Peroxisomal fatty-acid beta-oxidation

Peroxisomal beta-oxidation chain-shortens acyl-CoAs two carbons per turn inside the peroxisomal matrix. In fungi such as budding yeast and in plants it is the only fatty-acid beta-oxidation system of the cell, whereas in animals it handles the substrates mitochondria cannot: very-long-chain fatty acids, 2-methyl-branched fatty acids (pristanic acid), the C27 bile-acid intermediates and dicarboxylic acids. Long-chain substrates enter as acyl-CoA through an ABC-D half-transporter dimer, which in yeast hydrolyses the thioester during transport so that the fatty acid is re-activated on the matrix side by an acyl-CoA synthetase; medium-chain fatty acids enter independently and are activated inside. In humans the two peroxisomal ABC-D half-transporters divide the substrates between them: ABCD1 (ALDP) takes straight-chain very-long-chain acyl-CoA, and ABCD3 (PMP70) takes the branched-chain, C27 bile-acid and dicarboxylic acyl-CoAs. Each turn uses four reactions with peroxisome-specific enzymes: an FAD acyl-CoA oxidase that passes electrons directly to O2 (making H2O2, degraded by catalase); hydration and NAD+-dependent dehydrogenation by multifunctional proteins (the D-specific, (3R)-hydroxyacyl-CoA-forming multifunctional enzyme type 2 in fungi and as the main animal enzyme, plus an L-specific bifunctional protein in animals); and thiolytic cleavage by peroxisomal 3-ketoacyl-CoA thiolases. Because the peroxisomal membrane is impermeable to NAD(H), NADP(H) and acetyl-CoA, the pathway also depends on matrix redox shuttles (a peroxisomal malate dehydrogenase reoxidising NADH) and on carnitine or glyoxylate-cycle routes that export the acetyl units. Unsaturated fatty acids additionally need auxiliary enzymes: a delta3-delta2-enoyl-CoA isomerase and an NADPH-dependent 2,4-dienoyl-CoA reductase, whose NADPH is regenerated inside the peroxisome by NADP-dependent isocitrate dehydrogenase. In humans, single-enzyme defects (ACOX1, HSD17B4, EHHADH, SCP2, ABCD1) and peroxisome biogenesis disorders cause accumulation of very-long-chain and branched fatty acids and bile-acid intermediates 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
YeastPathways:YEAST-FAO-PWY
fatty acid oxidation pathway (S. cerevisiae, SGD YeastPathways)
YeastCyc lists activation (FAA1-4, FAT1), POX1 oxidase, FOX2 as (3S) enoyl-CoA hydratase and (3S)-3-hydroxyacyl-CoA dehydrogenase, POT1 thiolase and ECI1/DCI1 isomerase. FOX2 acts via (3R) intermediates (PMID:1551874); SPS19, IDP3, MDH3 and PXA1/PXA2 are missing.
GO:0006635
fatty acid beta-oxidation
Module-level process.
GO:0033540
fatty acid beta-oxidation using acyl-CoA oxidase
The peroxisomal spiral is initiated by acyl-CoA oxidases.
PMID:17028011
Peroxisomal beta-oxidation--a metabolic pathway with multiple functions.
Mammals have beta-oxidation in mitochondria and peroxisomes whereas plants and most fungi have it only in peroxisomes; type 1 and type 2 multifunctional enzymes act with opposite stereochemistry.
PMID:12697341
The biochemistry of peroxisomal beta-oxidation in the yeast Saccharomyces cerevisiae.
Yeast peroxisomal beta-oxidation requires classical and auxiliary enzymes; Pxa1p-Pxa2p resembles human ALDP and Ant1p exchanges peroxisomal AMP for ATP.
PMID:1551874
Peroxisomal multifunctional beta-oxidation protein of Saccharomyces cerevisiae. Molecular analysis of the fox2 gene and gene product.
FOX2 has 2-enoyl-CoA hydratase 2 and D-3-hydroxyacyl-CoA dehydrogenase activities and lacks crotonase and L-3-hydroxyacyl-CoA dehydrogenase, so yeast beta-oxidation proceeds via D-3-hydroxyacyl-CoA.
PMID:9452501
IDP3 encodes a peroxisomal NADP-dependent isocitrate dehydrogenase required for the beta-oxidation of unsaturated fatty acids.
Saturated fatty acid degradation in S. cerevisiae is confined to peroxisomes; peroxisomal Idp3p is needed for growth on unsaturated but not saturated fatty acids, regenerating NADPH for the dienoyl-CoA reductase.
PMID:9268358
The Saccharomyces cerevisiae peroxisomal 2,4-dienoyl-CoA reductase is encoded by the oleate-inducible gene SPS19.
Sps19p is a peroxisomal-matrix NADPH-dependent 2,4-dienoyl-CoA reductase required for growth on petroselinic acid.
PMID:11302517
Eci1p uses a PTS1 to enter peroxisomes: either its own or that of a partner, Dci1p.
Eci1p is the peroxisomal delta3,delta2-enoyl-CoA isomerase essential for beta-oxidation of unsaturated fatty acids and can be co-imported with Dci1p.
PMID:7628449
The membrane of peroxisomes in Saccharomyces cerevisiae is impermeable to NAD(H) and acetyl-CoA under in vivo conditions.
mdh3 disruption impairs beta-oxidation in intact cells and prevents growth on oleate; the peroxisomal membrane is impermeable to NAD(H) and acetyl-CoA in vivo.
PMID:28928432
Two NAD-linked redox shuttles maintain the peroxisomal redox balance in Saccharomyces cerevisiae.
On oleate, peroxisomal NADH from beta-oxidation is reoxidised by the malate dehydrogenase (Mdh3p) malate/oxaloacetate shuttle; a Gpd1p-dependent shuttle can also contribute.
PMID:22493507
Peroxisomal fatty acid uptake mechanism in Saccharomyces cerevisiae.
Pxa1p-Pxa2p hydrolyses very-long-chain acyl-CoA before transporting the fatty acid, which is re-esterified by Faa2p and/or Fat1p on the inner surface; the mechanism is shared with human ABCD1 and ABCD2.
file:human/ABCD3/ABCD3-ai-review.yaml
ABCD3 gene review (human)
The acyl-CoA import step (UniProtKB:P28288, GO:0015607, peroxisomal membrane) matches the completed human ABCD3 review; ABCD1 (P33897) carries the same core function in its DRAFT review.
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.
file:yeast/IDP3/IDP3-ai-review.yaml
IDP3 gene review (S. cerevisiae)
Core function GO:0004450 in the peroxisomal matrix, regenerating NADPH for 2,4-dienoyl-CoA reductase in beta-oxidation of unsaturated fatty acids.
file:yeast/MDH3/MDH3-ai-review.yaml
MDH3 gene review (S. cerevisiae)
Core function GO:0030060 in the peroxisomal matrix, reoxidising NADH generated by fatty acid beta-oxidation.
12Nodes
11Parts
0Variant Sets
0Variants
11Annotons
9Connections

