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

Function consistency and core coverage

20 gene-function check(s) reflected in core functions · 0 conflict(s) · 12 evidence or coverage gap(s) (33 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.

Annoton	Participant	Function	Assessment
vlcad_activity	ACADVL (human) UniProtKB:P49748 Family Representative	very-long-chain fatty acyl-CoA dehydrogenase activity GO:0017099	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
vlcad_activity	ACAD9 (human) UniProtKB:Q9H845 Family Representative	very-long-chain fatty acyl-CoA dehydrogenase activity GO:0017099	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.
vlcad_activity	Acadvl / CG7461 (Drosophila) UniProtKB:A1ZBJ2 Family Representative	very-long-chain fatty acyl-CoA dehydrogenase activity GO:0017099	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
vlcad_activity	Egm / dACAD9 / CG9006 (Drosophila) UniProtKB:Q5U117 Family Representative	very-long-chain fatty acyl-CoA dehydrogenase activity GO:0017099	Non Core Supported The review explicitly retains this function as non-core; promotion into core_functions is not implied.
mcad_activity	ACADM (human) UniProtKB:P11310 Family Representative	medium-chain fatty acyl-CoA dehydrogenase activity GO:0070991	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mcad_activity	Mcad / CG12262 (Drosophila) UniProtKB:Q9VSA3 Family Representative	medium-chain fatty acyl-CoA dehydrogenase activity GO:0070991	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
scad_activity	ACADS (human) UniProtKB:P16219 Family Representative	short-chain fatty acyl-CoA dehydrogenase activity GO:0016937	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
scad_activity	Arc42 / CG4703 (Drosophila) UniProtKB:Q9VDT1 Family Representative	short-chain fatty acyl-CoA dehydrogenase activity GO:0016937	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
scad_activity	CG4860 (Drosophila) UniProtKB:Q9VGC2 Family Representative	short-chain fatty acyl-CoA dehydrogenase activity GO:0016937	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.
lc_hydratase_activity	HADHA (human) UniProtKB:P40939 Family Representative	enoyl-CoA hydratase activity GO:0004300	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
lc_hydratase_activity	Mtpalpha / CG4389 (Drosophila) UniProtKB:Q8IPE8 Family Representative	enoyl-CoA hydratase activity GO:0004300	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
sc_hydratase_activity	ECHS1 (human) UniProtKB:P30084 Family Representative	enoyl-CoA hydratase activity GO:0004300	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
sc_hydratase_activity	Echs1 / CG6543 (Drosophila) UniProtKB:Q7JR58 Family Representative	enoyl-CoA hydratase activity GO:0004300	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
lc_hadh_activity	HADHA (human) UniProtKB:P40939 Family Representative	long-chain (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity GO:0016509	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
lc_hadh_activity	Mtpalpha / CG4389 (Drosophila) UniProtKB:Q8IPE8 Family Representative	long-chain (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity GO:0016509	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
sc_hadh_activity	HADH (human) UniProtKB:Q16836 Family Representative	(3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity GO:0003857	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
sc_hadh_activity	scully / scu (Drosophila; HSD17B10-type) UniProtKB:O18404 Family Representative	(3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity GO:0003857	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
lc_thiolase_activity	HADHB (human) UniProtKB:P55084 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).
lc_thiolase_activity	Mtpbeta / CG4581 (Drosophila) UniProtKB:Q9W1H8 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).
med_thiolase_activity	ACAA2 (human) UniProtKB:P42765 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).
med_thiolase_activity	Acaa / Yip2 / CG4600 (Drosophila) UniProtKB:Q9VL70 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).
sc_thiolase_activity	ACAT1 (human) UniProtKB:P24752 Family Representative	acetyl-CoA C-acetyltransferase activity GO:0003985	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
sc_thiolase_activity	Acat1 / CG10932 (Drosophila) UniProtKB:Q9W3N9 Family Representative	acetyl-CoA C-acetyltransferase activity GO:0003985	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
vlcad_activity	Very-long/long-chain acyl-CoA dehydrogenase (VLCAD/ACAD9) Family	very-long-chain fatty acyl-CoA dehydrogenase activity GO:0017099	Family Id Missing The family has no identifier linking it to a curated family review.
mcad_activity	Medium-chain acyl-CoA dehydrogenase (MCAD) Family	medium-chain fatty acyl-CoA dehydrogenase activity GO:0070991	Family Id Missing The family has no identifier linking it to a curated family review.
scad_activity	Short-chain acyl-CoA dehydrogenase (SCAD) Family	short-chain fatty acyl-CoA dehydrogenase activity GO:0016937	Family Id Missing The family has no identifier linking it to a curated family review.
lc_hydratase_activity	Trifunctional enzyme alpha subunit (HADHA / MTP alpha) Family	enoyl-CoA hydratase activity GO:0004300	Family Id Missing The family has no identifier linking it to a curated family review.
sc_hydratase_activity	Short-chain enoyl-CoA hydratase (ECHS1 / crotonase) Family	enoyl-CoA hydratase activity GO:0004300	Family Id Missing The family has no identifier linking it to a curated family review.
lc_hadh_activity	Trifunctional enzyme alpha subunit (HADHA / MTP alpha) Family	long-chain (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity GO:0016509	Family Id Missing The family has no identifier linking it to a curated family review.
sc_hadh_activity	Short-chain 3-hydroxyacyl-CoA dehydrogenase (HADH / SCHAD) Family	(3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity GO:0003857	Family Id Missing The family has no identifier linking it to a curated family review.
lc_thiolase_activity	Trifunctional enzyme beta subunit (HADHB / MTP beta) Family	acetyl-CoA C-acyltransferase activity GO:0003988	Family Id Missing The family has no identifier linking it to a curated family review.
med_thiolase_activity	3-ketoacyl-CoA thiolase (ACAA2) Family	acetyl-CoA C-acyltransferase activity GO:0003988	Family Id Missing The family has no identifier linking it to a curated family review.
sc_thiolase_activity	Acetoacetyl-CoA thiolase (ACAT1 / T2) Family	acetyl-CoA C-acetyltransferase activity GO:0003985	Family Id Missing The family has no identifier linking it to a curated family review.

