IVD

UniProt ID: P26440
Organism: Homo sapiens
Review Status: IN PROGRESS
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Gene Description

Isovaleryl-CoA dehydrogenase (IVD) is a mitochondrial matrix, FAD-dependent flavoenzyme of the acyl-CoA dehydrogenase (ACAD) family. It catalyzes the third step of leucine catabolism, downstream of the branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex, namely the alpha,beta-dehydrogenation of isovaleryl-CoA (3-methylbutanoyl-CoA) to 3-methylcrotonyl-CoA (3-methylbut-2-enoyl-CoA), transferring the abstracted electrons from its FAD prosthetic group to the electron-transfer flavoprotein (ETF). The active enzyme is a homotetramer with one FAD per subunit and a catalytic glutamate acting as the proton acceptor. To a lesser extent it also dehydrogenates short-chain saturated acyl-CoA thioesters (e.g. butanoyl-, pentanoyl-, hexanoyl-CoA), a promiscuous activity distinct from its physiological role. IVD is synthesized as a cytosolic precursor with a cleavable N-terminal mitochondrial targeting sequence and imported into the mitochondrial matrix, where the transit peptide is removed to yield the mature protein. Loss-of-function variants cause isovaleric acidemia, the first recognized organic acidemia, an autosomal-recessive inborn error of leucine metabolism marked by accumulation of isovaleric acid and its conjugates and a characteristic sweaty-feet odor.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005739 mitochondrion
IBA
GO_REF:0000033 		ACCEPT
Summary: IVD is active in the mitochondrion; specifically it is a mitochondrial matrix enzyme. Correct but less precise than the mitochondrial matrix annotations for this protein.
Reason: IVD is an established mitochondrial-matrix flavoenzyme, so localization to the mitochondrion is correct. This IBA is well supported phylogenetically and by direct evidence for the human protein, though it is more general than the mitochondrial matrix (GO:0005759) annotations also present for this gene.
Supporting Evidence:
PMID:2063866
isovaleryl-CoA dehydrogenase (IVD), a mitochondrial matrix enzyme
GO:0006552 L-leucine catabolic process
IBA
GO_REF:0000033 		ACCEPT
Summary: IVD catalyzes the third step of leucine catabolism, converting isovaleryl-CoA to 3-methylcrotonyl-CoA. This is a core biological process for the gene, well supported by both phylogeny and direct human enzymology.
Reason: Leucine catabolism is the defining physiological role of IVD; deficiency causes isovaleric acidemia, an inborn error of leucine metabolism. The IBA is concordant with the experimental (IDA) annotation to the same term.
Supporting Evidence:
PMID:2063866
Isovaleric acidemia (IVA) is an inborn error of leucine metabolism and is caused by a genetically determined deficiency of isovaleryl-CoA dehydrogenase (IVD)
GO:0008470 3-methylbutanoyl-CoA dehydrogenase activity
IBA
GO_REF:0000033 		ACCEPT
Summary: This is the core molecular function of IVD - isovaleryl-CoA (3-methylbutanoyl-CoA) dehydrogenase activity (EC 1.3.8.4). The current ontology primary label for GO:0008470 is "3-methylbutanoyl-CoA dehydrogenase activity", which is the systematic name for isovaleryl-CoA dehydrogenase activity.
Reason: IVD is the eponymous isovaleryl-CoA dehydrogenase; this activity is confirmed by direct human enzymology (purified enzyme and active-site mutagenesis) and is the phylogenetically conserved function of the orthology group. Correct term at the appropriate specificity.
Supporting Evidence:
PMID:7640268
Isovaleryl-CoA dehydrogenase (IVD) is a homotetrameric flavoenzyme which catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA.
GO:0003995 acyl-CoA dehydrogenase activity
IEA
GO_REF:0000002 		ACCEPT
Summary: Family-level acyl-CoA dehydrogenase activity assigned from InterPro domain membership. Correct but less specific than the isovaleryl-CoA dehydrogenase activity (GO:0008470) captured by the experimental annotations.
Reason: IVD belongs to the acyl-CoA dehydrogenase family and the InterPro-based parent-level MF is not wrong. It is a generalization of the specific core function; acceptable as a broader IEA that is consistent with the more precise GO:0008470 annotations.
Supporting Evidence:
PMID:7640268
Isovaleryl-CoA dehydrogenase (IVD) is a homotetrameric flavoenzyme which catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA.
GO:0005739 mitochondrion
IEA
GO_REF:0000117 		ACCEPT
Summary: Mitochondrion localization from an ARBA machine-learning model. Correct; IVD is a mitochondrial matrix protein.
Reason: Consistent with experimental localization to the mitochondrial matrix. Broader than the mitochondrial matrix term but not incorrect.
Supporting Evidence:
PMID:2063866
isovaleryl-CoA dehydrogenase (IVD), a mitochondrial matrix enzyme
GO:0005759 mitochondrial matrix
IEA
GO_REF:0000044 		ACCEPT
Summary: Mitochondrial matrix localization derived from UniProtKB SubCellular Location mapping. This is the correct, specific subcellular compartment for IVD.
Reason: IVD is a soluble mitochondrial matrix flavoenzyme, imported as a precursor and processed after removal of its N-terminal transit peptide. The matrix localization is directly supported in the literature.
Supporting Evidence:
PMID:2063866
isovaleryl-CoA dehydrogenase (IVD), a mitochondrial matrix enzyme
GO:0008470 3-methylbutanoyl-CoA dehydrogenase activity
IEA
GO_REF:0000120 		ACCEPT
Summary: Core isovaleryl-CoA (3-methylbutanoyl-CoA) dehydrogenase activity, assigned electronically via RHEA:12276 / EC 1.3.8.4. Concordant with the experimental annotations.
Reason: This IEA (mapped from EC 1.3.8.4 and Rhea reaction RHEA:12276) captures the same core catalytic activity confirmed experimentally for the human enzyme.
Supporting Evidence:
PMID:7640268
Isovaleryl-CoA dehydrogenase (IVD) is a homotetrameric flavoenzyme which catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA.
GO:0016627 oxidoreductase activity, acting on the CH-CH group of donors
IEA
GO_REF:0000002 		ACCEPT
Summary: High-level oxidoreductase (acting on CH-CH group of donors) activity from InterPro. IVD catalyzes alpha,beta-dehydrogenation, forming a C=C double bond, so this general MF is correct.
Reason: This is a correct grandparent-level term for the acyl-CoA dehydrogenase reaction (CH-CH dehydrogenation). It is very general but not wrong; retained as a broad IEA subsumed by the specific GO:0008470 annotation.
Supporting Evidence:
PMID:7640268
Isovaleryl-CoA dehydrogenase (IVD) is a homotetrameric flavoenzyme which catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA.
GO:0016937 short-chain fatty acyl-CoA dehydrogenase activity
IEA
GO_REF:0000120 		MARK AS OVER ANNOTATED