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.

Reaction chaining (advisory)

✓ every PRECEDES step chains, or its break is acknowledged via chaining_status.

  • peroxisomal_substrate_entry → acyl_coa_oxidation [NOT_CHECKED]
    Intraperoxisomal acyl-CoA made by the acyl-CoA synthetase is the acyl-CoA oxidase substrate; the transporter step does not involve a CoA product.
  • acyl_coa_oxidation → hydration_dehydrogenation [VERIFIED]
    shared: 2eenoylcoa
  • hydration_dehydrogenation → thiolytic_cleavage [MAPPING_GAP]
    The multifunctional-protein annotons are typed only with their hydratase activity (product 3-hydroxyacyl-CoA); the dehydrogenase domain of the same protein (GO:0106386 / GO:0003857) makes the 3-oxoacyl-CoA thiolase substrate.
  • thiolytic_cleavage → acyl_coa_oxidation [VERIFIED]
    shared: acylcoa
  • unsaturated_auxiliary → hydration_dehydrogenation [NOT_CHECKED]
    The isomerase returns (2E)-enoyl-CoA, the hydratase 2 substrate; the matcher compares the NADPH-regenerating and reductase leaves as well.

Function consistency and core coverage

17 gene-function check(s) reflected in core functions · 0 conflict(s) · 6 evidence or coverage gap(s) (38 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
abcd_transport_activity PXA1 (Saccharomyces cerevisiae)
UniProtKB:P41909
Family Representative 		long-chain fatty acid transmembrane transporter activity
GO:0005324 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
abcd_transport_activity PXA2 (Saccharomyces cerevisiae)
UniProtKB:P34230
Family Representative 		long-chain fatty acid transmembrane transporter activity
GO:0005324 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
abcd_transport_activity ABCD1 (human; straight-chain very-long-chain acyl-CoA)
UniProtKB:P33897
Family Representative 		long-chain fatty acid transmembrane transporter activity
GO:0005324 		Review Disagreement
The review removes, modifies, or marks this term over-annotated and provides no retained/core support. Review the rationale; rejection of an evidence row alone is not a biological NOT.
abcd_transport_activity ABCD3 (human, PMP70; branched-chain, C27 bile-acid and dicarboxylic acyl-CoA)
UniProtKB:P28288
Family Representative 		long-chain fatty acid transmembrane transporter activity
GO:0005324 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
faa2_activity FAA2 (Saccharomyces cerevisiae)
UniProtKB:P39518
Family Representative 		long-chain fatty acid-CoA ligase activity
GO:0004467 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
acox_activity ACOX1 (human, straight-chain/VLCFA)
UniProtKB:Q15067
Family Representative 		acyl-CoA oxidase activity
GO:0003997 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
acox_activity ACOX3 (human, branched/pristanoyl)
UniProtKB:O15254
Family Representative 		acyl-CoA oxidase activity
GO:0003997 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
acox_activity POX1 (Saccharomyces cerevisiae)
UniProtKB:P13711
Family Representative 		acyl-CoA oxidase activity
GO:0003997 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hsd17b4_activity HSD17B4 (human)
UniProtKB:P51659
Family Representative 		(2E)-enoyl-CoA hydratase 2 activity (D-specific)
GO:0080023 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hsd17b4_activity FOX2 (Saccharomyces cerevisiae)
UniProtKB:Q02207
Family Representative 		(2E)-enoyl-CoA hydratase 2 activity (D-specific)
GO:0080023 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ehhadh_activity EHHADH (human)
UniProtKB:Q08426
Family Representative 		enoyl-CoA hydratase activity (L-specific)
GO:0004300 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
acaa1_activity ACAA1 (human)
UniProtKB:P09110
Family Representative 		acetyl-CoA C-acyltransferase activity
GO:0003988 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
