HADH encodes a soluble mitochondrial matrix 3-hydroxyacyl-CoA dehydrogenase that functions as a homodimer. It catalyzes the NAD+-dependent oxidation of L-(3S)-3-hydroxyacyl-CoA to 3-ketoacyl-CoA, the third reaction of mitochondrial fatty-acid beta-oxidation, with a preference for short- and medium-chain substrates. Structural studies support a histidine general base assisted by a neighboring glutamate in the catalytic mechanism. HADH is expressed in liver, kidney, pancreas, heart and skeletal muscle. It also restrains amino-acid-stimulated insulin secretion through an inhibitory association with glutamate dehydrogenase (GLUD1), a mechanism characterized in mouse pancreatic islets. Loss of this regulatory interaction provides an explanation for the hyperinsulinaemic hypoglycaemia associated with biallelic human HADH defects. The dehydrogenase reaction and inhibition of GLUD1 represent distinct molecular roles; the regulatory interaction is less directly characterized in human beta-cells.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003857 (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred core molecular function. This is the defining catalytic activity of HADH/SCHAD, directly demonstrated for the human enzyme by purified-protein biochemistry and crystallography and by patient-mutant expression studies. The IBA call is at the correct level of specificity and is strongly corroborated by experimental annotations on the same term. Reason: Bona fide enzymatic function supported across the 3-hydroxyacyl-CoA dehydrogenase family and by direct human experimental data (PMID:10231530, PMID:11489939, PMID:16725361). Supporting Evidence: PMID:10231530 catalyzes the oxidation of the hydroxyl group of L-3-hydroxyacyl-CoA to a keto group, concomitant with the reduction of NAD+ to NADH |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Mitochondrial localization is consistent with the matrix location in which HADH performs beta-oxidation. The more precise matrix annotation is also retained. Reason: This is a correct location of a core function. A broader location is not non-core merely because a more specific child term is available. UniProt assigns the mitochondrial matrix location and the human cloning study identifies a mitochondrial import peptide (PMID:8687463). Supporting Evidence: file:human/HADH/HADH-uniprot.txt Mitochondrion matrix |
| GO:0006635 fatty acid beta-oxidation | IBA GO_REF:0000033 | ACCEPT | Summary: Core biological process. HADH catalyzes the third step of the mitochondrial beta-oxidation cycle; this is its principal pathway role, supported by enzymology, the UniProt-curated pathway assignment, and patient deficiency phenotypes. Reason: Directly supported by experimental data and UniProt pathway curation (lipid metabolism; fatty acid beta-oxidation). Supporting Evidence: PMID:11489939 This is the first defect in fatty acid beta-oxidation that has been associated with hyperinsulinism |
| GO:0003857 (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (multi-method) inference of the core catalytic activity. Redundant with the experimental and IBA annotations on the same term and correct. Reason: Same correct molecular function as the experimentally supported annotation. |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt places HADH in the mitochondrial matrix, the compartment of its beta-oxidation reaction. The Reactome location assertions are consistent with that assignment; a mitochondrial proteomics annotation is broader and does not itself establish matrix sublocalization. Reason: Matches the curated UniProt 'Mitochondrion matrix' location and is the most precise localization for HADH. Supporting Evidence: file:human/HADH/HADH-uniprot.txt Mitochondrion matrix |
| GO:0006631 fatty acid metabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: HADH directly participates in fatty acid metabolism by catalyzing the third reaction of mitochondrial beta-oxidation. Reason: This pathway-level process describes the metabolic role of the demonstrated hydroxyacyl-CoA oxidation reaction. It is retained alongside the more specific beta-oxidation process; it is not a competing molecular-function classification (PMID:10231530). Supporting Evidence: PMID:10231530 catalyzes the oxidation of the hydroxyl group of L-3-hydroxyacyl-CoA to a keto group, concomitant with the reduction of NAD+ to NADH |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000002 | MODIFY | Summary: HADH is an oxidoreductase, but the experimentally supported hydroxyacyl-CoA reaction provides a more informative molecular-function term. Reason: Refine this valid broad enzyme-class assertion to GO:0003857, (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity, which HADH already carries with experimental support. This is a specificity correction, not a rejection of the InterPro inference or of oxidoreductase chemistry. Proposed replacements: (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity Supporting Evidence: PMID:10231530 catalyzes the oxidation of the hydroxyl group of L-3-hydroxyacyl-CoA to a keto group, concomitant with the reduction of NAD+ to NADH |