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

16 complete review(s) · 12 with deep research · 0 missing review · 9 reviewed but lacking deep research

Gene	Review	Complete	Deep research
Acaa Q9VL70	✓	✓	✗
ACAA2 P42765	✓	✓	✗
ACAD9 Q9H845	✓	42/44	✓
ACADM P11310	✓	46/50	✗
ACADS P16219	✓	29/30	✗
Acadvl A1ZBJ2	✓	✓	✓
ACADVL P49748	✓	36/42	✗
ACAT1 P24752	✓	43/49	✗
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	✓	✓	✓

Tree

Mitochondrial fatty acid beta-oxidation spiralMetabolic Pathwayfatty_acid_beta_oxidation

Parts
1. 1. alpha,beta-dehydrogenation of acyl-CoA (FAD-dependent)
2. Step 1: acyl-CoA dehydrogenaseReactionacad_step
  
  Variants
  1. Chain-length-specific acyl-CoA dehydrogenases by acyl-CoA chain length (One Or More)
    
    Very-long / long-chain acyl-CoA dehydrogenase (VLCAD / ACAD9)Reactionvlcad_variant
    
    Annotons
    
    VLCAD/ACAD9: very-long-chain acyl-CoA dehydrogenase Family: Very-long/long-chain acyl-CoA dehydrogenase (VLCAD/ACAD9)
    
    Medium-chain acyl-CoA dehydrogenase (MCAD)Reactionmcad_variant
    
    Annotons
    
    MCAD: medium-chain acyl-CoA dehydrogenase Family: Medium-chain acyl-CoA dehydrogenase (MCAD)
    
    Short-chain acyl-CoA dehydrogenase (SCAD)Reactionscad_variant
    
    Annotons
    
    SCAD: short-chain acyl-CoA dehydrogenase Family: Short-chain acyl-CoA dehydrogenase (SCAD)
3. 2. hydration of (2E)-enoyl-CoA to (3S)-3-hydroxyacyl-CoA
4. Step 2: enoyl-CoA hydrataseReactionech_step
  
  Variants
  1. Chain-length-specific enoyl-CoA hydratases by acyl-CoA chain length (One Or More)
    
    Long-chain enoyl-CoA hydratase (MTP alpha subunit, HADHA)Reactionlc_hydratase_variant
    
    Annotons
    
    HADHA/MTP-alpha: long-chain enoyl-CoA hydratase Family: Trifunctional enzyme alpha subunit (HADHA / MTP alpha)
    
    Short/medium-chain enoyl-CoA hydratase (ECHS1, crotonase)Reactionsc_hydratase_variant
    
    Annotons
    
    ECHS1: short-chain enoyl-CoA hydratase (crotonase) Family: Short-chain enoyl-CoA hydratase (ECHS1 / crotonase)
5. 3. NAD+-dependent oxidation of (3S)-3-hydroxyacyl-CoA to 3-ketoacyl-CoA
6. Step 3: 3-hydroxyacyl-CoA dehydrogenaseReactionhadh_step
  
  Variants
  1. 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 Family: Trifunctional enzyme alpha subunit (HADHA / MTP alpha)
    
    Short/medium-chain 3-hydroxyacyl-CoA dehydrogenase (HADH / SCHAD)Reactionsc_hadh_variant
    
    Annotons
    
    HADH: short/medium-chain 3-hydroxyacyl-CoA dehydrogenase Family: Short-chain 3-hydroxyacyl-CoA dehydrogenase (HADH / SCHAD)
7. 4. thiolytic cleavage of 3-ketoacyl-CoA to acetyl-CoA + chain-shortened acyl-CoA
8. Step 4: 3-ketoacyl-CoA thiolaseReactionthiolase_step
  
  Variants
  1. Chain-length-specific 3-ketoacyl-CoA thiolases by acyl-CoA chain length (One Or More)
    
    Long-chain 3-ketoacyl-CoA thiolase (MTP beta subunit, HADHB)Reactionlc_thiolase_variant
    
    Annotons
    
    HADHB/MTP-beta: long-chain 3-ketoacyl-CoA thiolase Family: Trifunctional enzyme beta subunit (HADHB / MTP beta)
    
    Medium/long-chain 3-ketoacyl-CoA thiolase (ACAA2)Reactionmed_thiolase_variant
    
    Annotons
    
    ACAA2: 3-ketoacyl-CoA thiolase Family: 3-ketoacyl-CoA thiolase (ACAA2)
    
    Short-chain / acetoacetyl-CoA thiolase (ACAT1, T2)Reactionsc_thiolase_variant
    
    Annotons
    
    ACAT1: acetoacetyl-CoA thiolase (T2) Family: Acetoacetyl-CoA thiolase (ACAT1 / T2)

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

hadh_step -> thiolase_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.