acaa1_activity POT1 (Saccharomyces cerevisiae)
UniProtKB:P27796
Family Representative 		acetyl-CoA C-acyltransferase activity
GO:0003988 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
scp2_activity SCP2 (human, SCPx/SCP2)
UniProtKB:P22307
Family Representative 		propionyl-CoA C2-trimethyltridecanoyltransferase (branched thiolase) activity
GO:0050632 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
eci_activity ECI1 (Saccharomyces cerevisiae)
UniProtKB:Q05871
Family Representative 		delta(3)-delta(2)-enoyl-CoA isomerase activity
GO:0004165 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
eci_activity ECI2 (human)
UniProtKB:O75521
Family Representative 		delta(3)-delta(2)-enoyl-CoA isomerase activity
GO:0004165 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
decr_activity SPS19 (Saccharomyces cerevisiae)
UniProtKB:P32573
Family Representative 		2,4-dienoyl-CoA reductase (NADPH) activity
GO:0008670 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
decr_activity DECR2 (human)
UniProtKB:Q9NUI1
Family Representative 		2,4-dienoyl-CoA reductase (NADPH) activity
GO:0008670 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
idp3_activity IDP3 (Saccharomyces cerevisiae)
UniProtKB:P53982
Family Representative 		isocitrate dehydrogenase (NADP+) activity
GO:0004450 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mdh3_activity MDH3 (Saccharomyces cerevisiae)
UniProtKB:P32419
Family Representative 		L-malate dehydrogenase (NAD+) activity
GO:0030060 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
abcd_transport_activity ABC-D peroxisomal half-transporter family
PANTHER:PTHR11384
Family 		long-chain fatty acid transmembrane transporter activity
GO:0005324 		Family Function Unreviewed
The family review has no applicable adjudication supporting or excluding GO:0005324.
faa2_activity long-chain acyl-CoA synthetase family
PANTHER:PTHR43272:SF83
Family 		long-chain fatty acid-CoA ligase activity
GO:0004467 		Family Supported
Family review supports GO:0004467 for PANTHER:PTHR43272:SF83. Asserted by peroxisomal_beta_oxidation for FAA2; accepted by FAA1, FAA2, FAA3, FAA4 and ACSL4. SF33 is listed because it holds FAA2, although its Car members are not ligases.
faa2_activity long-chain acyl-CoA synthetase family
PANTHER:PTHR43272:SF22
Family 		long-chain fatty acid-CoA ligase activity
GO:0004467 		Family Supported
Family review supports GO:0004467 for PANTHER:PTHR43272:SF22. Asserted by peroxisomal_beta_oxidation for FAA2; accepted by FAA1, FAA2, FAA3, FAA4 and ACSL4. SF33 is listed because it holds FAA2, although its Car members are not ligases.
faa2_activity long-chain acyl-CoA synthetase family
PANTHER:PTHR43272:SF13
Family 		long-chain fatty acid-CoA ligase activity
GO:0004467 		Family Supported
Family review supports GO:0004467 for PANTHER:PTHR43272:SF13. Asserted by peroxisomal_beta_oxidation for FAA2; accepted by FAA1, FAA2, FAA3, FAA4 and ACSL4. SF33 is listed because it holds FAA2, although its Car members are not ligases.
faa2_activity long-chain acyl-CoA synthetase family
PANTHER:PTHR43272:SF28
Family 		long-chain fatty acid-CoA ligase activity
GO:0004467 		Family Supported
Family review supports GO:0004467 for PANTHER:PTHR43272:SF28. Asserted by peroxisomal_beta_oxidation for FAA2; accepted by FAA1, FAA2, FAA3, FAA4 and ACSL4. SF33 is listed because it holds FAA2, although its Car members are not ligases.
faa2_activity long-chain acyl-CoA synthetase family
PANTHER:PTHR43272:SF93
Family 		long-chain fatty acid-CoA ligase activity
GO:0004467 		Family Supported
Family review supports GO:0004467 for PANTHER:PTHR43272:SF93. Asserted by peroxisomal_beta_oxidation for FAA2; accepted by FAA1, FAA2, FAA3, FAA4 and ACSL4. SF33 is listed because it holds FAA2, although its Car members are not ligases.
faa2_activity long-chain acyl-CoA synthetase family
