Mitochondrial fatty acid beta-oxidation spiral (cross-species)

The core four-step spiral of mitochondrial fatty acid beta-oxidation, by which saturated fatty acyl-CoA esters are degraded two carbons at a time, releasing one acetyl-CoA and a chain-shortened acyl-CoA per turn that re-enters the cycle. The four obligate reactions are (1) FAD-dependent alpha,beta-dehydrogenation of acyl-CoA to (2E)-enoyl-CoA by an acyl-CoA dehydrogenase; (2) hydration of the trans double bond to (3S)-3-hydroxyacyl-CoA by an enoyl-CoA hydratase; (3) NAD+-dependent oxidation to 3-ketoacyl-CoA by a 3-hydroxyacyl-CoA dehydrogenase; and (4) thiolytic cleavage by a 3-ketoacyl-CoA thiolase to yield acetyl-CoA plus an acyl-CoA shortened by two carbons. Each step is carried out by a family of chain-length-specific isozymes: as the acyl chain shortens through successive turns of the spiral, the enzyme that acts changes. The long-chain steps 2-4 are performed by the membrane-bound mitochondrial trifunctional protein (MTP, an alpha2-beta2 heterotetramer whose alpha subunit carries the hydratase and dehydrogenase activities and whose beta subunit carries the thiolase), whereas the medium- and short-chain steps are carried out by separate soluble matrix enzymes. This module is built cross-species: each catalytic role is grounded with both the human enzyme(s) and the Drosophila melanogaster ortholog(s), so the conserved enzymatic logic and the species-specific gene complement can be compared directly. The chain-length axis is modelled as a variant set at each step; "use MF specific for chain length" where such a molecular-function term exists, with a fall-back to the general activity where it does not. This module covers the SATURATED spiral. Degradation of UNSATURATED fatty acids additionally requires an auxiliary-enzyme cassette - a delta(3),delta(2)-enoyl-CoA isomerase (fly mitochondrial CG4592/CG4594/CG4598 vs peroxisomal Dci), a delta(3,5),delta(2,4)-dienoyl-CoA isomerase (fly Ech1), and a 2,4-dienoyl-CoA reductase (DECR1, for which no clean Drosophila ortholog is currently assignable) - which are curated in the project but not modelled as variant sets here; see the Fatty Acid beta-Oxidation project page (unsaturated cassette section) for details.

MODULE:fatty_acid_beta_oxidationDRAFTMetabolic Pathwaymodules/fatty_acid_beta_oxidation.yaml
fatty acid beta-oxidationGO:0006635
GO:0006635
fatty acid beta-oxidation
Module grounded in the GO biological-process term for mitochondrial fatty acid beta-oxidation; all participant catalytic roles are children of this process.
file:human/HADHB/HADHB-ai-review.yaml
HADHB gene review (human)
The human gene reviews in this repository (ACADVL, ACAD9, ACADM, ACADS, HADHA, HADHB, ECHS1, HADH, ACAT1, ACAA2) supply the verified UniProt accessions, GO molecular-function terms, and chain-length assignments used to ground each step.
15Nodes
4Parts
4Variant Sets
10Variants
10Annotons
4Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:fatty_acid_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.

  • acad_step → ech_step [MAPPING_GAP]
    Step 1 produces (2E)-enoyl-CoA, which the crotonase reaction RHEA:16105 ((3S)-3-hydroxyacyl-CoA = (2E)-enoyl-CoA + H2O) consumes. However the enoyl-CoA hydratase MF GO:0004300 maps only to RHEA:20724 (the (3E)-enoyl-CoA variant), so the automated GO->RHEA chaining check sees no shared intermediate. The chemistry is correct; the gap is in the GO:0004300->RHEA mapping (missing RHEA:16105).
  • ech_step → hadh_step [VERIFIED]
    shared: 3s3hydroxyacylcoa
  • hadh_step → thiolase_step [VERIFIED]
    shared: 3oxoacylcoa

