HIBADH is the mitochondrial-matrix enzyme 3-hydroxyisobutyrate dehydrogenase (EC 1.1.1.31), a homodimeric NAD(+)-dependent oxidoreductase of the HIBADH-related (6-phosphogluconate/3-hydroxyisobutyrate dehydrogenase) family with a Rossmann-fold NAD-binding domain. It catalyzes the reversible oxidation of 3-hydroxyisobutyrate (3-hydroxy-2-methylpropanoate) to methylmalonate semialdehyde (2-methyl-3-oxopropanoate) with reduction of NAD(+) to NADH, a step in the mitochondrial catabolism of the branched-chain amino acid L-valine. The methylmalonate-semialdehyde product is subsequently metabolized by methylmalonate-semialdehyde dehydrogenase (ALDH6A1). The protein is synthesized as a precursor with an N-terminal transit peptide that is cleaved on import into the mitochondrial matrix. It is broadly expressed, with notable activity in liver and fibroblasts.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (PAN-GO) inference of mitochondrial localization, consistent with the UniProt subcellular location and the N-terminal mitochondrial transit peptide. Correct but non-core relative to the more specific mitochondrial matrix term. Reason: Localization is well supported (UniProt "Mitochondrion"; transit peptide 1-36), but the specific compartment is the mitochondrial matrix (GO:0005759, Reactome TAS), which is the core location for this soluble matrix enzyme. Supporting Evidence: file:human/HIBADH/HIBADH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion. |
| GO:0006574 L-valine catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that HIBADH acts in valine catabolism, in agreement with the experimental IDA annotation and the UniProt pathway assignment. Reason: Consistent with the directly demonstrated valine-degradation role (PMID:16466957) and the UniProt PATHWAY statement. Supporting Evidence: file:human/HIBADH/HIBADH-uniprot.txt PATHWAY: Amino-acid degradation; L-valine degradation. |
| GO:0008442 3-hydroxyisobutyrate dehydrogenase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of the diagnostic enzymatic activity, redundant with and corroborated by the experimental IDA annotation. Reason: Matches the directly demonstrated 3-hydroxyisobutyrate dehydrogenase activity (PMID:16466957) and the UniProt catalytic activity / EC 1.1.1.31. Supporting Evidence: file:human/HIBADH/HIBADH-uniprot.txt Reaction=3-hydroxy-2-methylpropanoate + NAD(+) = 2-methyl-3- |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic subcellular-location inference (UniProt SubCell mapping), consistent with the authoritative UniProt "Mitochondrion" location. Correct but non-core relative to mitochondrial matrix. Reason: Redundant with the more specific matrix location; retained as corroborating localization. Supporting Evidence: file:human/HIBADH/HIBADH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion. |
| GO:0008442 3-hydroxyisobutyrate dehydrogenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic inference of the enzymatic activity from InterPro IPR011548 / Rhea:17681 / EC 1.1.1.31; concordant with the experimental IDA annotation. Reason: Correctly assigns the diagnostic activity; supported experimentally by PMID:16466957 and by the UniProt catalytic-activity statement. Supporting Evidence: file:human/HIBADH/HIBADH-uniprot.txt EC=1.1.1.31 |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO assignment of the generic parent activity. Not wrong, but far less informative than the specific, experimentally supported 3-hydroxyisobutyrate dehydrogenase activity (GO:0008442) that is also annotated. Reason: Over-general: the specific molecular function GO:0008442 is already annotated (IDA) and should be used; a bare oxidoreductase-activity term adds no functional specificity. |
| GO:0050661 NADP binding | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO assignment (IPR006115, a 6-phosphogluconate-dehydrogenase-like NADP-binding signature) generically maps to NADP binding. HIBADH's physiological cofactor is NAD(+), not NADP; the catalytic reaction and the structurally resolved cofactor (PDB 2GF2, NADH complex) use NAD. Reason: Over-propagated from the shared Rossmann/6PGD-like fold. The demonstrated reaction uses NAD(+) (Rhea:17681; UniProt catalytic activity), and there is no evidence for NADP as a physiological cofactor. Retained (electronic, not experimental) but flagged as an over-annotation; NAD binding (GO:0051287) is the appropriate cofactor-binding term. Supporting Evidence: file:human/HIBADH/HIBADH-uniprot.txt Reaction=3-hydroxy-2-methylpropanoate + NAD(+) = 2-methyl-3- |
