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.
| 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 |
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Download this section (compressed HTML)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?
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.
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