Summary: Short-chain fatty acyl-CoA dehydrogenase activity (EC 1.3.8.1) assigned electronically. IVD does have measurable activity toward short-chain acyl-CoA substrates (e.g. butanoyl-, pentanoyl-CoA), but this is a minor, promiscuous activity rather than its physiological function.
Reason: UniProt notes that IVD acts on short-chain acyl-CoA thioesters only "to a lesser extent"; the physiological role is leucine catabolism via isovaleryl-CoA dehydrogenase activity (GO:0008470). Retaining EC 1.3.8.1 as an independent core MF over-states a secondary in-vitro side activity; better represented as non-core / over-annotated.
Supporting Evidence:
PMID:3597357
They all utilized electron transfer flavoprotein (ETF) or phenazine methosulfate (PMS) as an electron acceptor.
GO:0050660 flavin adenine dinucleotide binding
IEA
GO_REF:0000002 		ACCEPT
Summary: FAD binding, assigned from InterPro. IVD is a flavoprotein carrying one non-covalently bound FAD per subunit, its essential redox cofactor.
Reason: The FAD cofactor is directly established by the X-ray structure and by UV/visible spectroscopy of the purified enzyme; FAD binding is required for catalysis. Correct and core to the mechanism.
Supporting Evidence:
PMID:3597357
that each contains 1 mol of FAD per subunit.
PMID:7640268
Isovaleryl-CoA dehydrogenase (IVD) is a homotetrameric flavoenzyme which catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA.
GO:0070991 medium-chain fatty acyl-CoA dehydrogenase activity
IEA
GO_REF:0000116 		MARK AS OVER ANNOTATED
Summary: Medium-chain fatty acyl-CoA dehydrogenase activity assigned from a RHEA mapping of the hexanoyl-CoA (C6) reaction. IVD can dehydrogenate hexanoyl-CoA in vitro, but medium-chain acyl-CoA oxidation is the physiological role of MCAD (ACADM), not IVD.
Reason: Hexanoyl-CoA is a weak, promiscuous in-vitro substrate captured only by an automated Rhea-to-GO reaction mapping. IVD's physiological function is isovaleryl-CoA dehydrogenation in leucine catabolism; annotating a dedicated medium-chain acyl-CoA dehydrogenase MF over-states an incidental side activity and risks confusion with MCAD.
Supporting Evidence:
PMID:3597357
Kinetic parameters Vappmax and Kappm) of these enzymes for
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome. 		MARK AS OVER ANNOTATED
Summary: Bare protein binding from a high-throughput yeast two-hybrid binary interactome screen (HuRI), reporting interactions with ACTN3 (Q08043) and GPSM3 (Q9Y4H4). The term is uninformative about IVD's actual molecular function, and the partners are cytoskeletal/G-protein-signaling proteins of unclear physiological relevance to a mitochondrial matrix enzyme.
Reason: The generic protein binding term (GO:0005515) conveys no functional information and derives from a systematic large-scale Y2H hit rather than a curated, biologically interpreted interaction. Per curation guidance, bare protein binding is not retained as an informative function; it is kept but marked as over-annotated rather than removed.
Supporting Evidence:
PMID:32296183
reference interactome map of human binary protein interactions, or 'HuRI'.
GO:0006552 L-leucine catabolic process
IEA
GO_REF:0000120 		ACCEPT
Summary: L-leucine catabolic process assigned electronically (UniPathway UPA00363). This is the core biological process for IVD and is concordant with the experimental (IDA) and phylogenetic (IBA) annotations to the same term.
Reason: IVD catalyzes a committed step of the leucine degradation pathway; the electronic pathway assignment matches the experimentally established role.
Supporting Evidence:
PMID:2063866
Isovaleric acidemia (IVA) is an inborn error of leucine metabolism and is caused by a genetically determined deficiency of isovaleryl-CoA dehydrogenase (IVD)
GO:0008470 3-methylbutanoyl-CoA dehydrogenase activity
TAS
Reactome:R-HSA-9914837 		ACCEPT
Summary: Isovaleryl-CoA dehydrogenase activity, from a Reactome pathway describing IVD mutants failing to synthesize beta-methylcrotonyl-CoA. Captures the core catalytic function.
Reason: Reactome authoritatively assigns this catalytic activity to IVD, matching the direct experimental annotations. Core molecular function.
Supporting Evidence:
PMID:7640268
Isovaleryl-CoA dehydrogenase (IVD) is a homotetrameric flavoenzyme which catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA.
GO:0005739 mitochondrion
IDA
GO_REF:0000052 		ACCEPT
Summary: Mitochondrion localization from Human Protein Atlas immunofluorescence (IDA). Correct; consistent with the mitochondrial matrix localization of IVD.
Reason: Direct immunofluorescence evidence for mitochondrial localization, in agreement with the established matrix localization of the enzyme. Broader than the matrix term but not incorrect.
Supporting Evidence:
PMID:2063866
isovaleryl-CoA dehydrogenase (IVD), a mitochondrial matrix enzyme
GO:0005759 mitochondrial matrix
ISS
GO_REF:0000024 		ACCEPT
Summary: Mitochondrial matrix localization by sequence similarity to rat IVD (P12007). Correct, specific compartment for this enzyme.
Reason: The matrix localization is orthology-conserved and directly supported for the human protein. Appropriate specific cellular component term.
Supporting Evidence:
PMID:2063866
isovaleryl-CoA dehydrogenase (IVD), a mitochondrial matrix enzyme
GO:0005759 mitochondrial matrix
TAS
Reactome:R-HSA-70745 		ACCEPT
Summary: Mitochondrial matrix localization asserted by Reactome for the isovaleryl-CoA dehydrogenation reaction. Correct compartment.
Reason: Reactome places the IVD-catalyzed reaction in the mitochondrial matrix, consistent with the biochemical and orthology evidence.
Supporting Evidence:
PMID:2063866
isovaleryl-CoA dehydrogenase (IVD), a mitochondrial matrix enzyme
GO:0005759 mitochondrial matrix
TAS
Reactome:R-HSA-9914837 		ACCEPT
Summary: Mitochondrial matrix localization asserted by Reactome (isovaleric acidemia pathway). Correct compartment for IVD.
Reason: Reactome localizes IVD to the mitochondrial matrix, in agreement with the established subcellular location. Duplicate of the other matrix annotations, which is acceptable.
Supporting Evidence:
PMID:2063866
isovaleryl-CoA dehydrogenase (IVD), a mitochondrial matrix enzyme
GO:0005739 mitochondrion
HTP
PMID:34800366
Quantitative high-confidence human mitochondrial proteome an... 		ACCEPT
Summary: Mitochondrion localization from a high-throughput, high-confidence human mitochondrial proteome study (MitoCoP). Consistent with the known mitochondrial matrix localization of IVD.
Reason: IVD is confidently detected in a rigorously defined mitochondrial proteome, corroborating its mitochondrial localization. Broader than the matrix term but correct.
Supporting Evidence:
PMID:34800366
mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP).
GO:0006552 L-leucine catabolic process
IDA
PMID:7640268
Identification of the active site catalytic residue in human... 		ACCEPT
