl-CoA hydratase activity (L-specific)GO:0004300
Substrates: 2-trans-enoyl-CoA (medium-chain / dicarboxylic; H2O) NAD+ (for the (3S)-HAD dehydrogenase domain, GO:0003857)
Products: L-3-hydroxyacyl-CoA then 3-oxoacyl-CoA NADH

Locations

peroxisomal matrixGO:0005782

L-specific hydration + (3S)-dehydrogenation.

Part 3: thiolytic cleavage (-> acetyl/propionyl-CoA)
Peroxisomal thiolases (ACAA1 / SCPx-SCP2)Reactionthiolytic_cleavage

Annotons

ACAA1: straight-chain 3-ketoacyl-CoA thiolase
acaa1_activity
Participant: Family: ACAA1 / peroxisomal 3-ketoacyl-CoA thiolase family
Family:
ACAA1 / peroxisomal 3-ketoacyl-CoA thiolase familyPANTHER:PTHR43853
Representative Members: ACAA1 (human)UniProtKB:P09110

Function

acetyl-CoA C-acyltransferase activityGO:0003988
Substrates: 3-oxoacyl-CoA (straight-chain) coenzyme A
Products: acyl-CoA (shortened by C2) acetyl-CoA

Locations

peroxisomal matrixGO:0005782

Thiolytic cleavage of straight-chain 3-oxoacyl-CoA (+ acetyl-CoA).

SCP2 (SCPx): branched/bile-acid thiolase + sterol carrier
scp2_activity
Participant: Family: SCP2 / SCPx thiolase + sterol-carrier family
Family:
SCP2 / SCPx thiolase + sterol-carrier familyPANTHER:PTHR42870
Representative Members: SCP2 (human, SCPx/SCP2)UniProtKB:P22307

Function

propionyl-CoA C2-trimethyltridecanoyltransferase (branched thiolase) activityGO:0050632
Substrates: 3-oxopristanoyl-CoA / 24-oxo-bile-acyl-CoA (branched) coenzyme A
Products: shortened acyl-CoA + propionyl-CoA (branched) choloyl-CoA / bile-acid-CoA (bile-acid branch)

Locations

peroxisomal matrixGO:0005782

Thiolytic cleavage of branched/bile-acid 3-oxoacyl-CoA (+ sterol transfer).