Distal L-leucine catabolism

A reusable four-position pathway that converts leucine-derived 3-methylbutanoyl-CoA (isovaleryl-CoA) to acetoacetate and acetyl-CoA. The pathway comprises acyl-CoA dehydrogenation, biotin-dependent carboxylation, methylglutaconyl-CoA hydration, and HMG-CoA cleavage. It separates reaction roles from lineage-specific enzyme families and cellular locations. Upstream leucine transamination and branched-chain 2-oxoacid dehydrogenation are outside the module; the terminal HMG-CoA lyase reaction can also serve other HMG-CoA-generating pathways.

MODULE:leucine_catabolismDRAFTMetabolic Pathwaymodules/leucine_catabolism.yaml

L-leucine catabolic processGO:0006552

GO:0006552

L-leucine catabolic process

GO:0006552 supplies the biological-process context for degradation of L-leucine.

Reactome:R-HSA-70895

Branched-chain amino acid catabolism

Human Reactome provides a curated instance of the ordered distal reactions, while the module abstracts away mitochondrial localization.

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

Human IVD gene review

P26440 grounds the eukaryotic dehydrogenase instance.

file:human/MCCC1/MCCC1-ai-review.yaml

Human MCCC1 gene review

Q96RQ3 grounds the eukaryotic MCC alpha-subunit role.

file:human/MCCC2/MCCC2-ai-review.yaml

Human MCCC2 gene review

Q9HCC0 grounds the eukaryotic MCC beta-subunit role.

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

Human AUH gene review

Q13825 grounds the eukaryotic hydratase-family instance.

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

Human HMGCL gene review

P35914 grounds the eukaryotic terminal lyase instance.

file:PSEPK/ivd/ivd-ai-review.yaml

PSEPK ivd gene review

Q88FM5 supplies 3-methylbutanoyl-CoA dehydrogenase activity.

file:PSEPK/mccA/mccA-ai-review.yaml

PSEPK mccA gene review

Q88FM2 supplies the MCC biotin-carboxylase/carrier subunit.

file:PSEPK/mccB/mccB-ai-review.yaml

PSEPK mccB gene review

Q88FM4 supplies the MCC carboxyltransferase subunit.

file:PSEPK/liuC/liuC-ai-review.yaml

PSEPK liuC gene review

Q88FM3 supplies the bacterial methylglutaconyl-CoA hydratase.

file:PSEPK/mvaB/mvaB-ai-review.yaml

PSEPK mvaB gene review

Q88H25 supplies a PSEPK HMG-CoA lyase instance.

7Nodes

4Parts

1Variant Sets

2Variants

6Annotons

3Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:leucine_catabolism 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.

Function consistency and core coverage

8 gene-function check(s) reflected in core functions · 0 conflict(s) · 6 evidence or coverage gap(s) (16 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
ivd_activity	human IVD UniProtKB:P26440 Family Representative	3-methylbutanoyl-CoA dehydrogenase activity GO:0008470	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ivd_activity	PSEPK Ivd UniProtKB:Q88FM5 Family Representative	3-methylbutanoyl-CoA dehydrogenase activity GO:0008470	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mcc_alpha_activity	human MCCC1 UniProtKB:Q96RQ3 Family Representative	biotin carboxylase activity GO:0004075	Non Core Supported The review explicitly retains this function as non-core; promotion into core_functions is not implied.
mcc_alpha_activity	PSEPK MccA UniProtKB:Q88FM2 Family Representative	biotin carboxylase activity GO:0004075	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mcc_beta_activity	human MCCC2 UniProtKB:Q9HCC0 Family Representative	methylcrotonoyl-CoA carboxylase activity GO:0004485	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mcc_beta_activity	PSEPK MccB UniProtKB:Q88FM4 Family Representative	methylcrotonoyl-CoA carboxylase activity GO:0004485	Annotation Supported A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
auh_activity	human AUH UniProtKB:Q13825 Family Representative	methylglutaconyl-CoA hydratase activity GO:0004490	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
liuC_activity	PSEPK LiuC UniProtKB:Q88FM3 Family Representative	methylglutaconyl-CoA hydratase activity GO:0004490	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hmgcl_activity	human HMGCL UniProtKB:P35914 Family Representative	hydroxymethylglutaryl-CoA lyase activity GO:0004419	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hmgcl_activity	PSEPK MvaB UniProtKB:Q88H25 Family Representative	hydroxymethylglutaryl-CoA lyase activity GO:0004419	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ivd_activity	isovaleryl-CoA dehydrogenases PANTHER:PTHR43884:SF12 Family	3-methylbutanoyl-CoA dehydrogenase activity GO:0008470	Family Function Unreviewed Family review leaves GO:0003995 UNRESOLVED. The inventory extends beyond acyl-CoA dehydrogenases to nitroalkane oxidases, monooxygenases and desulfinases; even SF12 mixes different reactions. Within the ACAD9 branch, direct protein-interaction studies show ECSIT-induced deflavination and loss of dehydrogenase activity during complex-I assembly (PMID:34646991). Catalytic potential and assembly function are alternative biochemical states, not evidence of constitutive pseudoenzyme inactivity. Neither substrate specificity nor complex-I assembly transfers to the entire family. A complete set of function-bearing branches is not delimited, so no exhaustive family or subfamily grant is asserted. For BACSU FadE O32176 in SF12, convergent yusJ and etfAB regulatory/growth phenotypes plus enzyme/ETF identities support a target-specific inferred ETF-linked activity, now accepted in the gene review. Direct transfer between isolated proteins remains unmeasured. That target inference does not delimit every function-bearing branch of this mixed family.
mcc_alpha_activity	MCC alpha subunits PANTHER:PTHR18866:SF33 Family	biotin carboxylase activity GO:0004075	Family Supported Family review supports GO:0004075 for PANTHER:PTHR18866:SF33. The biotin carboxylase half-reaction is common to MCC/PCC alpha subunits (SF33) and the DUR1,2 carboxylase domain; leucine_catabolism selects SF33. Human MCCC1 keeps it as a non-core partial activity of its BC domain, beside contributes_to the complete MCC activity.
mcc_beta_activity	MCC beta subunits PANTHER:PTHR22855:SF13 Family	methylcrotonoyl-CoA carboxylase activity GO:0004485	Family Review Missing No supported structured family review is available for PANTHER:PTHR22855:SF13.
auh_activity	AUH-family hydratases PANTHER:PTHR11941:SF12 Family	methylglutaconyl-CoA hydratase activity GO:0004490	Family Function Unreviewed The family review has no applicable adjudication supporting or excluding GO:0004490.
liuC_activity	function-gated bacterial LiuC crotonase family InterPro:IPR001753 Family	methylglutaconyl-CoA hydratase activity GO:0004490	Family Review Missing No supported structured family review is available for InterPro:IPR001753.
hmgcl_activity	HMG-CoA lyases PANTHER:PTHR42738 Family	hydroxymethylglutaryl-CoA lyase activity GO:0004419	Family Review Missing No supported structured family review is available for PANTHER:PTHR42738.