| GO:0016509 long-chain (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity | IEA GO_REF:0000116 | MARK AS OVER ANNOTATED | Summary: Pig HADH has experimentally measured long-chain substrate activity, and human UniProt transfers the C16 reaction by similarity. This supports biochemical capability but does not establish a physiological long-chain role for human HADH. Reason: GO:0016509 covers 13–22-carbon substrates; RHEA:31159 is the C16 hydroxyhexadecanoyl-CoA reaction transferred from pig P00348. The inspected PMID:2817332 abstract reports medium-chain preference and similar medium/long-chain Km values, but these do not establish comparable catalytic efficiency or a physiological human long-chain contribution. Mark the inferred functional assignment as over-annotated rather than retaining it as a demonstrated secondary physiological role. The closest ENZYME_SPECIFICITY rationale is in vitro activity of uncertain functional relevance; its no-alternative-enzyme condition is not met because HADHA supplies the dedicated long-chain pathway step. Do not call the observed pig activity absent or assay noise, and do not infer a wrong-paralog transfer. Full kinetic tables were not inspected. Supporting Evidence: PMID:2817332 most active with medium-chain substrates file:human/HADH/HADH-uniprot.txt Reaction=(3S)-hydroxyhexadecanoyl-CoA + NAD(+) = 3-oxohexadecanoyl-CoA PMID:2817332 Km values for medium-chain and long-chain substrates are almost equal |
| GO:0016616 oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor | IEA GO_REF:0000002 | MODIFY | Summary: HADH oxidizes a substrate CH-OH group using NAD+, and its identified hydroxyacyl-CoA substrate permits a more specific activity assignment. Reason: Refine the donor/acceptor-class term to the experimentally supported GO:0003857 already present in this review. The broader chemistry is correct, but the named substrate and NAD+ cofactor support the more precise dehydrogenase term. Proposed replacements: (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity Supporting Evidence: PMID:10231530 catalyzes the oxidation of the hydroxyl group of L-3-hydroxyacyl-CoA to a keto group, concomitant with the reduction of NAD+ to NADH |
| GO:0070403 NAD+ binding | IEA GO_REF:0000002 | ACCEPT | Summary: HADH binds NAD+ as the oxidizing cofactor of its core dehydrogenase reaction. The structural study describes cofactor-bound and substrate/ternary complexes. Reason: Cofactor binding is directly coupled to the core catalytic function; retain the existing electronic and experimental assertions without proposing redundant new terms (PMID:10840044). Supporting Evidence: PMID:10840044 significant shifting of the NAD(+)-binding domain relative to the C-terminal domain occurs in the ternary and substrate-bound complexes |
| GO:0005739 mitochondrion | IEA GO_REF:0000107 | ACCEPT | Summary: Mitochondrial localization is consistent with the matrix location in which HADH performs beta-oxidation. The more precise matrix annotation is also retained. Reason: This is a correct location of a core function. A broader location is not non-core merely because a more specific child term is available. UniProt assigns the mitochondrial matrix location and the human cloning study identifies a mitochondrial import peptide (PMID:8687463). Supporting Evidence: file:human/HADH/HADH-uniprot.txt Mitochondrion matrix |
| GO:0006635 fatty acid beta-oxidation | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic inference of the core beta-oxidation process, redundant with and consistent with the experimental (IDA) and IBA annotations on this term. Reason: Correct core biological process supported by experimental evidence. |
| GO:0009410 response to xenobiotic stimulus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Fenofibrate increased measured hydroxyacyl-CoA dehydrogenase activity in rat skeletal muscle. RGD assigns the response to rat Hadh/Q9WVK7, from which the human annotation is transferred. Reason: The RGD source annotation and its cited rat experiment provide positive support for a contextual response, rather than a new catalytic activity or a hormone/receptor function. Retain as non-core with the species and experimental setting explicit; this does not establish the same response directly in human tissue (PMID:12176671). The inspected abstract reports tissue-level enzyme measurements and does not expose substrate or isozyme-selectivity methods; it therefore does not independently resolve HADH from HADHA or other contributors. Retention follows the RGD gene attribution with this limitation, not a claim that isozyme-specific evidence was independently verified. Supporting Evidence: PMID:12176671 significantly increased by fenofibrate treatment |