Summary: Direct experimental evidence (active-site characterization of human IVD) that IVD converts isovaleryl-CoA to 3-methylcrotonyl-CoA, the step of leucine catabolism. Core biological process.
Reason: The physiological role in leucine degradation is established by direct enzymology on the human protein and is the defining function of IVD.
Supporting Evidence:
PMID:7640268
Isovaleryl-CoA dehydrogenase (IVD) is a homotetrameric flavoenzyme which catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA.
GO:0008470 3-methylbutanoyl-CoA dehydrogenase activity
IDA
PMID:7640268
Identification of the active site catalytic residue in human... 		ACCEPT
Summary: Direct experimental demonstration of isovaleryl-CoA (3-methylbutanoyl-CoA) dehydrogenase activity for the human enzyme, including identification of the catalytic active-site glutamate by site-directed mutagenesis. This is the core molecular function.
Reason: Gold-standard experimental evidence - recombinant wild-type IVD is most active on isovaleryl-CoA, and mutation of the catalytic glutamate abolishes activity, directly establishing the enzyme's molecular function.
Supporting Evidence:
PMID:7640268
Isovaleryl-CoA dehydrogenase (IVD) is a homotetrameric flavoenzyme which catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA.
PMID:7640268
The E254G and E254Q mutant IVDs had no detectable
GO:0009083 branched-chain amino acid catabolic process
IDA
PMID:7640268
Identification of the active site catalytic residue in human... 		ACCEPT
Summary: Branched-chain amino acid catabolic process - leucine is a branched-chain amino acid, and IVD acts in its degradation. This is a correct parent process of the leucine catabolic process annotation.
Reason: Leucine catabolism (the specific step catalyzed by IVD) is a component of branched-chain amino acid catabolism; the annotation is correct, if broader than the leucine-specific term.
Supporting Evidence:
PMID:7640268
Isovaleryl-CoA dehydrogenase (IVD) is a homotetrameric flavoenzyme which catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA.
GO:0042802 identical protein binding
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Identical protein binding (self-association), transferred by similarity from rat IVD (P12007). IVD is a homotetramer, so subunit self-association is a real structural property.
Reason: Homotetramer formation is directly established by biochemistry and the crystal structure, so identical protein binding is biologically real. However it describes an oligomerization property rather than the enzyme's core catalytic function; kept as a supporting, non-core annotation.
Supporting Evidence:
PMID:3597357
indicating a homotetrameric
PMID:7640268
Isovaleryl-CoA dehydrogenase (IVD) is a homotetrameric flavoenzyme
GO:0008470 3-methylbutanoyl-CoA dehydrogenase activity
IDA
PMID:3597357
Purification and properties of short chain acyl-CoA, medium ... 		ACCEPT
Summary: Isovaleryl-CoA dehydrogenase activity demonstrated on IVD purified to homogeneity from human liver; the product of the isovaleryl-CoA reaction was identified as 3-methylcrotonyl-CoA. Core molecular function.
Reason: Direct biochemical evidence from the purified human enzyme identifies the isovaleryl-CoA to 3-methylcrotonyl-CoA reaction, confirming the core catalytic activity of IVD.
Supporting Evidence:
PMID:3597357
IV dehydrogenase/isovaleryl-CoA reactions were identified as crotonyl-CoA,
GO:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase
IDA
PMID:3597357
Purification and properties of short chain acyl-CoA, medium ... 		KEEP AS NON CORE
Summary: Fatty acid beta-oxidation using acyl-CoA dehydrogenase, from a study characterizing IVD alongside short- and medium-chain acyl-CoA dehydrogenases and showing it uses ETF as electron acceptor. IVD contributes to this only via its minor short-chain acyl-CoA dehydrogenase activity.
Reason: The purified enzyme does act on short-chain saturated acyl-CoA substrates and uses ETF, so a peripheral role in the first (dehydrogenation) step of fatty-acid beta-oxidation is plausible. However, IVD's physiological role is leucine catabolism, not beta-oxidation, and dedicated short/medium-chain ACADs (ACADS, ACADM) carry out this step in vivo; retained as a non-core annotation.
Supporting Evidence:
PMID:3597357
They all utilized electron transfer flavoprotein (ETF) or phenazine methosulfate (PMS) as an electron acceptor.
GO:0006552 L-leucine catabolic process
ISS
GO_REF:0000024 		ACCEPT
Summary: L-leucine catabolic process by sequence similarity to rat IVD (P12007). Concordant with the experimental and phylogenetic annotations to the same core process.
Reason: The leucine catabolism role is orthology-conserved and experimentally established for human IVD. Correct core biological process.
Supporting Evidence:
PMID:2063866
Isovaleric acidemia (IVA) is an inborn error of leucine metabolism and is caused by a genetically determined deficiency of isovaleryl-CoA dehydrogenase (IVD)
GO:0008470 3-methylbutanoyl-CoA dehydrogenase activity
ISS
GO_REF:0000024 		ACCEPT
Summary: Isovaleryl-CoA dehydrogenase activity by sequence similarity to rat IVD (P12007). Concordant with the direct experimental annotations. Core molecular function.
Reason: The catalytic activity is orthology-conserved and directly demonstrated for the human enzyme; correct core function at the appropriate specificity.
Supporting Evidence:
PMID:7640268
Isovaleryl-CoA dehydrogenase (IVD) is a homotetrameric flavoenzyme which catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA.
GO:0005759 mitochondrial matrix
NAS
PMID:2063866
Molecular characterization of four different classes of muta... 		ACCEPT
Summary: Mitochondrial matrix localization, stated in a study of IVD mutations in isovaleric acidemia which describes IVD as a mitochondrial matrix enzyme imported as a precursor and processed to its mature form. Correct compartment.
Reason: The cited paper explicitly identifies IVD as a mitochondrial matrix enzyme, supporting the specific subcellular localization.
Supporting Evidence:
PMID:2063866
isovaleryl-CoA dehydrogenase (IVD), a mitochondrial matrix enzyme
GO:0008470 3-methylbutanoyl-CoA dehydrogenase activity
TAS
PMID:3446585
Isolation of cDNA clones coding for rat isovaleryl-CoA dehyd... 		ACCEPT
Summary: Isovaleryl-CoA dehydrogenase activity, from the cDNA-cloning and chromosome-15-assignment study that molecularly identified the IVD gene. A traceable author statement of the gene's enzymatic identity. Core molecular function.
Reason: This foundational paper cloned the isovaleryl-CoA dehydrogenase cDNA and assigned the gene, providing a traceable basis for the enzyme's identity. The activity is amply confirmed by later direct assays; retained as a valid TAS for the core function.
Supporting Evidence:
PMID:3446585
the isovaleryl-CoA dehydrogenase gene

