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
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Combined Automated Annotation using Multiple IEA Methods
RGD ISO annotations to rat from other mammalian species
Glucagon activates mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in vivo by decreasing the extent of succinylation of the enzyme.
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Glucagon activates Hmgcs2 by lowering succinyl-CoA and reducing enzyme succinylation from ~40% to <10%.
"glucagon increases the activity of HMG-CoA synthase by lowering the concentration of succinyl-CoA and thus decreasing the extent of succinylation of the enzyme"
Rat mitochondrial and cytosolic 3-hydroxy-3-methylglutaryl-CoA synthases are encoded by two different genes.
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Rat mitochondrial HMG-CoA synthase is encoded by a separate gene from the cytosolic isoform, with a 37-residue mitochondrial targeting peptide.
"The expression product of the cDNA in Escherichia coli has HMG-CoA synthase activity"
Regulation of mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase protein by starvation, fat feeding, and diabetes.
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Hmgcs2 protein increases with cAMP, dexamethasone, starvation, fat feeding, and diabetes; decreases with insulin and refeeding.
"The amount of mitochondrial HMG-CoA synthase protein rapidly increased in response to cyclic AMP, dexamethasone, starvation, fat feeding, and diabetes, whereas it was decreased by insulin and refeeding"
Effect of squalene synthase inhibition on the expression of hepatic cholesterol biosynthetic enzymes, LDL receptor, and cholesterol 7 alpha hydroxylase.
The rat mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme-A-synthase gene contains elements that mediate its multihormonal regulation and tissue specificity.
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The Hmgcs2 gene spans at least 24 kbp with 10 exons, and the proximal promoter contains liver-specific enhancers and cis-elements for multihormonal regulation.
"a liver-specific enzyme, is a constituent of the HMG-CoA cycle responsible for ketone-body synthesis"
Developmental changes in mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene expression in rat liver, intestine and kidney.
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Hmgcs2 is expressed in liver, intestine, and kidney of suckling rats with postnatal induction, disappearing from intestine and kidney upon weaning to high-carbohydrate diet.
"Kidney-cortex mitochondria from suckling rats were able to produce low amounts of ketone bodies from oleate"
Vanadate treatment restores the expression of genes for key enzymes in the glucose and ketone bodies metabolism in the liver of diabetic rats.
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Vanadate (insulin mimetic) normalizes the diabetes-induced increase in Hmgcs2 expression.
"The increase in the expression of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCoAS) gene, the key regulatory enzyme in the ketone bodies production pathway, observed in diabetic rats was also blocked by vanadate"
The expression of mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme-A synthase in neonatal rat intestine and liver is under transcriptional control.
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Hmgcs2 expression in neonatal intestine and liver is transcriptionally regulated, with expression in enterocytes and mitochondrial (not cytosolic) localization of the protein.
"hepatic pre-mRNA of mitochondrial HOMeGlt-CoA synthase from suckling rats follows a pattern of expression identical to that of mature hepatic mRNA"
Post-transcriptional induction of beta 1-adrenergic receptor by retinoic acid, but not triiodothyronine, in C6 glioma cells expressing thyroid hormone receptors.
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T3 induces mitochondrial HMG-CoA synthase expression in C6 glioma cells expressing thyroid hormone receptor alpha 1.
"Cells expressing TR alpha 1, but not wild-type cells, were responsive to T3 as shown by increased expression of mitochrondrial hydroxymethylglutaryl CoA synthase after T3 exposure"
The effect of fasting/refeeding and insulin treatment on the expression of the regulatory genes of ketogenesis in intestine and liver of suckling rats.
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Insulin decreases Hmgcs2 activity and mRNA in suckling rat liver and intestine. Hmgcs2 correlates better with ketogenic rate than CPT I.
"the ketogenic rate correlated better to mit. HMG-CoA synthase than CPT I, and liver was the main organ regulating ketogenesis"
The effect of dexamethasone treatment on the expression of the regulatory genes of ketogenesis in intestine and liver of suckling rats.
Hormonal regulation of the mRNA encoding the ketogenic enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in neonatal primary cultures of cortical astrocytes and meningeal fibroblasts.
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Hydrocortisone causes 4-fold increase in Hmgcs2 mRNA in neonatal meningeal fibroblasts and cortical astrocytes.