| GO:0009725 response to hormone | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Low-dose growth hormone increased measured hydroxyacyl-CoA dehydrogenase in myocardium of rats with heart failure. RGD assigns the response to rat Hadh/Q9WVK7, from which the human annotation is transferred. Reason: The RGD source annotation and its cited rat experiment provide positive support for a contextual response, rather than a new catalytic activity or a hormone/receptor function. Retain as non-core with the species and experimental setting explicit; this does not establish the same response directly in human tissue (PMID:18191600). The inspected abstract reports tissue-level enzyme measurements and does not expose substrate or isozyme-selectivity methods; it therefore does not independently resolve HADH from HADHA or other contributors. Retention follows the RGD gene attribution with this limitation, not a claim that isozyme-specific evidence was independently verified. Supporting Evidence: PMID:18191600 were higher in HF-GH1 than in HF |
| GO:0014823 response to activity | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Exercise training increased measured hydroxyacyl-CoA dehydrogenase activity in rat gastrocnemius and soleus. RGD assigns the response to rat Hadh/Q9WVK7, from which the human annotation is transferred. Reason: The RGD source annotation and its cited rat experiment provide positive support for a contextual response, rather than a new catalytic activity or a hormone/receptor function. Retain as non-core with the species and experimental setting explicit; this does not establish the same response directly in human tissue (PMID:8231758). The inspected abstract reports tissue-level enzyme measurements and does not expose substrate or isozyme-selectivity methods; it therefore does not independently resolve HADH from HADHA or other contributors. Retention follows the RGD gene attribution with this limitation, not a claim that isozyme-specific evidence was independently verified. Supporting Evidence: PMID:8231758 3-hydroxyacyl-CoA-dehydrogenase (HADH) activities in the gastrocnemius (G) and soleus (S) |
| GO:0032868 response to insulin | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Insulin treatment normalized elevated hydroxyacyl-CoA dehydrogenase activity in diabetic rat diaphragm. RGD assigns the response to rat Hadh/Q9WVK7, from which the human annotation is transferred. Reason: The RGD source annotation and its cited rat experiment provide positive support for a contextual response, rather than a new catalytic activity or a hormone/receptor function. Retain as non-core with the species and experimental setting explicit; this does not establish the same response directly in human tissue (PMID:7050060). The inspected abstract reports tissue-level enzyme measurements and does not expose substrate or isozyme-selectivity methods; it therefore does not independently resolve HADH from HADHA or other contributors. Retention follows the RGD gene attribution with this limitation, not a claim that isozyme-specific evidence was independently verified. Supporting Evidence: PMID:7050060 returned to normal with insulin treatment |
| GO:0046676 negative regulation of insulin secretion | IEA GO_REF:0000107 | ACCEPT | Summary: HADH has an additional regulatory role that restrains insulin secretion. Mouse Hadh loss activates glutamate dehydrogenase and causes amino-acid-sensitive insulin hypersecretion; human HADH deficiency can also cause hyperinsulinism, although the reported phenotypes are not uniform. Reason: This is a distinct regulatory function represented in core_functions, not non-core solely because HADH is also a beta-oxidation enzyme. The inhibitory mechanism is established chiefly in mouse islets and transferred to human by orthology; the existing broader regulation terms are valid alongside negative regulation (PMID:20670938). Supporting Evidence: PMID:21990309 insulin secretion in response to glucose and glucose plus palmitate was elevated in isolated islets of knockout mice PMID:20670938 reflecting the loss of an inhibitory protein-protein interaction of SCHAD upon GDH |