Core Functions

FAD-dependent dehydrogenation of isovaleryl-CoA (3-methylbutanoyl-CoA) to 3-methylcrotonyl-CoA in the mitochondrial matrix, the committed dehydrogenation step of leucine catabolism, transferring electrons to the electron-transfer flavoprotein (ETF).

Molecular Function:
3-methylbutanoyl-CoA dehydrogenase activity
Directly Involved In:
L-leucine catabolic process
Cellular Locations:
mitochondrial matrix
Supporting Evidence:
  • PMID:7640268
    Isovaleryl-CoA dehydrogenase (IVD) is a homotetrameric flavoenzyme which catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA.
  • PMID:3597357
    IV dehydrogenase/isovaleryl-CoA reactions were identified as crotonyl-CoA,

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000116
Automatic Gene Ontology annotation based on Rhea mapping
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:2063866
Molecular characterization of four different classes of mutations in the isovaleryl-CoA dehydrogenase gene responsible for isovaleric acidemia.
PMID:32296183
A reference map of the human binary protein interactome.
PMID:3446585
Isolation of cDNA clones coding for rat isovaleryl-CoA dehydrogenase and assignment of the gene to human chromosome 15.
PMID:34800366
Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
PMID:3597357
Purification and properties of short chain acyl-CoA, medium chain acyl-CoA, and isovaleryl-CoA dehydrogenases from human liver.
PMID:7640268
Identification of the active site catalytic residue in human isovaleryl-CoA dehydrogenase.
Reactome:R-HSA-70745
isovaleryl-CoA + FAD => beta-methylcrotonyl-CoA + FADH2
Reactome:R-HSA-9914837
IVD mutants don't synthesize beta-methylcrotonyl-CoA

Suggested Questions for Experts

Q: Beyond isovaleryl-CoA, does IVD make any physiologically meaningful contribution to short-chain fatty acid beta-oxidation in vivo, or is its short/medium-chain acyl-CoA activity purely an in-vitro promiscuity redundant with ACADS/ACADM?

Q: Are the reported binary interactions with ACTN3 and GPSM3 (from high-throughput Y2H) reproducible and physiologically relevant, or are they screen artifacts unrelated to the mitochondrial matrix localization of IVD?

Suggested Experiments

Experiment: Quantify the in-vivo flux contribution of IVD to short-chain acyl-CoA dehydrogenation using stable-isotope-labeled substrates in IVD-null versus ACADS/ACADM-null cells, to test whether its short-chain activity is physiologically significant.

📚 Additional Documentation

Notes

(IVD-notes.md)

IVD (Isovaleryl-CoA dehydrogenase, mitochondrial) — review notes

UniProtKB: P26440 | HGNC:6186 | Gene 3712 | Chr 15q15 | EC 1.3.8.4 (also 1.3.8.1)

Core biology (verified)

IVD is a mitochondrial-matrix, FAD-dependent flavoenzyme of the acyl-CoA dehydrogenase
(ACAD) family. It catalyses the third step of leucine catabolism, downstream of the
branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex: the alpha,beta-dehydrogenation
of isovaleryl-CoA (3-methylbutanoyl-CoA) to 3-methylcrotonyl-CoA (3-methylbut-2-enoyl-CoA),
transferring electrons via its FAD to the electron-transfer flavoprotein (ETF).

  • Reaction / substrate specificity established biochemically on purified human liver enzyme
    PMID:3597357;
    same paper shows ETF/PMS as electron acceptors and homotetrameric structure with 1 mol FAD/subunit.
  • Catalytic mechanism / active-site glutamate (E254 in mature numbering; Glu-286 in precursor)
    identified by mutagenesis PMID:7640268.
    This paper is the UniProt evidence for FUNCTION and the EC assignments (1.3.8.4, 1.3.8.1).
  • Cofactor FAD and homotetramer confirmed by X-ray structure at 2.6 A PMID:9214289 (UniProt COFACTOR/SUBUNIT).
  • Mitochondrial matrix localization: NAS PMID:2063866;
    precursor imported and processed from 45 kDa to 43 kDa mature form (transit peptide 1-32, cleaved after Ala-32).
  • Chromosome 15 assignment and cDNA cloning: PMID:3446585 (rat cDNA + human chr15 mapping).

Disease

Isovaleric acidemia (IVA; MIM:243500; MONDO:0009475), the first recognised organic acidemia,
autosomal recessive; "sweaty feet" odor. Deficiency blocks leucine catabolism -> accumulation of
isovaleric acid, 3-hydroxyisovaleric acid, isovalerylcarnitine (C5), isovalerylglycine; secondary
hyperammonemia (isovaleryl-CoA inhibits NAGS). Corroborated by disorder KB
(~/repos/dismech/kb/disorders/Isovaleric_Acidemia.yaml; MONDO:0009475).

GOA annotation review summary

  • MF core: GO:0008470 (3-methylbutanoyl-CoA dehydrogenase activity = isovaleryl-CoA dehydrogenase
    activity, EC 1.3.8.4). Multiple IDA (PMID:7640268, PMID:3597357), TAS (Reactome, PMID:3446585),
    IBA, ISS, IEA — all ACCEPT (core). Current ontology label is "3-methylbutanoyl-CoA dehydrogenase activity".
  • GO:0050660 FAD binding (IEA InterPro) — ACCEPT, supported by X-ray/COFACTOR.
  • GO:0006552 L-leucine catabolic process — core BP; IDA/IBA/ISS/IEA — ACCEPT.
  • GO:0009083 branched-chain amino acid catabolic process (IDA) — ACCEPT (parent process; leucine is BCAA).
  • CC: GO:0005759 mitochondrial matrix (NAS/ISS/TAS/IEA) — ACCEPT core; GO:0005739 mitochondrion
    (IBA/IEA/IDA-HPA/HTP) — ACCEPT (broader but correct).
  • GO:0003995 acyl-CoA dehydrogenase activity (IEA InterPro) — parent MF; KEEP but generalization of the
    specific 0008470 — MARK_AS_OVER_ANNOTATED / ACCEPT as family-level. Keep as ACCEPT (correct, less specific).
  • GO:0016627 oxidoreductase acting on CH-CH (IEA) — grandparent MF, ACCEPT (correct, general).
  • GO:0016937 short-chain fatty acyl-CoA dehydrogenase activity (IEA, EC 1.3.8.1) — IVD does have minor
    short-chain acyl-CoA (butanoyl/pentanoyl) activity (EC 1.3.8.1 in UniProt) — ACCEPT as non-core / MARK_AS_OVER_ANNOTATED
    (secondary "to a lesser extent" activity, not physiological core).
  • GO:0070991 medium-chain fatty acyl-CoA dehydrogenase activity (IEA RHEA hexanoyl-CoA) — hexanoyl-CoA is
    medium-chain (C6); UniProt lists hexanoyl-CoA as a minor substrate. This is a promiscuous in-vitro
    side activity, not the physiological function -> MARK_AS_OVER_ANNOTATED.
  • GO:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase (IDA PMID:3597357) — IVD's short-chain
    activity is a minor contribution to FA beta-oxidation; keep as non-core.
  • GO:0005515 protein binding (IPI, HuRI PMID:32296183; ACTN3, GPSM3) — bare "protein binding", high-throughput
    Y2H binary interactome; uninformative -> MARK_AS_OVER_ANNOTATED (do NOT REMOVE per policy).
  • GO:0042802 identical protein binding (ISS from rat P12007) — homotetramer, self-association is real
    (structure PMID:9214289) -> ACCEPT/KEEP_AS_NON_CORE.