Gene-review completeness (10/10 grounded genes reviewed)

9 complete review(s) · 2 with deep research · 0 missing review · 8 reviewed but lacking deep research

Gene	Review	Complete	Deep research
AUH Q13825	✓	22/23	✗
HMGCL P35914	✓	✓	✗
IVD P26440	✓	✓	✗
ivd Q88FM5	✓	✓	✗
liuC Q88FM3	✓	✓	✓
mccA Q88FM2	✓	✓	✗
mccB Q88FM4	✓	✓	✗
MCCC1 Q96RQ3	✓	✓	✗
MCCC2 Q9HCC0	✓	✓	✗
mvaB Q88H25	✓	✓	✓

Tree

Distal L-leucine catabolismMetabolic Pathwayleucine_catabolism

Parts
1. 1. 3-methylcrotonyl-CoA formation
2. 3-methylbutanoyl-CoA dehydrogenaseReactionivd_step
  
  Annotons
  - 3-methylbutanoyl-CoA dehydrogenase Family: isovaleryl-CoA dehydrogenases
3. 2. 3-methylglutaconyl-CoA formation
4. 3-methylcrotonyl-CoA carboxylase complexProtein Complexmcc_step
  
  Annotons
  - MCC biotin-carboxylase and carrier subunit Family: MCC alpha subunits
  - MCC carboxyltransferase subunit Family: MCC beta subunits
5. 3. HMG-CoA formation
6. Methylglutaconyl-CoA hydrationReactionhydratase_step
  
  Variants
  1. Methylglutaconyl-CoA hydratase family by enzyme family (One Or More)
    
    AUH-family hydrataseReactioneukaryotic_auh_route
    
    Annotons
    
    AUH methylglutaconyl-CoA hydratase Family: AUH-family hydratases
    
    LiuC-family hydrataseReactionbacterial_liuC_route
    
    Annotons
    
    LiuC methylglutaconyl-CoA hydratase Family: function-gated bacterial LiuC crotonase family
7. 4. acetoacetate and acetyl-CoA formation
8. HMG-CoA lyaseReactionhmgcl_step
  
  Annotons
  - HMG-CoA lyase Family: HMG-CoA lyases

Details

Distal L-leucine catabolismMetabolic Pathwayleucine_catabolism

L-leucine catabolic processGO:0006552

Exact human and bacterial UniProt accessions are exemplars rather than taxonomic restrictions. Mitochondrial matrix localization is valid for eukaryotic instances but is not a pathway-wide requirement and is absent from the reusable module context. Enzyme-bound FAD is represented as the Ivd cofactor rather than a consumed substrate. The distinct eukaryotic AUH and bacterial LiuC hydratase implementations are modeled as alternatives. The bacterial LiuC selector combines a broad crotonase-family record with the exact GO function and a concrete exemplar because the available PANTHER family is not specific for this reaction. No ancestral PTN node is asserted without verified PAINT IBD evidence.

Connections

ivd_step -> mcc_step Provides Input For

Ivd supplies 3-methylcrotonyl-CoA to the MCC complex.

mcc_step -> hydratase_step Provides Input For

MCC supplies 3-methylglutaconyl-CoA to a hydratase.

hydratase_step -> hmgcl_step Provides Input For

Hydration supplies HMG-CoA to the terminal lyase.