"glucocorticoid hydrocortisone effects a selective fourfold increase in mHS mRNA abundances"
Atypical expression of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in subcutaneous adipose tissue of male rats.
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Hmgcs2 is atypically expressed in subcutaneous adipose tissue in a testosterone-dependent, sex-specific, and age-dependent manner.
"The expression of mtHMG-CoA synthase is suppressed in SC fat pads of castrated male rats whereas treatment of castrated rats with testosterone restores a normal level of expression"
Mitochondrial 3-hydroxy-3-methylglutaryl coenzyme A synthase and carnitine palmitoyltransferase II as potential control sites for ketogenesis during mitochondrion and peroxisome proliferation.
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3-thia fatty acids increase Hmgcs2 activity, protein, and mRNA, suggesting it retains control over ketogenesis when CPT-I is bypassed.
"Hepatic mitochondrial carnitine palmitoyltransferase (CPT) -II and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase activities, immunodetectable proteins, and mRNA levels increased in parallel"
Cholesterol biosynthesis regulation and protein changes in rat liver following treatment with fluvastatin.
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Fluvastatin induces compensatory upregulation of cholesterol biosynthesis pathway enzymes including HMG-CoA synthase.
"Major effects were evident in the cholesterol biosynthesis pathway including the induction of enzymes upstream and downstream of the target enzyme HMG CoA reductase"
Opposite effect of prolactin and prostaglandin F(2 alpha) on the expression of luteal genes as revealed by rat cDNA expression array.
Effects of fatty acids and growth hormone on liver fatty acid binding protein and PPARalpha in rat liver.
Analysis of genes differentially expressed in astrocytes stimulated with lipopolysaccharide using cDNA arrays.
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Hmgcs2 is upregulated in LPS-stimulated astrocytes.
"mitochondrial hydroxymethylglutaryl-CoA synthase (HMG-CoA synthase), aldehyde dehydrogenase 2, macrophage inflammatory protein 1 (MIP-1) and neurotensin receptor 2"
Down-regulation of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by insulin: the role of the forkhead transcription factor FKHRL1.
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Insulin represses HMGCS2 via FKHRL1/FOXO3a-mediated transcriptional inhibition.
"insulin rapidly inhibiting the expression of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (HMGCS2) gene"
Impaired ketogenesis is a major mechanism for disturbed hepatic fatty acid metabolism in rats with long-term cholestasis and after relief of biliary obstruction.
Expression of mitochondrial HMGCoA synthase and glutaminase in the colonic mucosa is modulated by bacterial species.
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Butyrate-producing bacteria (Clostridium paraputrificum) restore colonic Hmgcs2 expression in germ-free rats.
"the intestinal flora, through butyrate production, could control the expression of colonic mHMGCoA synthase"
Molecular mechanism investigation of phenobarbital-induced serum cholesterol elevation in rat livers by microarray analysis.
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Phenobarbital decreases Hmgcs2 mRNA in rat liver.
"it was only weakly observed after the repeated PB treatments, presumably owing to a decrease in HMG-CoA synthase mRNA content"
Differential action of 13-HPODE on PPARalpha downstream genes in rat Fao and human HepG2 hepatoma cell lines.
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13-HPODE (linoleic acid oxidation product) activates PPARalpha in rat hepatoma cells.
"no remarkable induction of the PPARalpha target genes ACO, CPT1A, mitochondrial HMG-CoA synthase and delta9-desaturase was observed"
Restraint stress alters the duodenal expression of genes important for lipid metabolism in rat.
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Restraint stress upregulates Hmgcs2 in rat duodenum, likely mediated by glucocorticoids.
"immobilization preferentially stimulated the expression of genes related to lipid metabolism, including genes encoding mitochondrial HMG-CoA synthase"
Chronic quercetin exposure affects fatty acid catabolism in rat lung.
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Chronic dietary quercetin upregulates Hmgcs2 in rat lung.
"Up-regulation of genes (Hmgcs2, Ech1, Acox1, Pcca, Lpl and Acaa2) was verified and confirmed by quantitative real time PCR"
Effects of 4-hydroxynonenal on mitochondrial 3-hydroxy-3-methylglutaryl (HMG-CoA) synthase.