Deep research (falcon) was requested but the file did not appear within the poll window;
review grounded in UniProt P26440, GOA, cached PMIDs, and the Isovaleric_Acidemia disorder KB.

📄 View Raw YAML

 
id: P26440
gene_symbol: IVD
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  Isovaleryl-CoA dehydrogenase (IVD) is a mitochondrial matrix, FAD-dependent
  flavoenzyme of the acyl-CoA dehydrogenase (ACAD) family. It catalyzes the third
  step of leucine catabolism, downstream of the branched-chain alpha-ketoacid
  dehydrogenase (BCKDH) complex, namely the alpha,beta-dehydrogenation of
  isovaleryl-CoA (3-methylbutanoyl-CoA) to 3-methylcrotonyl-CoA
  (3-methylbut-2-enoyl-CoA), transferring the abstracted electrons from its FAD
  prosthetic group to the electron-transfer flavoprotein (ETF). The active enzyme
  is a homotetramer with one FAD per subunit and a catalytic glutamate acting as
  the proton acceptor. To a lesser extent it also dehydrogenates short-chain
  saturated acyl-CoA thioesters (e.g. butanoyl-, pentanoyl-, hexanoyl-CoA), a
  promiscuous activity distinct from its physiological role. IVD is synthesized as
  a cytosolic precursor with a cleavable N-terminal mitochondrial targeting
  sequence and imported into the mitochondrial matrix, where the transit peptide is
  removed to yield the mature protein. Loss-of-function variants cause isovaleric
  acidemia, the first recognized organic acidemia, an autosomal-recessive inborn
  error of leucine metabolism marked by accumulation of isovaleric acid and its
  conjugates and a characteristic sweaty-feet odor.
alternative_products:
- name: '1'
  id: P26440-1
- name: '2'
  id: P26440-2
  sequence_note: VSP_045193
existing_annotations:
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: IVD is active in the mitochondrion; specifically it is a mitochondrial
      matrix enzyme. Correct but less precise than the mitochondrial matrix
      annotations for this protein.
    action: ACCEPT
    reason: IVD is an established mitochondrial-matrix flavoenzyme, so localization
      to the mitochondrion is correct. This IBA is well supported phylogenetically
      and by direct evidence for the human protein, though it is more general than
      the mitochondrial matrix (GO:0005759) annotations also present for this gene.
    supported_by:
    - reference_id: PMID:2063866
      supporting_text: isovaleryl-CoA dehydrogenase (IVD), a mitochondrial matrix enzyme
- term:
    id: GO:0006552
    label: L-leucine catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: IVD catalyzes the third step of leucine catabolism, converting
      isovaleryl-CoA to 3-methylcrotonyl-CoA. This is a core biological process for
      the gene, well supported by both phylogeny and direct human enzymology.
    action: ACCEPT
    reason: Leucine catabolism is the defining physiological role of IVD; deficiency
      causes isovaleric acidemia, an inborn error of leucine metabolism. The IBA is
      concordant with the experimental (IDA) annotation to the same term.
    supported_by:
    - reference_id: PMID:2063866
      supporting_text: Isovaleric acidemia (IVA) is an inborn error of leucine metabolism
        and is caused by a genetically determined deficiency of isovaleryl-CoA dehydrogenase
        (IVD)
- term:
    id: GO:0008470
    label: 3-methylbutanoyl-CoA dehydrogenase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: This is the core molecular function of IVD - isovaleryl-CoA
      (3-methylbutanoyl-CoA) dehydrogenase activity (EC 1.3.8.4). The current
      ontology primary label for GO:0008470 is "3-methylbutanoyl-CoA dehydrogenase
      activity", which is the systematic name for isovaleryl-CoA dehydrogenase
      activity.
    action: ACCEPT
    reason: IVD is the eponymous isovaleryl-CoA dehydrogenase; this activity is
      confirmed by direct human enzymology (purified enzyme and active-site
      mutagenesis) and is the phylogenetically conserved function of the orthology
      group. Correct term at the appropriate specificity.
    supported_by:
    - reference_id: PMID:7640268
      supporting_text: Isovaleryl-CoA dehydrogenase (IVD) is a homotetrameric flavoenzyme
        which catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA.
- term:
    id: GO:0003995
    label: acyl-CoA dehydrogenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Family-level acyl-CoA dehydrogenase activity assigned from InterPro
      domain membership. Correct but less specific than the isovaleryl-CoA
      dehydrogenase activity (GO:0008470) captured by the experimental annotations.
    action: ACCEPT
    reason: IVD belongs to the acyl-CoA dehydrogenase family and the InterPro-based
      parent-level MF is not wrong. It is a generalization of the specific core
      function; acceptable as a broader IEA that is consistent with the more precise
      GO:0008470 annotations.
    supported_by:
    - reference_id: PMID:7640268
      supporting_text: Isovaleryl-CoA dehydrogenase (IVD) is a homotetrameric flavoenzyme
        which catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: Mitochondrion localization from an ARBA machine-learning model. Correct;
      IVD is a mitochondrial matrix protein.
    action: ACCEPT
    reason: Consistent with experimental localization to the mitochondrial matrix.
      Broader than the mitochondrial matrix term but not incorrect.
    supported_by:
    - reference_id: PMID:2063866
      supporting_text: isovaleryl-CoA dehydrogenase (IVD), a mitochondrial matrix enzyme
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Mitochondrial matrix localization derived from UniProtKB SubCellular
      Location mapping. This is the correct, specific subcellular compartment for IVD.
    action: ACCEPT
    reason: IVD is a soluble mitochondrial matrix flavoenzyme, imported as a
      precursor and processed after removal of its N-terminal transit peptide. The
      matrix localization is directly supported in the literature.
    supported_by:
    - reference_id: PMID:2063866
      supporting_text: isovaleryl-CoA dehydrogenase (IVD), a mitochondrial matrix enzyme
- term:
    id: GO:0008470
    label: 3-methylbutanoyl-CoA dehydrogenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Core isovaleryl-CoA (3-methylbutanoyl-CoA) dehydrogenase activity,
      assigned electronically via RHEA:12276 / EC 1.3.8.4. Concordant with the
      experimental annotations.
    action: ACCEPT
    reason: This IEA (mapped from EC 1.3.8.4 and Rhea reaction RHEA:12276) captures
      the same core catalytic activity confirmed experimentally for the human enzyme.
    supported_by:
    - reference_id: PMID:7640268
      supporting_text: Isovaleryl-CoA dehydrogenase (IVD) is a homotetrameric flavoenzyme
        which catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA.
- term:
    id: GO:0016627