PANTHER:PTHR43272:SF101
Family 		long-chain fatty acid-CoA ligase activity
GO:0004467 		Family Supported
Family review supports GO:0004467 for PANTHER:PTHR43272:SF101. Asserted by peroxisomal_beta_oxidation for FAA2; accepted by FAA1, FAA2, FAA3, FAA4 and ACSL4. SF33 is listed because it holds FAA2, although its Car members are not ligases.
faa2_activity long-chain acyl-CoA synthetase family
PANTHER:PTHR43272:SF32
Family 		long-chain fatty acid-CoA ligase activity
GO:0004467 		Family Supported
Family review supports GO:0004467 for PANTHER:PTHR43272:SF32. Asserted by peroxisomal_beta_oxidation for FAA2; accepted by FAA1, FAA2, FAA3, FAA4 and ACSL4. SF33 is listed because it holds FAA2, although its Car members are not ligases.
faa2_activity long-chain acyl-CoA synthetase family
PANTHER:PTHR43272:SF33
Family 		long-chain fatty acid-CoA ligase activity
GO:0004467 		Family Supported
Family review supports GO:0004467 for PANTHER:PTHR43272:SF33. Asserted by peroxisomal_beta_oxidation for FAA2; accepted by FAA1, FAA2, FAA3, FAA4 and ACSL4. SF33 is listed because it holds FAA2, although its Car members are not ligases.
acox_activity ACOX / peroxisomal acyl-CoA oxidase family
PANTHER:PTHR10909
Family 		acyl-CoA oxidase activity
GO:0003997 		Family Supported
Family review supports GO:0003997 FAMILY_WIDE. Asserted by peroxisomal_beta_oxidation; accepted by POX1, ACOX1, ACOX2 and ACOX3.
hsd17b4_activity HSD17B4 / FOX2 D-specific multifunctional enzyme type 2
Family 		(2E)-enoyl-CoA hydratase 2 activity (D-specific)
GO:0080023 		Family Id Missing
The family has no identifier linking it to a curated family review.
ehhadh_activity EHHADH / L-bifunctional protein family
PANTHER:PTHR23309
Family 		enoyl-CoA hydratase activity (L-specific)
GO:0004300 		Family Supported
Family review supports GO:0004300 FAMILY_WIDE. Asserted by peroxisomal_beta_oxidation; accepted by EHHADH.
acaa1_activity ACAA1 / peroxisomal 3-ketoacyl-CoA thiolase family
PANTHER:PTHR43853
Family 		acetyl-CoA C-acyltransferase activity
GO:0003988 		Family Supported
Family review supports GO:0003988 FAMILY_WIDE. Asserted by peroxisomal_beta_oxidation, phenylacetate_catabolism and bacterial_fatty_acid_beta_oxidation; accepted by every reviewed member. 3-oxoacyl-CoA thiolysis is shared by all characterized members, including PaaJ (SF2).
scp2_activity SCP2 / SCPx thiolase + sterol-carrier family
Family 		propionyl-CoA C2-trimethyltridecanoyltransferase (branched thiolase) activity
GO:0050632 		Family Id Missing
The family has no identifier linking it to a curated family review.
eci_activity enoyl-CoA delta-isomerase (ECI2-type) family
PANTHER:PTHR43684:SF1
Family 		delta(3)-delta(2)-enoyl-CoA isomerase activity
GO:0004165 		Family Supported
Family review supports GO:0004165 for PANTHER:PTHR43684:SF1. Asserted by peroxisomal_beta_oxidation; accepted by ECI1 and Dci; DCI1 keeps it as non-core.
decr_activity peroxisomal 2,4-dienoyl-CoA reductase family
PANTHER:PTHR43296
Family 		2,4-dienoyl-CoA reductase (NADPH) activity
GO:0008670 		Family Supported
Family review supports GO:0008670 FAMILY_WIDE. Asserted by peroxisomal_beta_oxidation; accepted by SPS19.
idp3_activity NADP-specific isocitrate dehydrogenase family (peroxisomal isoform)
PANTHER:PTHR11822
Family 		isocitrate dehydrogenase (NADP+) activity
GO:0004450 		Family Supported
Family review supports GO:0004450 FAMILY_WIDE. Asserted by peroxisomal_beta_oxidation for IDP3; accepted by IDP1, IDP2, IDP3 and bacterial Icd.
mdh3_activity peroxisomal malate dehydrogenase subfamily
PANTHER:PTHR11540:SF72
Family 		L-malate dehydrogenase (NAD+) activity
GO:0030060 		Family Supported
Family review supports GO:0030060 FAMILY_WIDE. Asserted by glyoxylate_cycle, malate_aspartate_shuttle, gluconeogenesis and peroxisomal_beta_oxidation (SF72); accepted by every reviewed isozyme.