Gene-review completeness (21/21 grounded genes reviewed)

21 complete review(s) · 2 with deep research · 0 missing review · 19 reviewed but lacking deep research

Gene Review Complete Deep research
Acaa Q9VL70 ✓ ✓ ✗
ACAA2 P42765 ✓ ✓ ✗
ACAD9 Q9H845 ✓ ✓ ✓
ACADM P11310 ✓ ✓ ✗
ACADS P16219 ✓ ✓ ✗
Acadvl A1ZBJ2 ✓ ✓ ✗
ACADVL P49748 ✓ ✓ ✗
ACAT1 P24752 ✓ ✓ ✗
Acat1 Q9W3N9 ✓ ✓ ✗
Arc42 Q9VDT1 ✓ ✓ ✗
CG4860 Q9VGC2 ✓ ✓ ✗
ECHS1 P30084 ✓ ✓ ✗
Echs1 Q7JR58 ✓ ✓ ✗
Egm Q5U117 ✓ ✓ ✗
HADH Q16836 ✓ ✓ ✗
HADHA P40939 ✓ ✓ ✗
HADHB P55084 ✓ ✓ ✓
Mcad Q9VSA3 ✓ ✓ ✗
Mtpalpha Q8IPE8 ✓ ✓ ✗
Mtpbeta Q9W1H8 ✓ ✓ ✗
scu O18404 ✓ ✓ ✗

Details

Mitochondrial fatty acid beta-oxidation spiralMetabolic Pathwayfatty_acid_beta_oxidation
fatty acid beta-oxidationGO:0006635

Cross-species module: each catalytic role is grounded with both human and Drosophila melanogaster orthologs (FAMILY selectors with representative_members). Chain-length specificity is modelled as a ONE_OR_MORE variant set per step, since multiple isozymes can act across the successive turns of the spiral as the chain shortens. Human accessions and GO MF/location terms are verified against the per-gene reviews in genes/human/. Drosophila accessions are from UniProtKB (taxon 7227); most are unreviewed (TrEMBL) and are given as orienting orthologous exemplars, not reviewed assertions. The medium/short-chain 3-hydroxyacyl-CoA dehydrogenase has no confidently assigned Drosophila ortholog (marked "?" in the source species comparison). ACAT1 is included for completeness of the thiolase step but its core role is ketone-body/isoleucine metabolism (cross-referenced to MODULE:ketone_body_oxidation), not long-chain beta-oxidation.

Connections

acad_step -> ech_step Precedes
ech_step -> hadh_step Precedes
thiolase_step -> acad_step Provides Input For
The chain-shortened acyl-CoA produced by the thiolase re-enters step 1, making the pathway a spiral that iterates until the chain is fully degraded.
Part 1: alpha,beta-dehydrogenation of acyl-CoA (FAD-dependent)
Step 1: acyl-CoA dehydrogenaseReactionacad_step
Variant set: Chain-length-specific acyl-CoA dehydrogenases by acyl-CoA chain length (One Or More)

The acyl-CoA dehydrogenase that acts depends on the current acyl-chain length; very-long/long-, medium-, and short-chain isozymes hand off as the spiral shortens the chain. Each has a chain-length-specific MF term.

Very-long / long-chain acyl-CoA dehydrogenase (VLCAD / ACAD9)Reactionvlcad_variant

Annotons

VLCAD/ACAD9: very-long-chain acyl-CoA dehydrogenase
vlcad_activity
Participant: Family: Very-long/long-chain acyl-CoA dehydrogenase (VLCAD/ACAD9)
Family:
Very-long/long-chain acyl-CoA dehydrogenase (VLCAD/ACAD9)
Representative Members: ACADVL (human)UniProtKB:P49748 ACAD9 (human)UniProtKB:Q9H845 Acadvl / CG7461 (Drosophila)UniProtKB:A1ZBJ2 Egm / dACAD9 / CG9006 (Drosophila)UniProtKB:Q5U117