    label: oxidoreductase activity, acting on the CH-CH group of donors
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: High-level oxidoreductase (acting on CH-CH group of donors) activity
      from InterPro. IVD catalyzes alpha,beta-dehydrogenation, forming a C=C double
      bond, so this general MF is correct.
    action: ACCEPT
    reason: This is a correct grandparent-level term for the acyl-CoA dehydrogenase
      reaction (CH-CH dehydrogenation). It is very general but not wrong; retained as
      a broad IEA subsumed by the specific GO:0008470 annotation.
    supported_by:
    - reference_id: PMID:7640268
      supporting_text: Isovaleryl-CoA dehydrogenase (IVD) is a homotetrameric flavoenzyme
        which catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA.
- term:
    id: GO:0016937
    label: short-chain fatty acyl-CoA dehydrogenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Short-chain fatty acyl-CoA dehydrogenase activity (EC 1.3.8.1) assigned
      electronically. IVD does have measurable activity toward short-chain acyl-CoA
      substrates (e.g. butanoyl-, pentanoyl-CoA), but this is a minor, promiscuous
      activity rather than its physiological function.
    action: MARK_AS_OVER_ANNOTATED
    reason: UniProt notes that IVD acts on short-chain acyl-CoA thioesters only "to a
      lesser extent"; the physiological role is leucine catabolism via isovaleryl-CoA
      dehydrogenase activity (GO:0008470). Retaining EC 1.3.8.1 as an independent core
      MF over-states a secondary in-vitro side activity; better represented as
      non-core / over-annotated.
    supported_by:
    - reference_id: PMID:3597357
      supporting_text: They all utilized electron transfer flavoprotein (ETF) or phenazine
        methosulfate (PMS) as an electron acceptor.
- term:
    id: GO:0050660
    label: flavin adenine dinucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: FAD binding, assigned from InterPro. IVD is a flavoprotein carrying one
      non-covalently bound FAD per subunit, its essential redox cofactor.
    action: ACCEPT
    reason: The FAD cofactor is directly established by the X-ray structure and by
      UV/visible spectroscopy of the purified enzyme; FAD binding is required for
      catalysis. Correct and core to the mechanism.
    supported_by:
    - reference_id: PMID:3597357
      supporting_text: that each contains 1 mol of FAD per subunit.
    - reference_id: PMID:7640268
      supporting_text: Isovaleryl-CoA dehydrogenase (IVD) is a homotetrameric flavoenzyme
        which catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA.
- term:
    id: GO:0070991
    label: medium-chain fatty acyl-CoA dehydrogenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    summary: Medium-chain fatty acyl-CoA dehydrogenase activity assigned from a RHEA
      mapping of the hexanoyl-CoA (C6) reaction. IVD can dehydrogenate hexanoyl-CoA in
      vitro, but medium-chain acyl-CoA oxidation is the physiological role of MCAD
      (ACADM), not IVD.
    action: MARK_AS_OVER_ANNOTATED
    reason: Hexanoyl-CoA is a weak, promiscuous in-vitro substrate captured only by an
      automated Rhea-to-GO reaction mapping. IVD's physiological function is
      isovaleryl-CoA dehydrogenation in leucine catabolism; annotating a dedicated
      medium-chain acyl-CoA dehydrogenase MF over-states an incidental side activity
      and risks confusion with MCAD.
    supported_by:
    - reference_id: PMID:3597357
      supporting_text: Kinetic parameters Vappmax and Kappm) of these enzymes for
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Bare protein binding from a high-throughput yeast two-hybrid binary
      interactome screen (HuRI), reporting interactions with ACTN3 (Q08043) and GPSM3
      (Q9Y4H4). The term is uninformative about IVD's actual molecular function, and
      the partners are cytoskeletal/G-protein-signaling proteins of unclear
      physiological relevance to a mitochondrial matrix enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic protein binding term (GO:0005515) conveys no functional
      information and derives from a systematic large-scale Y2H hit rather than a
      curated, biologically interpreted interaction. Per curation guidance, bare
      protein binding is not retained as an informative function; it is kept but
      marked as over-annotated rather than removed.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: reference interactome map of human binary protein interactions,
        or 'HuRI'.
- term:
    id: GO:0006552
    label: L-leucine catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: L-leucine catabolic process assigned electronically (UniPathway
      UPA00363). This is the core biological process for IVD and is concordant with
      the experimental (IDA) and phylogenetic (IBA) annotations to the same term.
    action: ACCEPT
    reason: IVD catalyzes a committed step of the leucine degradation pathway; the
      electronic pathway assignment matches the experimentally established role.
    supported_by:
    - reference_id: PMID:2063866
      supporting_text: Isovaleric acidemia (IVA) is an inborn error of leucine metabolism
        and is caused by a genetically determined deficiency of isovaleryl-CoA dehydrogenase
        (IVD)
- term:
    id: GO:0008470
    label: 3-methylbutanoyl-CoA dehydrogenase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9914837
  qualifier: enables
  review:
    summary: Isovaleryl-CoA dehydrogenase activity, from a Reactome pathway describing
      IVD mutants failing to synthesize beta-methylcrotonyl-CoA. Captures the core
      catalytic function.
    action: ACCEPT
    reason: Reactome authoritatively assigns this catalytic activity to IVD, matching
      the direct experimental annotations. Core molecular function.
    supported_by:
    - reference_id: PMID:7640268
      supporting_text: Isovaleryl-CoA dehydrogenase (IVD) is a homotetrameric flavoenzyme
        which catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Mitochondrion localization from Human Protein Atlas immunofluorescence
      (IDA). Correct; consistent with the mitochondrial matrix localization of IVD.
    action: ACCEPT
    reason: Direct immunofluorescence evidence for mitochondrial localization, in
      agreement with the established matrix localization of the enzyme. Broader than
      the matrix term but not incorrect.
    supported_by:
    - reference_id: PMID:2063866
      supporting_text: isovaleryl-CoA dehydrogenase (IVD), a mitochondrial matrix enzyme
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Mitochondrial matrix localization by sequence similarity to rat IVD
      (P12007). Correct, specific compartment for this enzyme.
    action: ACCEPT
    reason: The matrix localization is orthology-conserved and directly supported for
      the human protein. Appropriate specific cellular component term.