Gene-review completeness (18/20 grounded genes reviewed)

15 complete review(s) · 12 with deep research · 2 missing review · 6 reviewed but lacking deep research

Gene Review Complete Deep research
ABCD1 P33897 ✓ 125/135 ✓
ABCD3 P28288 ✓ ✓ ✓
ACAA1 P09110 ✓ ✓ ✗
ACOX1 Q15067 ✓ 48/49 ✗
ACOX3 O15254 ✓ ✓ ✗
ECI1 Q05871 ✓ ✓ ✓
EHHADH Q08426 ✓ ✓ ✗
FAA2 P39518 ✓ 27/28 ✓
FOX2 Q02207 ✓ ✓ ✓
HSD17B4 P51659 ✓ ✓ ✗
IDP3 P53982 ✓ ✓ ✓
MDH3 P32419 ✓ ✓ ✓
ECI2 (human) O75521 ✗ — —
POT1 P27796 ✓ ✓ ✓
POX1 P13711 ✓ ✓ ✓
PXA1 P41909 ✓ ✓ ✓
PXA2 P34230 ✓ ✓ ✓
DECR2 (human) Q9NUI1 ✗ — —
SCP2 P22307 ✓ ✓ ✗
SPS19 P32573 ✓ ✓ ✓

Details

Context
EukaryotaNCBITaxon:2759
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
EukaryotaNCBITaxon:2759
peroxisomal matrixGO:0005782