Part 1: 3-methylcrotonyl-CoA formation

3-methylbutanoyl-CoA dehydrogenaseReactionivd_step

Annotons

3-methylbutanoyl-CoA dehydrogenase

ivd_activity

Participant: Family: isovaleryl-CoA dehydrogenases

Family:

isovaleryl-CoA dehydrogenasesPANTHER:PTHR43884:SF12

Representative Members: human IVDUniProtKB:P26440 PSEPK IvdUniProtKB:Q88FM5

Required Function:

3-methylbutanoyl-CoA dehydrogenase activityGO:0008470

Function

3-methylbutanoyl-CoA dehydrogenase activityGO:0008470

Substrates: 3-methylbutanoyl-CoA oxidized electron-transfer flavoprotein

Products: 3-methylcrotonyl-CoA reduced electron-transfer flavoprotein

Uses enzyme-bound FAD to transfer reducing equivalents from 3-methylbutanoyl-CoA to an electron-transfer flavoprotein.

Part 2: 3-methylglutaconyl-CoA formation

3-methylcrotonyl-CoA carboxylase complexProtein Complexmcc_step

methylcrotonoyl-CoA carboxylase complexGO:1905202

Annotons

MCC biotin-carboxylase and carrier subunit

mcc_alpha_activity

Participant: Family: MCC alpha subunits

Family:

MCC alpha subunitsPANTHER:PTHR18866:SF33

Representative Members: human MCCC1UniProtKB:Q96RQ3 PSEPK MccAUniProtKB:Q88FM2

Required Function:

biotin carboxylase activityGO:0004075

Function

biotin carboxylase activityGO:0004075

Substrates: biotinylated carrier domain hydrogencarbonate ATP

Products: carboxybiotinylated carrier domain ADP phosphate

Carboxylates its tethered biotin carrier for transfer of the carboxyl group by the beta subunit.

MCC carboxyltransferase subunit

mcc_beta_activity

Participant: Family: MCC beta subunits

Family:

MCC beta subunitsPANTHER:PTHR22855:SF13

Representative Members: human MCCC2UniProtKB:Q9HCC0 PSEPK MccBUniProtKB:Q88FM4

Required Function:

methylcrotonoyl-CoA carboxylase activityGO:0004485

Function

methylcrotonoyl-CoA carboxylase activityGO:0004485

Substrates: 3-methylcrotonyl-CoA carboxybiotinylated carrier domain

Products: 3-methylglutaconyl-CoA biotinylated carrier domain

Transfers the carboxyl group from carrier-bound carboxybiotin to 3-methylcrotonyl-CoA.

Part 3: HMG-CoA formation

Methylglutaconyl-CoA hydrationReactionhydratase_step

Variant set: Methylglutaconyl-CoA hydratase family by enzyme family (One Or More)

AUH-family hydrataseReactioneukaryotic_auh_route

Annotons

AUH methylglutaconyl-CoA hydratase

auh_activity

Participant: Family: AUH-family hydratases

Family:

AUH-family hydratasesPANTHER:PTHR11941:SF12

Representative Members: human AUHUniProtKB:Q13825

Required Function:

methylglutaconyl-CoA hydratase activityGO:0004490

Function

methylglutaconyl-CoA hydratase activityGO:0004490

Substrates: 3-methylglutaconyl-CoA water

Products: (S)-3-hydroxy-3-methylglutaryl-CoA

Hydrates 3-methylglutaconyl-CoA in the eukaryotic AUH family context.

LiuC-family hydrataseReactionbacterial_liuC_route

Annotons

LiuC methylglutaconyl-CoA hydratase

liuC_activity

Participant: Family: function-gated bacterial LiuC crotonase family

Family:

function-gated bacterial LiuC crotonase familyInterPro:IPR001753

Representative Members: PSEPK LiuCUniProtKB:Q88FM3

Required Function:

methylglutaconyl-CoA hydratase activityGO:0004490

Function

methylglutaconyl-CoA hydratase activityGO:0004490

Substrates: 3-methylglutaconyl-CoA water

Products: (S)-3-hydroxy-3-methylglutaryl-CoA

Hydrates 3-methylglutaconyl-CoA in the bacterial LiuC family context.

Part 4: acetoacetate and acetyl-CoA formation

HMG-CoA lyaseReactionhmgcl_step

Annotons

HMG-CoA lyase

hmgcl_activity

Participant: Family: HMG-CoA lyases

Family:

HMG-CoA lyasesPANTHER:PTHR42738

Representative Members: human HMGCLUniProtKB:P35914 PSEPK MvaBUniProtKB:Q88H25

Required Function:

hydroxymethylglutaryl-CoA lyase activityGO:0004419

Function

hydroxymethylglutaryl-CoA lyase activityGO:0004419

Substrates: (S)-3-hydroxy-3-methylglutaryl-CoA

Products: acetoacetate acetyl-CoA

Cleaves HMG-CoA to acetoacetate and acetyl-CoA; this reaction can be shared with other HMG-CoA degradation routes.