Function

very-long-chain fatty acyl-CoA dehydrogenase activityGO:0017099
Substrates: very-long/long-chain acyl-CoA FAD
Products: (2E)-enoyl-CoA FADH2

Locations

mitochondrial inner membraneGO:0005743

ACADVL is the canonical long/very-long-chain dehydrogenase of this step (its gene review keeps GO:0017099). ACAD9 is a paralog whose grouping here reflects its ancestral/secondary acyl-CoA dehydrogenase activity, but two caveats apply and are NOT to be read off the variant's GO:0017099 selector: (1) the ACAD9 gene review recommends MODIFY of GO:0017099 to GO:0004466 (long-chain acyl-CoA dehydrogenase activity), because ACAD9's optimal substrates are long-chain (C14-C18) rather than very-long-chain (C20+); and (2) ACAD9's — and its Drosophila ortholog Egm's — primary biological role is as a mitochondrial complex I assembly factor (Egm core function GO:0030674, protein-macromolecule adaptor activity), not fatty acid beta-oxidation. In Drosophila, Acadvl (CG7461) is the dehydrogenase ortholog and Egm/dACAD9 (CG9006) the complex I assembly factor; see the ACAD9 and Egm gene reviews for the per-gene calls.

Medium-chain acyl-CoA dehydrogenase (MCAD)Reactionmcad_variant

Annotons

MCAD: medium-chain acyl-CoA dehydrogenase
mcad_activity
Participant: Family: Medium-chain acyl-CoA dehydrogenase (MCAD)
Family:
Medium-chain acyl-CoA dehydrogenase (MCAD)
Representative Members: ACADM (human)UniProtKB:P11310 Mcad / CG12262 (Drosophila)UniProtKB:Q9VSA3

Function

medium-chain fatty acyl-CoA dehydrogenase activityGO:0070991
Substrates: medium-chain acyl-CoA FAD
Products: (2E)-enoyl-CoA FADH2

Locations

mitochondrial matrixGO:0005759
Short-chain acyl-CoA dehydrogenase (SCAD)Reactionscad_variant

Annotons

SCAD: short-chain acyl-CoA dehydrogenase
scad_activity
Participant: Family: Short-chain acyl-CoA dehydrogenase (SCAD)
Family:
Short-chain acyl-CoA dehydrogenase (SCAD)
Representative Members: ACADS (human)UniProtKB:P16219 Arc42 / CG4703 (Drosophila)UniProtKB:Q9VDT1 CG4860 (Drosophila)UniProtKB:Q9VGC2

Function

short-chain fatty acyl-CoA dehydrogenase activityGO:0016937
Substrates: short-chain acyl-CoA (e.g. butyryl-CoA) FAD
Products: (2E)-enoyl-CoA FADH2

Locations

mitochondrial matrixGO:0005759
Part 2: hydration of (2E)-enoyl-CoA to (3S)-3-hydroxyacyl-CoA
Step 2: enoyl-CoA hydrataseReactionech_step
Variant set: Chain-length-specific enoyl-CoA hydratases by acyl-CoA chain length (One Or More)

No long-chain-specific or short-chain-specific enoyl-CoA hydratase MF term exists in current GO (the long-chain term GO:0016508 is obsolete), so both variants ground to the general enoyl-CoA hydratase activity GO:0004300; the chain-length distinction is carried by the enzyme identity (MTP alpha vs ECHS1).

Long-chain enoyl-CoA hydratase (MTP alpha subunit, HADHA)Reactionlc_hydratase_variant

Annotons

HADHA/MTP-alpha: long-chain enoyl-CoA hydratase
lc_hydratase_activity
Participant: Family: Trifunctional enzyme alpha subunit (HADHA / MTP alpha)
Family:
Trifunctional enzyme alpha subunit (HADHA / MTP alpha)
Representative Members: HADHA (human)UniProtKB:P40939 Mtpalpha / CG4389 (Drosophila)UniProtKB:Q8IPE8

Function

enoyl-CoA hydratase activityGO:0004300
Substrates: long-chain (2E)-enoyl-CoA H2O
Products: long-chain (3S)-3-hydroxyacyl-CoA

Locations

mitochondrial inner membraneGO:0005743

The hydratase activity of the alpha subunit of the membrane-bound mitochondrial trifunctional protein (alpha2-beta2).