ALIGN (YeastPathways project, 2026-10): the human-centred peroxisomal module was extended to the fungal peroxisome-only system. S. cerevisiae representatives were added to the shared core steps (POX1 in the ACOX family PTHR10909; FOX2 in the D-specific MFE-2 role with HSD17B4; POT1 in PTHR43853 with ACAA1). EHHADH and SCPx remain animal-specific leaves. New optional parts: substrate entry (PXA1-PXA2/ABCD1/ABCD3, PTHR11384, GO:0005324; FAA2 re-activation, PTHR43272, GO:0004467), auxiliary unsaturated-FA enzymes (ECI1/ECI2 in PTHR43684, whose official PANTHER name is "FAMILY NOT NAMED"; SPS19/DECR2 in PTHR43296, GO:0008670; IDP3 NADPH regeneration, GO:0004450) and peroxisomal NAD+ regeneration (MDH3, PTHR11540:SF72, GO:0030060). IDP3 and MDH3 follow the completed yeast gene reviews. The module context gained Eukaryota; the importer is located in the peroxisomal membrane. Catalase (H2O2 removal), the carnitine export of acetyl units (carnitine_shuttle) and the glyoxylate cycle are downstream context. YeastCyc corrections: FOX2 is a (3R)-specific hydratase 2 / D-3-hydroxyacyl-CoA dehydrogenase (PMID:1551874), not the (3S) crotonase/L-HAD written in YEAST-FAO-PWY (EC 4.2.1.17, 1.1.1.35); SPS19, IDP3, MDH3, PXA1 and PXA2 are missing; FAA1, FAA3, FAA4 and FAT1 are cytosolic/membrane uptake-coupled synthetases rather than peroxisomal pathway enzymes (FAA2 is the peroxisomal one); DCI1 is listed as a delta3-delta2-enoyl-CoA isomerase, but UniProt names it a delta(3,5)-delta(2,4)-dienoyl-CoA isomerase and its demonstrated role is co-import of Eci1p (PMID:11302517), so it is not used as a representative. The DCI1 gene review places its core activity as the auxiliary delta(3,5)-delta(2,4)-dienoyl-CoA isomerase (GO:0051750, EC 5.3.3.21) on the Sps19p-dependent route and keeps the weak delta3-delta2 activity as non-core. GO-CAM disagreements: YeastPathways_YEAST-FAO-PWY places every activity in cytosol rather than the peroxisome, uses the broad GO:0019395 fatty acid oxidation, and types FOX2 with (3S)-specific GO:0004300/GO:0003857. Human details: the importer step carries both human half-transporters, ABCD1 (P33897, ALDP, straight-chain VLCFA-CoA, PTHR11384:SF21, review DRAFT) and ABCD3 (P28288, PMP70, branched-chain/bile-acid/dicarboxylic acyl-CoA, PTHR11384:SF62, review COMPLETE), as representative members of one family-level annoton rather than as two subfamily annotons, because the open GO:0005324-versus-GO:0015607 term choice above is a property of the step and not of either human paralogue. ACOX3 is GO:0016402 (pristanoyl-CoA oxidase); HSD17B4 is PTHR13078 in PANTHER 19.0 (PTHR45024 in UniProt, as is FOX2), so the D-bifunctional descriptor carries no PANTHER id; SCP2 is PTHR24314 in PANTHER 19.0. Disorders: ACOX1, HSD17B4 (D-BP), EHHADH, SCP2, ABCD1 (X-ALD) deficiencies; Zellweger spectrum (peroxisome biogenesis).

Connections

Matrix acyl-CoA enters the oxidase step.
The 2-trans-enoyl-CoA made by the oxidase is hydrated and dehydrogenated by the multifunctional proteins.
The 3-oxoacyl-CoA is thiolytically cleaved.
The chain-shortened acyl-CoA (minus two carbons) re-enters the oxidase step, iterating the spiral until the substrate is fully shortened.
Auxiliary enzymes return unsaturated intermediates to the core spiral as trans-2-enoyl-CoA.
NADH from the (3R)-hydroxyacyl-CoA dehydrogenase step is reoxidised by peroxisomal malate dehydrogenase.
Part 1: substrate entry and activation in the peroxisome (optional)
Peroxisomal acyl-CoA import and intraperoxisomal re-activationMetabolic Pathwayperoxisomal_substrate_entry

Long-chain acyl-CoAs are imported by an ABC-D transporter that, in yeast, releases the fatty acid into the matrix, where an acyl-CoA synthetase re-esterifies it. Cytosolic acyl-CoA synthetases that couple uptake to activation are upstream context.