    supported_by:
    - reference_id: PMID:2063866
      supporting_text: isovaleryl-CoA dehydrogenase (IVD), a mitochondrial matrix enzyme
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70745
  qualifier: located_in
  review:
    summary: Mitochondrial matrix localization asserted by Reactome for the
      isovaleryl-CoA dehydrogenation reaction. Correct compartment.
    action: ACCEPT
    reason: Reactome places the IVD-catalyzed reaction in the mitochondrial matrix,
      consistent with the biochemical and orthology evidence.
    supported_by:
    - reference_id: PMID:2063866
      supporting_text: isovaleryl-CoA dehydrogenase (IVD), a mitochondrial matrix enzyme
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9914837
  qualifier: located_in
  review:
    summary: Mitochondrial matrix localization asserted by Reactome (isovaleric
      acidemia pathway). Correct compartment for IVD.
    action: ACCEPT
    reason: Reactome localizes IVD to the mitochondrial matrix, in agreement with the
      established subcellular location. Duplicate of the other matrix annotations,
      which is acceptable.
    supported_by:
    - reference_id: PMID:2063866
      supporting_text: isovaleryl-CoA dehydrogenase (IVD), a mitochondrial matrix enzyme
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: Mitochondrion localization from a high-throughput, high-confidence human
      mitochondrial proteome study (MitoCoP). Consistent with the known mitochondrial
      matrix localization of IVD.
    action: ACCEPT
    reason: IVD is confidently detected in a rigorously defined mitochondrial proteome,
      corroborating its mitochondrial localization. Broader than the matrix term but
      correct.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP).
- term:
    id: GO:0006552
    label: L-leucine catabolic process
  evidence_type: IDA
  original_reference_id: PMID:7640268
  qualifier: involved_in
  review:
    summary: Direct experimental evidence (active-site characterization of human IVD)
      that IVD converts isovaleryl-CoA to 3-methylcrotonyl-CoA, the step of leucine
      catabolism. Core biological process.
    action: ACCEPT
    reason: The physiological role in leucine degradation is established by direct
      enzymology on the human protein and is the defining function of IVD.
    supported_by:
    - reference_id: PMID:7640268
      supporting_text: Isovaleryl-CoA dehydrogenase (IVD) is a homotetrameric flavoenzyme
        which catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA.
- term:
    id: GO:0008470
    label: 3-methylbutanoyl-CoA dehydrogenase activity
  evidence_type: IDA
  original_reference_id: PMID:7640268
  qualifier: enables
  review:
    summary: Direct experimental demonstration of isovaleryl-CoA (3-methylbutanoyl-CoA)
      dehydrogenase activity for the human enzyme, including identification of the
      catalytic active-site glutamate by site-directed mutagenesis. This is the core
      molecular function.
    action: ACCEPT
    reason: Gold-standard experimental evidence - recombinant wild-type IVD is most
      active on isovaleryl-CoA, and mutation of the catalytic glutamate abolishes
      activity, directly establishing the enzyme's molecular function.
    supported_by:
    - reference_id: PMID:7640268
      supporting_text: Isovaleryl-CoA dehydrogenase (IVD) is a homotetrameric flavoenzyme
        which catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA.
    - reference_id: PMID:7640268
      supporting_text: The E254G and E254Q mutant IVDs had no detectable
- term:
    id: GO:0009083
    label: branched-chain amino acid catabolic process
  evidence_type: IDA
  original_reference_id: PMID:7640268
  qualifier: involved_in
  review:
    summary: Branched-chain amino acid catabolic process - leucine is a branched-chain
      amino acid, and IVD acts in its degradation. This is a correct parent process of
      the leucine catabolic process annotation.
    action: ACCEPT
    reason: Leucine catabolism (the specific step catalyzed by IVD) is a component of
      branched-chain amino acid catabolism; the annotation is correct, if broader than
      the leucine-specific term.
    supported_by:
    - reference_id: PMID:7640268
      supporting_text: Isovaleryl-CoA dehydrogenase (IVD) is a homotetrameric flavoenzyme
        which catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Identical protein binding (self-association), transferred by similarity
      from rat IVD (P12007). IVD is a homotetramer, so subunit self-association is a
      real structural property.
    action: KEEP_AS_NON_CORE
    reason: Homotetramer formation is directly established by biochemistry and the
      crystal structure, so identical protein binding is biologically real. However it
      describes an oligomerization property rather than the enzyme's core catalytic
      function; kept as a supporting, non-core annotation.
    supported_by:
    - reference_id: PMID:3597357
      supporting_text: indicating a homotetrameric
    - reference_id: PMID:7640268
      supporting_text: Isovaleryl-CoA dehydrogenase (IVD) is a homotetrameric flavoenzyme
- term:
    id: GO:0008470
    label: 3-methylbutanoyl-CoA dehydrogenase activity
  evidence_type: IDA
  original_reference_id: PMID:3597357
  qualifier: enables
  review:
    summary: Isovaleryl-CoA dehydrogenase activity demonstrated on IVD purified to
      homogeneity from human liver; the product of the isovaleryl-CoA reaction was
      identified as 3-methylcrotonyl-CoA. Core molecular function.
    action: ACCEPT
    reason: Direct biochemical evidence from the purified human enzyme identifies the
      isovaleryl-CoA to 3-methylcrotonyl-CoA reaction, confirming the core catalytic
      activity of IVD.
    supported_by:
    - reference_id: PMID:3597357
      supporting_text: IV dehydrogenase/isovaleryl-CoA reactions were identified as
        crotonyl-CoA,
- term:
    id: GO:0033539
    label: fatty acid beta-oxidation using acyl-CoA dehydrogenase
  evidence_type: IDA
  original_reference_id: PMID:3597357
  qualifier: involved_in
  review:
    summary: Fatty acid beta-oxidation using acyl-CoA dehydrogenase, from a study
      characterizing IVD alongside short- and medium-chain acyl-CoA dehydrogenases and
      showing it uses ETF as electron acceptor. IVD contributes to this only via its
      minor short-chain acyl-CoA dehydrogenase activity.
    action: KEEP_AS_NON_CORE
    reason: The purified enzyme does act on short-chain saturated acyl-CoA substrates
      and uses ETF, so a peripheral role in the first (dehydrogenation) step of
      fatty-acid beta-oxidation is plausible. However, IVD's physiological role is
      leucine catabolism, not beta-oxidation, and dedicated short/medium-chain ACADs
      (ACADS, ACADM) carry out this step in vivo; retained as a non-core annotation.
    supported_by:
    - reference_id: PMID:3597357
      supporting_text: They all utilized electron transfer flavoprotein (ETF) or phenazine
        methosulfate (PMS) as an electron acceptor.
- term:
    id: GO:0006552
    label: L-leucine catabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: L-leucine catabolic process by sequence similarity to rat IVD (P12007).
      Concordant with the experimental and phylogenetic annotations to the same core
      process.
    action: ACCEPT
    reason: The leucine catabolism role is orthology-conserved and experimentally
      established for human IVD. Correct core biological process.
    supported_by:
    - reference_id: PMID:2063866
      supporting_text: Isovaleric acidemia (IVA) is an inborn error of leucine metabolism
        and is caused by a genetically determined deficiency of isovaleryl-CoA dehydrogenase
        (IVD)
- term:
    id: GO:0008470
    label: 3-methylbutanoyl-CoA dehydrogenase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Isovaleryl-CoA dehydrogenase activity by sequence similarity to rat IVD
      (P12007). Concordant with the direct experimental annotations. Core molecular
      function.
    action: ACCEPT
    reason: The catalytic activity is orthology-conserved and directly demonstrated
      for the human enzyme; correct core function at the appropriate specificity.
    supported_by:
    - reference_id: PMID:7640268
      supporting_text: Isovaleryl-CoA dehydrogenase (IVD) is a homotetrameric flavoenzyme
        which catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: NAS
  original_reference_id: PMID:2063866
  qualifier: located_in
  review:
    summary: Mitochondrial matrix localization, stated in a study of IVD mutations in
      isovaleric acidemia which describes IVD as a mitochondrial matrix enzyme imported
      as a precursor and processed to its mature form. Correct compartment.
    action: ACCEPT
    reason: The cited paper explicitly identifies IVD as a mitochondrial matrix enzyme,
      supporting the specific subcellular localization.
    supported_by:
    - reference_id: PMID:2063866
      supporting_text: isovaleryl-CoA dehydrogenase (IVD), a mitochondrial matrix enzyme
- term:
    id: GO:0008470
    label: 3-methylbutanoyl-CoA dehydrogenase activity
  evidence_type: TAS
  original_reference_id: PMID:3446585
  qualifier: enables
  review:
    summary: Isovaleryl-CoA dehydrogenase activity, from the cDNA-cloning and
      chromosome-15-assignment study that molecularly identified the IVD gene. A
      traceable author statement of the gene's enzymatic identity. Core molecular
      function.
    action: ACCEPT
    reason: This foundational paper cloned the isovaleryl-CoA dehydrogenase cDNA and
      assigned the gene, providing a traceable basis for the enzyme's identity. The
      activity is amply confirmed by later direct assays; retained as a valid TAS for
      the core function.
    supported_by:
    - reference_id: PMID:3446585
      supporting_text: the isovaleryl-CoA dehydrogenase gene
core_functions:
- description: FAD-dependent dehydrogenation of isovaleryl-CoA (3-methylbutanoyl-CoA)
    to 3-methylcrotonyl-CoA in the mitochondrial matrix, the committed dehydrogenation
    step of leucine catabolism, transferring electrons to the electron-transfer
    flavoprotein (ETF).
  molecular_function:
    id: GO:0008470
    label: 3-methylbutanoyl-CoA dehydrogenase activity
  directly_involved_in:
  - id: GO:0006552
    label: L-leucine catabolic process
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: PMID:7640268
    supporting_text: Isovaleryl-CoA dehydrogenase (IVD) is a homotetrameric flavoenzyme
      which catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA.
  - reference_id: PMID:3597357
    supporting_text: IV dehydrogenase/isovaleryl-CoA reactions were identified as
      crotonyl-CoA,
suggested_questions:
- question: Beyond isovaleryl-CoA, does IVD make any physiologically meaningful
    contribution to short-chain fatty acid beta-oxidation in vivo, or is its
    short/medium-chain acyl-CoA activity purely an in-vitro promiscuity redundant
    with ACADS/ACADM?
- question: Are the reported binary interactions with ACTN3 and GPSM3 (from
    high-throughput Y2H) reproducible and physiologically relevant, or are they
    screen artifacts unrelated to the mitochondrial matrix localization of IVD?
suggested_experiments:
- description: Quantify the in-vivo flux contribution of IVD to short-chain acyl-CoA
    dehydrogenation using stable-isotope-labeled substrates in IVD-null versus
    ACADS/ACADM-null cells, to test whether its short-chain activity is
    physiologically significant.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:2063866
  title: Molecular characterization of four different classes of mutations in the
    isovaleryl-CoA dehydrogenase gene responsible for isovaleric acidemia.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; establishes IVD as a mitochondrial matrix enzyme
      and that its deficiency causes isovaleric acidemia (leucine metabolism disorder).
      Used as source for matrix localization (NAS) and the leucine-catabolism role.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified HuRI interactome paper. Correctly cited for the IPI
      protein-binding annotation (ACTN3, GPSM3), but these are high-throughput binary
      Y2H hits of unclear physiological relevance to a mitochondrial matrix enzyme;
      supports only a generic, over-annotated protein binding term.
- id: PMID:3446585
  title: Isolation of cDNA clones coding for rat isovaleryl-CoA dehydrogenase and
    assignment of the gene to human chromosome 15.
  findings: []
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
- id: PMID:3597357
  title: Purification and properties of short chain acyl-CoA, medium chain acyl-CoA,
    and isovaleryl-CoA dehydrogenases from human liver.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. Purified human IVD to homogeneity, identified the
      isovaleryl-CoA reaction product as 3-methylcrotonyl-CoA, showed homotetrameric
      structure with 1 FAD/subunit and ETF as electron acceptor. Anchors the core MF,
      FAD binding, homotetramer, and the minor short-chain activity annotations.
- id: PMID:7640268
  title: Identification of the active site catalytic residue in human isovaleryl-CoA
    dehydrogenase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. Defines the catalytic active-site glutamate by
      mutagenesis and confirms isovaleryl-CoA dehydrogenase activity of the human
      enzyme; the UniProt evidence for FUNCTION and EC 1.3.8.4/1.3.8.1. Primary source
      for the core molecular function.
- id: Reactome:R-HSA-70745
  title: isovaleryl-CoA + FAD => beta-methylcrotonyl-CoA + FADH2
  findings: []
- id: Reactome:R-HSA-9914837
  title: IVD mutants don't synthesize beta-methylcrotonyl-CoA
  findings: []