Short/medium-chain enoyl-CoA hydratase (ECHS1, crotonase)Reactionsc_hydratase_variant

Annotons

ECHS1: short-chain enoyl-CoA hydratase (crotonase)
sc_hydratase_activity
Participant: Family: Short-chain enoyl-CoA hydratase (ECHS1 / crotonase)
Family:
Short-chain enoyl-CoA hydratase (ECHS1 / crotonase)
Representative Members: ECHS1 (human)UniProtKB:P30084 Echs1 / CG6543 (Drosophila)UniProtKB:Q7JR58

Function

enoyl-CoA hydratase activityGO:0004300
Substrates: short/medium-chain (2E)-enoyl-CoA H2O
Products: short/medium-chain (3S)-3-hydroxyacyl-CoA

Locations

mitochondrial matrixGO:0005759

ECHS1 is a soluble matrix crotonase that also acts in valine and other branched-chain amino-acid catabolism beyond the beta-oxidation spiral.

Part 3: NAD+-dependent oxidation of (3S)-3-hydroxyacyl-CoA to 3-ketoacyl-CoA
Step 3: 3-hydroxyacyl-CoA dehydrogenaseReactionhadh_step
Variant set: Chain-length-specific 3-hydroxyacyl-CoA dehydrogenases by acyl-CoA chain length (One Or More)
Long-chain 3-hydroxyacyl-CoA dehydrogenase (MTP alpha subunit, HADHA)Reactionlc_hadh_variant

Annotons

HADHA/MTP-alpha: long-chain 3-hydroxyacyl-CoA dehydrogenase
lc_hadh_activity
Participant: Family: Trifunctional enzyme alpha subunit (HADHA / MTP alpha)
Family:
Trifunctional enzyme alpha subunit (HADHA / MTP alpha)
Representative Members: HADHA (human)UniProtKB:P40939 Mtpalpha / CG4389 (Drosophila)UniProtKB:Q8IPE8

Function

long-chain (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activityGO:0016509
Substrates: long-chain (3S)-3-hydroxyacyl-CoA NAD+
Products: long-chain 3-oxoacyl-CoA NADH

Locations

mitochondrial inner membraneGO:0005743
Short/medium-chain 3-hydroxyacyl-CoA dehydrogenase (HADH / SCHAD)Reactionsc_hadh_variant

Annotons

HADH: short/medium-chain 3-hydroxyacyl-CoA dehydrogenase
sc_hadh_activity
Participant: Family: Short-chain 3-hydroxyacyl-CoA dehydrogenase (HADH / SCHAD)
Family:
Short-chain 3-hydroxyacyl-CoA dehydrogenase (HADH / SCHAD)
Representative Members: HADH (human)UniProtKB:Q16836 scully / scu (Drosophila; HSD17B10-type)UniProtKB:O18404

Function

(3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activityGO:0003857
Substrates: short/medium-chain (3S)-3-hydroxyacyl-CoA NAD+
Products: short/medium-chain 3-oxoacyl-CoA NADH

Locations

mitochondrial matrixGO:0005759

HADH (SCHAD) is the human soluble matrix short/medium-chain enzyme, distinct from the long-chain HADHA; it also has a moonlighting role regulating insulin secretion via GLUD1 inhibition. Drosophila lacks a clean 1:1 ortholog of the classical HADH1/SCHAD (type-I, 3HCDH fold, Pfam PF00725) - the FlyBase Had1/Had2 genes are actually CRYL1 (L-gulonate-3-dehydrogenase) orthologs. The fly enzyme that covers this step is scully (scu, O18404), the ortholog of human HSD17B10 (type-II 3-hydroxyacyl-CoA dehydrogenase, SDR fold, Pfam PF00106): a blinded OpenScientist analysis plus a direct enzymatic assay (PMID:12917011) confirm (3S)-3-hydroxyacyl-CoA dehydrogenase activity, with catalytic residues 100% conserved vs human HSD17B10. scully is multifunctional (also steroid dehydrogenase and the MRPP2 subunit of mitochondrial RNase P), and long-chain step 3 in the fly is carried by MTP (Mtpalpha). Grounded here as the type-II fly counterpart; see genes/DROME/scu.