Connections

The fatty acid delivered by the ABC-D transporter is re-activated in the matrix.
Part 1: acyl-CoA import across the peroxisomal membrane
ABC-D peroxisomal acyl-CoA transporterTransport Stepabcd_import

Annotons

PXA1-PXA2 / ABCD1: peroxisomal ABC-D acyl-CoA transporter
abcd_transport_activity
Participant: Family: ABC-D peroxisomal half-transporter family
Family:
ABC-D peroxisomal half-transporter familyPANTHER:PTHR11384
Representative Members: PXA1 (Saccharomyces cerevisiae)UniProtKB:P41909 PXA2 (Saccharomyces cerevisiae)UniProtKB:P34230 ABCD1 (human; straight-chain very-long-chain acyl-CoA)UniProtKB:P33897 ABCD3 (human, PMP70; branched-chain, C27 bile-acid and dicarboxylic acyl-CoA)UniProtKB:P28288

Function

long-chain fatty acid transmembrane transporter activityGO:0005324
Substrates: very-long-chain acyl-CoA (cytosol) ATP
Products: fatty acid (peroxisomal matrix) CoA (released) ADP + phosphate

Locations

peroxisomal membraneGO:0005778

Heterodimeric (yeast) or homodimeric (human) ABC-D half-transporter importing long-chain acyl groups.

Open term choice. The human ABCD1 review keeps GO:0015607 (ABC-type fatty-acyl-CoA transporter) as core, while the PXA1 and PXA2 reviews use GO:0005324 (long-chain fatty acid transmembrane transporter), because PMID:22493507 shows the yeast complex hydrolyses the acyl-CoA and moves only the fatty acid, which Faa2p/Fat1p re-activate inside. GO:0015607 implies the acyl-CoA itself crosses the membrane, so this annoton follows the PXA1/PXA2 term pending a decision on whether the hydrolysis-coupled mechanism holds family-wide. Both human reviews that cover this step use GO:0015607 (ABCD3 complete, ABCD1 draft), so the divergence is between the yeast and human evidence rather than within either.

Part 2: intraperoxisomal re-activation to acyl-CoA
Peroxisomal acyl-CoA synthetaseReactionintraperoxisomal_activation

Annotons

FAA2: peroxisomal acyl-CoA synthetase
faa2_activity
Participant: Family: long-chain acyl-CoA synthetase family
Family:
long-chain acyl-CoA synthetase family
Representative Members: FAA2 (Saccharomyces cerevisiae)UniProtKB:P39518

Function

long-chain fatty acid-CoA ligase activityGO:0004467
Substrates: fatty acid ATP CoA
Products: acyl-CoA AMP + diphosphate

Re-esterify imported (and medium-chain) fatty acids to acyl-CoA in the peroxisome. In animals, intraperoxisomal activation is less defined and not represented here.

Part 2: acyl-CoA oxidation (O2 -> H2O2)
Acyl-CoA oxidasesReactionacyl_coa_oxidation

Annotons

ACOX/POX1: 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 POX1 (Saccharomyces cerevisiae)UniProtKB:P13711

Function

acyl-CoA oxidase activityGO:0003997
Substrates: acyl-CoA (ACOX1/POX1 straight-chain; 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 3: hydration + dehydrogenation (multifunctional proteins)
Multifunctional proteins (D-specific MFE-2; L-specific bifunctional protein)Reactionhydration_dehydrogenation

Annotons

HSD17B4/FOX2: D-specific multifunctional enzyme type 2 (hydratase 2 + (3R)-HAD)
hsd17b4_activity
Participant: Family: HSD17B4 / FOX2 D-specific multifunctional enzyme type 2
Family:
HSD17B4 / FOX2 D-specific multifunctional enzyme type 2
Representative Members: HSD17B4 (human)UniProtKB:P51659 FOX2 (Saccharomyces cerevisiae)UniProtKB:Q02207

Function

(2E)-enoyl-CoA hydratase 2 activity (D-specific)GO:0080023
Substrates: 2-trans-enoyl-CoA (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 (sole route in fungi; main route in animals).

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 (animals; absent from budding yeast).

Part 4: thiolytic cleavage (-> acetyl/propionyl-CoA)
Peroxisomal thiolasesReactionthiolytic_cleavage

Annotons

ACAA1/POT1: 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 POT1 (Saccharomyces cerevisiae)UniProtKB:P27796

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 family
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 (animals).