| GO:0050796 regulation of insulin secretion | IEA GO_REF:0000107 | ACCEPT | Summary: HADH has an additional regulatory role that restrains insulin secretion. Mouse Hadh loss activates glutamate dehydrogenase and causes amino-acid-sensitive insulin hypersecretion; human HADH deficiency can also cause hyperinsulinism, although the reported phenotypes are not uniform. Reason: This is a distinct regulatory function represented in core_functions, not non-core solely because HADH is also a beta-oxidation enzyme. The inhibitory mechanism is established chiefly in mouse islets and transferred to human by orthology; the existing broader regulation terms are valid alongside negative regulation (PMID:20670938). Supporting Evidence: PMID:20670938 reflecting the loss of an inhibitory protein-protein interaction of SCHAD upon GDH |
| GO:0120162 positive regulation of cold-induced thermogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Based on the mouse Hadh knockout phenotype (impaired cold tolerance / adaptive thermogenesis). This is a downstream physiological consequence of impaired fatty-acid oxidation rather than a distinct molecular function of HADH; appropriate to retain as a non-core, organism-level process. Reason: Mouse-derived physiological phenotype downstream of FAO; non-core. Supporting Evidence: PMID:21990309 SCHAD plays an important role in adaptive thermogenesis |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Mitochondrial localization is consistent with the matrix location in which HADH performs beta-oxidation. The more precise matrix annotation is also retained. Reason: This is a correct location of a core function. A broader location is not non-core merely because a more specific child term is available. UniProt assigns the mitochondrial matrix location and the human cloning study identifies a mitochondrial import peptide (PMID:8687463). Supporting Evidence: file:human/HADH/HADH-uniprot.txt Mitochondrion matrix |
| GO:0003857 (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity | EXP PMID:10231530 Biochemical characterization and crystal structure determina... | ACCEPT | Summary: Recombinant human heart SCHAD was characterized by enzymology and an NAD+-bound crystal structure. Substrate positioning in this paper was modeled; actual substrate and ternary complex structures were reported in the later PMID:10840044 study. Reason: Direct human enzyme biochemistry supports the core dehydrogenase activity (PMID:10231530). Supporting Evidence: PMID:10231530 catalyzes the oxidation of the hydroxyl group of L-3-hydroxyacyl-CoA to a keto group, concomitant with the reduction of NAD+ to NADH |
| GO:0003857 (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity | EXP PMID:16725361 Reye-like syndrome resulting from novel missense mutations i... | ACCEPT | Summary: Human patient variants were expressed and assayed: D45G altered NADH Km and Y214H had no detectable activity in the paper’s mature-chain numbering, corresponding to canonical precursor D57G and Y226H. These are separate from the P258L variant, whose published number already refers to the precursor. Reason: Independent experimental confirmation of the core dehydrogenase activity through mutant enzymology. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: GOA cites PMID:34800366 for this mitochondrial proteomics annotation. The mitochondrial location is independently consistent with UniProt and the targeting sequence; the HADH-specific supplementary proteomic row has not been independently inspected. Reason: This is a correct location of a core function. A broader location is not non-core merely because a more specific child term is available. UniProt assigns the mitochondrial matrix location and the human cloning study identifies a mitochondrial import peptide (PMID:8687463). The cited study is retained as curated GOA evidence, not claimed as an independently verified HADH-specific detection from its title or main article text. Supporting Evidence: file:human/HADH/HADH-uniprot.txt Mitochondrion matrix |
| GO:0050796 regulation of insulin secretion | ISS GO_REF:0000024 | ACCEPT | Summary: HADH has an additional regulatory role that restrains insulin secretion. Mouse Hadh loss activates glutamate dehydrogenase and causes amino-acid-sensitive insulin hypersecretion; human HADH deficiency can also cause hyperinsulinism, although the reported phenotypes are not uniform. Reason: This is a distinct regulatory function represented in core_functions, not non-core solely because HADH is also a beta-oxidation enzyme. The inhibitory mechanism is established chiefly in mouse islets and transferred to human by orthology; the existing broader regulation terms are valid alongside negative regulation (PMID:20670938). Supporting Evidence: PMID:21990309 Blood glucose concentrations in the fasted and postprandial state were significantly lower in hadh(-/-) mice, whereas insulin levels were elevated PMID:20670938 reflecting the loss of an inhibitory protein-protein interaction of SCHAD upon GDH |