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Chronic ethanol increases 4-HNE adduct on Hmgcs2, with compensatory protein increase.
"ethanol consumption increases the formation of a 4-HNE adduct with mitochondrial HMG-CoA synthase"
Identification of palmitoylated mitochondrial proteins using a bio-orthogonal azido-palmitate analogue.
Dissimilar properties of vaccenic versus elaidic acid in beta-oxidation activities and gene regulation in rat liver cells.
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Elaidic acid increases Hmgcs2 gene expression >100% in rat hepatocytes.
"gene expression of CPT I, hydroxyacyl-CoA dehydrogenase and hydroxymethylglutaryl-CoA synthase was at least 100% increased"
Quantitative maps of protein phosphorylation sites across 14 different rat organs and tissues.
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Phosphorylation at Ser-440 and Ser-477 identified by mass spectrometry.
"we present the broadest tissue catalogue of phosphoproteins to date, covering 31,480 phosphorylation sites on 7,280 proteins quantified across 14 rat organs and tissues"
Falcon (Edison Scientific) deep research report on rat Hmgcs2 (P22791)
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Identity verified -- rat Hmgcs2 maps to UniProt P22791 and is the mitochondrial HMG-CoA synthase, distinct from cytosolic HMGCS1.
"A rat proteomics table explicitly maps **Hmgcs2 → UniProtKB accession P22791** and annotates the protein as mitochondrial hydroxymethylglutaryl‑CoA synthase, validating that the accession/gene/organism match the requested target"
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HMGCS2 catalyzes the committed/irreversible step of mitochondrial ketogenesis, condensing acetyl-CoA with acetoacetyl-CoA to form HMG-CoA.
"catalyzes the condensation of **acetyl‑CoA** with **acetoacetyl‑CoA** to form **3‑hydroxy‑3‑methylglutaryl‑CoA (HMG‑CoA)** and free CoA (with H2O), representing the committed/irreversible step in mitochondrial ketogenesis"
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The mitochondrial ketogenic isoform HMGCS2 is distinct from the cytosolic cholesterol-biosynthesis isoform HMGCS1; conflating them is a cross-annotation error.
"The literature distinguishes mitochondrial **HMGCS2** (ketogenesis) from **HMGCS1** (cytosolic HMG‑CoA synthase used in cholesterol biosynthesis), which is essential to avoid cross‑annotation errors"
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Mitochondrial HMG-CoA does not freely cross the inner mitochondrial membrane, so HMGCS2 is functionally separated from cytosolic HMGCS1.
"mitochondrial HMG‑CoA does not freely cross the inner mitochondrial membrane; therefore mitochondrial HMGCS2 is functionally separated from cytosolic HMGCS1, reinforcing the need for precise isoenzyme annotation"
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HMGCS2 is synthesized with a cleavable mitochondrial targeting peptide and localizes to the mitochondrial matrix for ketogenesis.
"synthesized as an immature cytosolic protein bearing a **mitochondrial targeting peptide** that is cleaved after import into the mitochondrial matrix, consistent with matrix localization for ketogenesis"
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The HMG-CoA produced by HMGCS2 is cleaved by HMG-CoA lyase (HMGCL) to yield acetoacetate, the first ketone body.
"HMGCS2 produces mitochondrial HMG‑CoA, which is subsequently cleaved by **HMG‑CoA lyase (HMGCL)** to yield **acetoacetate**"
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HMGCS2 performs the rate-limiting first irreversible step of mitochondrial ketogenesis.
"HMGCS2 performs the **rate-limiting / first irreversible step of mitochondrial ketogenesis**, generating the precursor used for ketone body production"
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Liver-specific Hmgcs2 knockout abolishes fasting-induced hyperketonemia, confirming the in vivo ketogenic role.
"liver‑specific Hmgcs2 knockout mice fail to mount fasting‑induced hyperketonemia"
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HMGCS2 is subject to layered regulation including transcriptional control via AMPK/PPARalpha and post-translational modifications.
"HMGCS2 transcriptional control via AMPK/PPARα pathways"
Transfection of the ketogenic mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase cDNA into Mev-1 cells corrects their auxotrophy for mevalonate.
OpenScientist assessment of Hmgcs2 mevalonate and isoprenoid synthesis