Part 4: thiolytic cleavage of 3-ketoacyl-CoA to acetyl-CoA + chain-shortened acyl-CoA
Step 4: 3-ketoacyl-CoA thiolaseReactionthiolase_step
Variant set: Chain-length-specific 3-ketoacyl-CoA thiolases by acyl-CoA chain length (One Or More)

No chain-length-specific thiolase MF term exists, so the straight-chain thiolases ground to the general acetyl-CoA C-acyltransferase activity GO:0003988; the acetoacetyl-CoA-specific ACAT1 grounds to acetyl-CoA C-acetyltransferase activity GO:0003985.

Long-chain 3-ketoacyl-CoA thiolase (MTP beta subunit, HADHB)Reactionlc_thiolase_variant

Annotons

HADHB/MTP-beta: long-chain 3-ketoacyl-CoA thiolase
lc_thiolase_activity
Participant: Family: Trifunctional enzyme beta subunit (HADHB / MTP beta)
Family:
Trifunctional enzyme beta subunit (HADHB / MTP beta)
Representative Members: HADHB (human)UniProtKB:P55084 Mtpbeta / CG4581 (Drosophila)UniProtKB:Q9W1H8

Function

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

Locations

mitochondrial inner membraneGO:0005743

The thiolase activity of the beta subunit of the membrane-bound mitochondrial trifunctional protein (alpha2-beta2).

Medium/long-chain 3-ketoacyl-CoA thiolase (ACAA2)Reactionmed_thiolase_variant

Annotons

ACAA2: 3-ketoacyl-CoA thiolase
med_thiolase_activity
Participant: Family: 3-ketoacyl-CoA thiolase (ACAA2)
Family:
3-ketoacyl-CoA thiolase (ACAA2)
Representative Members: ACAA2 (human)UniProtKB:P42765 Acaa / Yip2 / CG4600 (Drosophila)UniProtKB:Q9VL70

Function

acetyl-CoA C-acyltransferase activityGO:0003988
Substrates: medium/long-chain 3-oxoacyl-CoA coenzyme A
Products: acetyl-CoA acyl-CoA (shortened by two carbons)

Locations

mitochondrial matrixGO:0005759

ACAA2 is the soluble matrix straight-chain thiolase, distinct from the MTP-embedded long-chain thiolase HADHB.

Short-chain / acetoacetyl-CoA thiolase (ACAT1, T2)Reactionsc_thiolase_variant

Annotons

ACAT1: acetoacetyl-CoA thiolase (T2)
sc_thiolase_activity
Participant: Family: Acetoacetyl-CoA thiolase (ACAT1 / T2)
Family:
Acetoacetyl-CoA thiolase (ACAT1 / T2)
Representative Members: ACAT1 (human)UniProtKB:P24752 Acat1 / CG10932 (Drosophila)UniProtKB:Q9W3N9

Function

acetyl-CoA C-acetyltransferase activityGO:0003985
Substrates: acetoacetyl-CoA coenzyme A
Products: acetyl-CoA

Locations

mitochondrial matrixGO:0005759

ACAT1 (mitochondrial "T2") cleaves the shortest (C4) acetoacetyl-CoA and is principally an enzyme of ketone-body metabolism and isoleucine catabolism rather than the long-chain spiral; see MODULE:ketone_body_oxidation. It is NOT the cholesterol-esterifying SOAT1/SOAT2 despite the shared "ACAT" nickname.