| GO:0070403 NAD+ binding | IDA PMID:10840044 Sequestration of the active site by interdomain shifting. Cr... | ACCEPT | Summary: HADH binds NAD+ as the oxidizing cofactor of its core dehydrogenase reaction. The structural study describes cofactor-bound and substrate/ternary complexes. Reason: Cofactor binding is directly coupled to the core catalytic function; retain the existing electronic and experimental assertions without proposing redundant new terms (PMID:10840044). Supporting Evidence: PMID:10840044 significant shifting of the NAD(+)-binding domain relative to the C-terminal domain occurs in the ternary and substrate-bound complexes |
| GO:0042802 identical protein binding | IDA PMID:10231530 Biochemical characterization and crystal structure determina... | KEEP AS NON CORE | Summary: Reflects the fact that HADH is an homodimer, established by crystallography and biochemistry. This is a quaternary-structure descriptor ('identical protein binding') rather than the bare uninformative 'protein binding', and it is experimentally grounded. It is not, however, a core catalytic/regulatory function in its own right. Reason: Experimentally supported self-association (homodimerization); structural property rather than a core function. Supporting Evidence: PMID:10231530 The homodimeric enzyme has been overexpressed in Escherichia coli, purified to homogeneity |
| GO:0003857 (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity | IDA PMID:11489939 Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydroge... | ACCEPT | Summary: Direct assay of the core activity in patient material and recombinant enzyme: SCHAD activity was markedly reduced in patient fibroblast mitochondria and the P258L variant had no catalytic activity, confirming HADH as the enzyme catalyzing this reaction. Reason: Experimental loss-of-function evidence directly tying HADH to the 3-hydroxyacyl-CoA dehydrogenase activity. Supporting Evidence: PMID:11489939 Expression studies showed that the P258L enzyme had no catalytic activity |
| GO:0006635 fatty acid beta-oxidation | IDA PMID:11489939 Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydroge... | ACCEPT | Summary: Direct evidence linking HADH to beta-oxidation: deficiency produces a fatty-acid-oxidation disorder with characteristic 3-hydroxy-acylcarnitine accumulation, the first FAO defect associated with hyperinsulinism. Reason: Experimentally supported core biological process (beta-oxidation). Supporting Evidence: PMID:11489939 This is the first defect in fatty acid beta-oxidation that has been associated with hyperinsulinism |
| GO:0120162 positive regulation of cold-induced thermogenesis | ISS PMID:21990309 Role of medium- and short-chain L-3-hydroxyacyl-CoA dehydrog... | KEEP AS NON CORE | Summary: Sequence-similarity annotation citing the mouse Hadh knockout thermogenesis phenotype. Downstream physiological consequence of impaired fatty-acid oxidation rather than a distinct molecular function; retain as non-core. Reason: Mouse-derived organismal phenotype downstream of FAO; non-core. Supporting Evidence: PMID:21990309 SCHAD plays an important role in adaptive thermogenesis |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-77254 | ACCEPT | Summary: Reactome traceable assertion placing HADH in the mitochondrial matrix as part of a beta-oxidation reaction (3-hydroxydodecanoyl-CoA oxidation). Correct, specific localization consistent with UniProt. Reason: Correct, specific mitochondrial matrix localization from curated pathway data. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-77312 | ACCEPT | Summary: Reactome matrix localization within the short-chain (3-hydroxybutanoyl-CoA) beta-oxidation reaction. Correct and consistent with the curated location. Reason: Correct mitochondrial matrix localization from curated pathway data. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-77323 | ACCEPT | Summary: Reactome matrix localization within the hexanoyl-CoA beta-oxidation reaction. Correct, consistent with curated location. Reason: Correct mitochondrial matrix localization from curated pathway data. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-77331 | ACCEPT | Summary: Reactome matrix localization within the octanoyl-CoA beta-oxidation reaction. Correct, consistent with curated location. Reason: Correct mitochondrial matrix localization from curated pathway data. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-77342 | ACCEPT | Summary: Reactome matrix localization within the decanoyl-CoA beta-oxidation reaction. Correct, consistent with curated location. Reason: Correct mitochondrial matrix localization from curated pathway data. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838035 | ACCEPT | Summary: This Reactome reaction is 'CLPXP binds mitochondrial matrix proteins'; HADH is annotated here as a matrix substrate of the quality-control protease, which correctly localizes it to the matrix. The location assertion is valid; it does not imply any protease/degradation function for HADH itself. Reason: Valid matrix localization arising from HADH being a CLPXP substrate (localization-only, not a HADH function). |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838081 | ACCEPT | Summary: Reactome 'LONP1 degrades mitochondrial matrix proteins'; HADH appears as a matrix substrate, correctly localizing it to the matrix. Location-only evidence, not a degradation function of HADH. Reason: Valid matrix localization from HADH being a LONP1 substrate (localization-only). |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838093 | ACCEPT | Summary: Reactome 'LONP1 binds mitochondrial matrix proteins'; HADH appears as a matrix substrate. Correct localization; location-only, not a HADH function. Reason: Valid matrix localization from HADH being a LONP1 substrate (localization-only). |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838289 | ACCEPT | Summary: Reactome 'CLPXP degrades mitochondrial matrix proteins'; HADH appears as a matrix substrate. Correct localization; location-only, not a HADH function. Reason: Valid matrix localization from HADH being a CLPXP substrate (localization-only). |
| GO:0005737 cytoplasm | IDA GO_REF:0000054 | ACCEPT | Summary: The cytoplasm annotation is compatible with HADH mitochondrial localization: GO:0005737 includes subcellular organelles and is not a synonym of cytosol. Reason: The official GO definition includes subcellular structures. Mitochondrial matrix localization therefore does not contradict cytoplasm. Retain this broad location without inventing a fusion-tag or import artifact; the LIFEdb experiment itself has not been independently re-examined. Supporting Evidence: file:human/HADH/HADH-uniprot.txt Mitochondrion matrix |
| GO:0003857 (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity | TAS PMID:8687463 Human short-chain L-3-hydroxyacyl-CoA dehydrogenase: cloning... | ACCEPT | Summary: Traceable assertion from the original human SCHAD cDNA cloning/characterization paper, which identified the protein as short-chain L-3-hydroxyacyl-CoA dehydrogenase. Correct core molecular function. Reason: Consistent with the experimentally established core dehydrogenase activity. Supporting Evidence: PMID:8687463 The cDNA encompassing the complete coding sequence of human liver short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) was isolated and characterized |
| GO:0005739 mitochondrion | TAS PMID:8687463 Human short-chain L-3-hydroxyacyl-CoA dehydrogenase: cloning... | ACCEPT | Summary: Mitochondrial localization is consistent with the matrix location in which HADH performs beta-oxidation. The more precise matrix annotation is also retained. Reason: This is a correct location of a core function. A broader location is not non-core merely because a more specific child term is available. UniProt assigns the mitochondrial matrix location and the human cloning study identifies a mitochondrial import peptide (PMID:8687463). Supporting Evidence: PMID:8687463 containing a mitochondrial import signal peptide of 12 amino acids file:human/HADH/HADH-uniprot.txt Mitochondrion matrix |
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Download this section (compressed HTML)Q: To what extent is HADH's regulation of insulin secretion mediated by direct GLUD1 inhibition versus by perturbation of short-chain acyl-CoA/3-hydroxyacyl-CoA pools from impaired beta-oxidation, and are these mechanisms separable in human beta-cells?
Q: Is the HADH-GLUD1 inhibitory interaction conserved and direct in human tissue (as opposed to the By-similarity/mouse-based evidence currently underpinning it), and what is its stoichiometry and regulation?
Experiment: Reconstitute purified human HADH with human GLUD1 in vitro and measure GLUD1 activity +/- HADH (and +/- HADH catalytic-dead mutants) to determine whether enzyme-inhibitor activity is independent of HADH's own catalysis.
Experiment: Generate beta-cell models expressing a catalytically dead but folding-competent HADH variant versus full knockout to dissociate the dehydrogenase activity from the GLUD1-inhibition / insulin-secretion-restraint function.
Experiment: Measure purified human HADH activity across C4–C16 substrates to quantify chain-length preferences, using HADHA as a comparator under matched assay conditions.
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