Part 5: auxiliary steps for unsaturated fatty acids (optional)
Auxiliary enzymes for unsaturated acyl-CoAs and their NADPH supplyMetabolic Pathwayunsaturated_auxiliary

Double bonds at odd positions are moved by a delta3-delta2-enoyl-CoA isomerase; double bonds at even positions give 2,4-dienoyl-CoA, which an NADPH-dependent reductase converts to 3-enoyl-CoA (then isomerised). The NADPH is regenerated in the matrix by NADP-dependent isocitrate dehydrogenase.

Connections

IDP3-made NADPH is consumed by the dienoyl-CoA reductase.
The 3-enoyl-CoA product is isomerised to 2-enoyl-CoA.
Part 1: delta3-delta2-enoyl-CoA isomerisation
Peroxisomal delta3-delta2-enoyl-CoA isomeraseReactionenoyl_coa_isomerisation

Annotons

ECI1/ECI2: delta3-delta2-enoyl-CoA isomerase
eci_activity
Participant: Family: enoyl-CoA delta-isomerase (ECI2-type) family
Family:
enoyl-CoA delta-isomerase (ECI2-type) family
Representative Members: ECI1 (Saccharomyces cerevisiae)UniProtKB:Q05871 ECI2 (human)UniProtKB:O75521

Function

delta(3)-delta(2)-enoyl-CoA isomerase activityGO:0004165
Substrates: (3Z)- or (3E)-enoyl-CoA
Products: (2E)-enoyl-CoA

Locations

peroxisomal matrixGO:0005782

Return unsaturated intermediates to the trans-2-enoyl-CoA of the core spiral.

Part 2: 2,4-dienoyl-CoA reduction
Peroxisomal 2,4-dienoyl-CoA reductaseReactiondienoyl_coa_reduction

Annotons

SPS19/DECR2: peroxisomal 2,4-dienoyl-CoA reductase
decr_activity
Participant: Family: peroxisomal 2,4-dienoyl-CoA reductase family
Family:
peroxisomal 2,4-dienoyl-CoA reductase familyPANTHER:PTHR43296
Representative Members: SPS19 (Saccharomyces cerevisiae)UniProtKB:P32573 DECR2 (human)UniProtKB:Q9NUI1

Function

2,4-dienoyl-CoA reductase (NADPH) activityGO:0008670
Substrates: (2E,4E)-dienoyl-CoA NADPH
Products: (3E)-enoyl-CoA NADP+

Locations

peroxisomal matrixGO:0005782

Reduce 2,4-dienoyl-CoA from even-position double bonds.

Part 3: intraperoxisomal NADPH regeneration
Peroxisomal NADP-dependent isocitrate dehydrogenaseReactionperoxisomal_nadph_regeneration

Annotons

IDP3: peroxisomal NADP-isocitrate dehydrogenase
idp3_activity
Participant: Family: NADP-specific isocitrate dehydrogenase family (peroxisomal isoform)
Family:
NADP-specific isocitrate dehydrogenase family (peroxisomal isoform)PANTHER:PTHR11822
Representative Members: IDP3 (Saccharomyces cerevisiae)UniProtKB:P53982

Function

isocitrate dehydrogenase (NADP+) activityGO:0004450
Substrates: isocitrate NADP+
Products: 2-oxoglutarate CO2 NADPH

Processes

NADPH regenerationGO:0006740

Locations

peroxisomal matrixGO:0005782

Regenerate matrix NADPH for 2,4-dienoyl-CoA reductase, because the peroxisomal membrane is impermeable to pyridine nucleotides.

Part 6: intraperoxisomal NAD+ regeneration (optional)
Peroxisomal malate dehydrogenase redox shuttleReactionperoxisomal_nad_regeneration

Annotons

MDH3: peroxisomal NAD-malate dehydrogenase
mdh3_activity
Participant: Family: peroxisomal malate dehydrogenase subfamily
Family:
peroxisomal malate dehydrogenase subfamilyPANTHER:PTHR11540:SF72
Representative Members: MDH3 (Saccharomyces cerevisiae)UniProtKB:P32419

Function

L-malate dehydrogenase (NAD+) activityGO:0030060
Substrates: oxaloacetate NADH
Products: L-malate NAD+

Locations

peroxisomal matrixGO:0005782

Reduce oxaloacetate to malate with the NADH produced by the (3R)-hydroxyacyl-CoA dehydrogenase step, regenerating matrix NAD+; malate and oxaloacetate cross the peroxisomal membrane.