Gene Ontology annotation through association of InterPro records with GO terms
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Gene Ontology annotation based on curation of immunofluorescence data
Gene Ontology annotation based on curation of intracellular localizations of expressed fusion proteins in living cells
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Automatic Gene Ontology annotation based on Rhea mapping
Combined Automated Annotation using Multiple IEA Methods
Biochemical characterization and crystal structure determination of human heart short chain L-3-hydroxyacyl-CoA dehydrogenase provide insights into catalytic mechanism.
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Human heart SCHAD catalyzes NAD+-dependent oxidation of L-3-hydroxyacyl-CoA to a 3-keto product as part of beta-oxidation; the enzyme is a homodimer and was characterized biochemically and crystallographically with NAD+/substrate.
"catalyzes the oxidation of the hydroxyl group of L-3-hydroxyacyl-CoA to a keto group, concomitant with the reduction of NAD+ to NADH"
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Catalytic mechanism: His158 acts as a general base abstracting the 3-OH proton, assisted by Glu170.
"His 158 serves as a general base, abstracting a proton from the 3-OH group of the substrate"
Sequestration of the active site by interdomain shifting. Crystallographic and spectroscopic evidence for distinct conformations of L-3-hydroxyacyl-CoA dehydrogenase.
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Crystal structures of apo-, cofactor-, and substrate-bound forms reveal NAD+-binding domain shifting relative to the C-terminal domain; supports NAD+ binding and catalytic mechanism.
"significant shifting of the NAD(+)-binding domain relative to the C-terminal domain occurs in the ternary and substrate-bound complexes"
Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion.
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First report linking a fatty-acid-oxidation defect (SCHAD/HADH deficiency, P258L) to hyperinsulinism, establishing HADH's role in insulin-secretion regulation.
"This is the first defect in fatty acid beta-oxidation that has been associated with hyperinsulinism"
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The disease-causing P258L variant abolishes catalytic activity, directly tying HADH to the 3-hydroxyacyl-CoA dehydrogenase reaction.
"Expression studies showed that the P258L enzyme had no catalytic activity"
Reye-like syndrome resulting from novel missense mutations in mitochondrial medium- and short-chain l-3-hydroxy-acyl-CoA dehydrogenase.
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Kinetic analysis of patient-derived M/SCHAD mutants (D45G altered NADH Km; Y214H no activity) confirms the human enzyme's 3-hydroxyacyl-CoA dehydrogenase activity and broadens the phenotype; supports a role in insulin regulation.
"This association suggests that there is a role for M/SCHAD in regulating the pancreatic secretion of insulin"
Mechanism of hyperinsulinism in short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency involves activation of glutamate dehydrogenase.
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Definitive mechanistic paper: pull-down experiments demonstrate a direct protein-protein interaction between SCHAD (HADH) and glutamate dehydrogenase (GDH), and show that SCHAD deficiency activates GDH by removing this inhibitory interaction, dysregulating amino-acid-stimulated insulin secretion. Establishes the GLUD1-inhibitor moonlighting function on firmer footing than the earlier speculative reports.
"reflecting the loss of an inhibitory protein-protein interaction of SCHAD upon GDH"
Role of medium- and short-chain L-3-hydroxyacyl-CoA dehydrogenase in the regulation of body weight and thermogenesis.
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Hadh-knockout mice show low glucose and elevated insulin, and isolated islets hypersecrete insulin in response to glucose and palmitate, supporting HADH's negative regulation of insulin secretion.
"insulin secretion in response to glucose and glucose plus palmitate was elevated in isolated islets of knockout mice"
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Hadh knockout impairs adaptive thermogenesis and body-weight regulation under high-fat/cold conditions.
"SCHAD plays an important role in adaptive thermogenesis"
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SCHAD/HADH is highly expressed in pancreatic islets of Langerhans, consistent with a direct role in beta-cell function.
"in the islets of Langerhans within the pancreas"
Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
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HADH is identified in a high-confidence quantitative human mitochondrial proteome, corroborating its mitochondrial localization.
"Quantitative high-confidence human mitochondrial proteome and its dynamics"
Human short-chain L-3-hydroxyacyl-CoA dehydrogenase: cloning and characterization of the coding sequence.
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Original cloning of human SCHAD cDNA; encodes a 314-aa protein with a 12-residue mitochondrial import peptide; expressed in liver, kidney, pancreas, heart and skeletal muscle.
"Northern blot analysis reveals SCHAD mRNA to be expressed in liver, kidney, pancreas, heart and skeletal muscle"
(S)-3-Hydroxydodecanoyl-CoA+NAD => 3-Oxododecanoyl-CoA+NADH+H
(S)-Hydroxybutanoyl-CoA+NAD => Acetoacetyl-CoA+NADH+H
(S)-Hydroxyhexanoyl-CoA+NAD => 3-Oxohexanoyl-CoA+NADH+H
(S)-Hydroxyoctanoyl-CoA+NAD => 3-Oxooctanoyl-CoA+NADH+H
(S)-Hydroxydecanoyl-CoA+NAD => 3-Oxodecanoyl-CoA+NADH+H
CLPXP binds mitochondrial matrix proteins
LONP1 degrades mitochondrial matrix proteins
LONP1 binds mitochondrial matrix proteins
CLPXP degrades mitochondrial matrix proteins