| GO:0051287 NAD binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO assignment of NAD binding, concordant with the NAD(+)-dependent catalytic reaction and with multiple structurally resolved NAD(+)-binding residues in the crystal structure (PDB 2GF2). Reason: NAD(+) is the physiological cofactor (Rhea:17681; EC 1.1.1.31), and UniProt records explicit NAD(+) BINDING sites from the crystal structure. This is a core cofactor-binding function. Supporting Evidence: file:human/HIBADH/HIBADH-uniprot.txt BINDING 40..68 |
| 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 the HuRI high-throughput binary (Y2H) interactome. The ~40 IntAct partners recorded in UniProt (e.g. ADAM33, AQP3, VAMP2/5, GOSR2, SEC22B, TFRC, TMEM-family proteins) are predominantly membrane/secretory-pathway proteins with no plausible physiological relationship to a soluble mitochondrial-matrix metabolic enzyme. The term is uninformative and the interactions are not established as biologically meaningful. Reason: Uninformative bare protein-binding term from a large-scale Y2H screen; conveys no specific molecular function. Per policy, an experimental IPI is not removed but is flagged as over-annotated. |
| GO:0006574 L-valine catabolic process | IEA GO_REF:0000041 | ACCEPT | Summary: UniPathway (UPA00362) electronic mapping to L-valine catabolic process, concordant with the experimental IDA annotation and the UniProt PATHWAY statement. Reason: Correct pathway assignment, independently supported experimentally (PMID:16466957). Supporting Evidence: file:human/HIBADH/HIBADH-uniprot.txt PATHWAY: Amino-acid degradation; L-valine degradation. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | KEEP AS NON CORE | Summary: High-throughput mitochondrial-proteome evidence (high-confidence human mitochondrial proteome) placing HIBADH in mitochondria. Consistent with the authoritative UniProt location and the transit peptide. Reason: Corroborates mitochondrial localization but is less specific than the mitochondrial matrix (GO:0005759) core location. Supporting Evidence: file:human/HIBADH/HIBADH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-508473 | ACCEPT | Summary: Reactome traceable assertion that HIBADH functions in the mitochondrial matrix (reverse reaction, methylmalonyl semialdehyde + NADH -> beta- hydroxyisobutyrate + NAD+). This is the correct specific compartment for this soluble matrix enzyme. Reason: Matrix localization is the appropriate specific location for a soluble valine-catabolism enzyme imported via a cleaved transit peptide. Supporting Evidence: file:human/HIBADH/HIBADH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-70885 | ACCEPT | Summary: Reactome traceable assertion (forward reaction, beta-hydroxyisobutyrate + NAD+ -> methylmalonyl semialdehyde + NADH) localizing HIBADH to the mitochondrial matrix. Duplicate of the matrix annotation from the reverse- direction reaction and equally valid. Reason: Correct specific location; consistent with UniProt mitochondrial location and the matrix nature of the valine-catabolism pathway. Supporting Evidence: file:human/HIBADH/HIBADH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion. |
| GO:0006574 L-valine catabolic process | IDA PMID:16466957 Clinical, biochemical, and molecular findings in three patie... | ACCEPT | Summary: Direct experimental assignment of HIBADH to L-valine degradation. Loupatty et al. cloned the human HIBADH cDNA, expressed it in E. coli, and confirmed 3-hydroxyisobutyrate dehydrogenase activity; UniProt cites this paper for the L-valine degradation PATHWAY. This is a core biological process. Reason: Experimentally grounded (heterologous expression demonstrating the valine-catabolism enzyme activity); anchors the gene's core role in branched-chain amino acid / valine catabolism. Supporting Evidence: PMID:16466957 the product of the HIBADH gene indeed displays 3-hydroxyisobutyrate dehydrogenase activity file:human/HIBADH/HIBADH-uniprot.txt PATHWAY: Amino-acid degradation; L-valine degradation. |
| GO:0008442 3-hydroxyisobutyrate dehydrogenase activity | IDA PMID:16466957 Clinical, biochemical, and molecular findings in three patie... | ACCEPT | Summary: Direct experimental demonstration of the molecular function: the HIBADH gene product expressed in E. coli displays 3-hydroxyisobutyrate dehydrogenase activity. This is the core molecular function, matching EC 1.1.1.31 and the UniProt catalytic-activity statement. Reason: Primary experimental evidence for the diagnostic NAD(+)-dependent 3-hydroxyisobutyrate dehydrogenase activity; the defining core function of the gene. Supporting Evidence: PMID:16466957 the product of the HIBADH gene indeed displays 3-hydroxyisobutyrate dehydrogenase activity file:human/HIBADH/HIBADH-uniprot.txt Reaction=3-hydroxy-2-methylpropanoate + NAD(+) = 2-methyl-3- |
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)