Hmgcs2 encodes the mitochondrial isoform of HMG-CoA synthase, the rate-limiting enzyme of ketogenesis. It catalyzes the condensation of acetyl-CoA with acetoacetyl-CoA to form HMG-CoA in the mitochondrial matrix (EC 2.3.3.10). HMG-CoA is subsequently cleaved by HMG-CoA lyase to produce acetoacetate, the first ketone body. The enzyme is expressed primarily in liver, kidney, and intestine, with atypical expression in subcutaneous adipose tissue of male rats. Its activity is regulated post-translationally by succinylation (inhibited) and desuccinylation by SIRT5 (activated), as well as transcriptionally by insulin (via FOXO3a/FKHRL1 repression), glucagon, glucocorticoids, cAMP, and fatty acids via PPARalpha. It is distinct from the cytosolic HMGCS1, which feeds the mevalonate/cholesterol biosynthetic pathway.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0010142 farnesyl diphosphate biosynthetic process, mevalonate pathway | IBA GO_REF:0000033 | UNDECIDED | Summary: Mitochondrial HMG-CoA synthase primarily supports ketogenesis, but its ability to supply mevalonate-pathway precursors cannot be categorically excluded. Reason: PMID:7961793 reports that ketogenic mitochondrial HMG-CoA synthase restores growth and acetate incorporation into cholesterol in engineered mevalonate-auxotrophic CHO cells, with immunocytochemical localization inside mitochondria. This establishes ectopic pathway capacity, not native rat mevalonate/isoprenoid flux. The focused OpenScientist report correctly emphasizes ketogenic physiology and ER-localized HMGCR, but its claim that no relevant complementation study was found overlooks this primary evidence; neither compartment separation nor unreported sterol phenotypes proves absolute exclusion. Its CSV also incorrectly calls GO:0008299 absent: the live QuickGO record retains this IEA. The source GO:0010142 IBA/IEA rows are absent from the current QuickGO release and the current PAINT slice lacks the FPP assertion at PTN000222418; version drift does not establish why they changed. Retain UNDECIDED pending physiological flux evidence and clarification of the ancestral assertion; do not manufacture a NOT annotation. GO:0010142 is itself obsolete in the GO release 2026-07-26 (consider GO:0019287 or GO:0045337); no replacement is proposed because native mevalonate-pathway participation is the unresolved question. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN000222418 · PTN000222418 SOURCE STALE OR MISSING The source GOA mevalonate/FPP assertion is absent from the current PAINT slice and current QuickGO target release. The node remains for synthase activity and acetyl-CoA metabolism. Version drift does not by itself establish biological loss, and the mitochondrial-enzyme complementation result must be reconciled. Supporting Evidence: PMID:7961793 The prototroph cell line Mev-SM can incorporate labeled acetate into cholesterol in the absence of mevalonate. |
| GO:0004421 hydroxymethylglutaryl-CoA synthase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Correct. The core molecular function of Hmgcs2. IBA from phylogenetic inference is consistent with the IDA evidence (PMID:1971108) showing the expressed cDNA product has HMG-CoA synthase activity. Supporting Evidence: file:rat/Hmgcs2/Hmgcs2-deep-research-bioreason-sft.md This chemistry is the committed entry point to ketogenesis file:rat/Hmgcs2/Hmgcs2-deep-research-falcon.md 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 |
| GO:0006084 acetyl-CoA metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Acetyl-CoA metabolism is a core process for Hmgcs2 because the enzyme directly consumes acetyl-CoA to synthesize HMG-CoA. Reason: The gene product catalyzes a chemical step involving acetyl-CoA rather than merely responding to its concentration. The broad metabolic-process annotation is accurate alongside the more specific ketogenesis annotation. |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Hmgcs2 is a mitochondrial enzyme, with its catalytic pool localized in the matrix. Reason: The broader mitochondrion annotation is experimentally and phylogenetically compatible with matrix localization. The specific matrix term adds precision without making this existing parent-compartment annotation incorrect. |
| GO:0004421 hydroxymethylglutaryl-CoA synthase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Correct automated annotation. Consistent with IDA evidence (PMID:1971108) and the core function of this enzyme. |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: Hmgcs2 is a mitochondrial enzyme, with its catalytic pool localized in the matrix. Reason: The broader mitochondrion annotation is experimentally and phylogenetically compatible with matrix localization. The specific matrix term adds precision without making this existing parent-compartment annotation incorrect. |
| GO:0006084 acetyl-CoA metabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: Acetyl-CoA metabolism is a core process for Hmgcs2 because the enzyme directly consumes acetyl-CoA to synthesize HMG-CoA. Reason: The gene product catalyzes a chemical step involving acetyl-CoA rather than merely responding to its concentration. The broad metabolic-process annotation is accurate alongside the more specific ketogenesis annotation. |
| GO:0008299 isoprenoid biosynthetic process | IEA GO_REF:0000002 | UNDECIDED | Summary: Mitochondrial HMG-CoA synthase primarily supports ketogenesis, but its ability to supply mevalonate-pathway precursors cannot be categorically excluded. Reason: PMID:7961793 reports that ketogenic mitochondrial HMG-CoA synthase restores growth and acetate incorporation into cholesterol in engineered mevalonate-auxotrophic CHO cells, with immunocytochemical localization inside mitochondria. This establishes ectopic pathway capacity, not native rat mevalonate/isoprenoid flux. The focused OpenScientist report correctly emphasizes ketogenic physiology and ER-localized HMGCR, but its claim that no relevant complementation study was found overlooks this primary evidence; neither compartment separation nor unreported sterol phenotypes proves absolute exclusion. Its CSV also incorrectly calls GO:0008299 absent: the live QuickGO record retains this IEA. The source GO:0010142 IBA/IEA rows are absent from the current QuickGO release and the current PAINT slice lacks the FPP assertion at PTN000222418; version drift does not establish why they changed. Retain UNDECIDED pending physiological flux evidence and clarification of the ancestral assertion; do not manufacture a NOT annotation. Supporting Evidence: PMID:7961793 The prototroph cell line Mev-SM can incorporate labeled acetate into cholesterol in the absence of mevalonate. |
| GO:0010142 farnesyl diphosphate biosynthetic process, mevalonate pathway | IEA GO_REF:0000002 | UNDECIDED | Summary: Mitochondrial HMG-CoA synthase primarily supports ketogenesis, but its ability to supply mevalonate-pathway precursors cannot be categorically excluded. Reason: PMID:7961793 reports that ketogenic mitochondrial HMG-CoA synthase restores growth and acetate incorporation into cholesterol in engineered mevalonate-auxotrophic CHO cells, with immunocytochemical localization inside mitochondria. This establishes ectopic pathway capacity, not native rat mevalonate/isoprenoid flux. The focused OpenScientist report correctly emphasizes ketogenic physiology and ER-localized HMGCR, but its claim that no relevant complementation study was found overlooks this primary evidence; neither compartment separation nor unreported sterol phenotypes proves absolute exclusion. Its CSV also incorrectly calls GO:0008299 absent: the live QuickGO record retains this IEA. The source GO:0010142 IBA/IEA rows are absent from the current QuickGO release and the current PAINT slice lacks the FPP assertion at PTN000222418; version drift does not establish why they changed. Retain UNDECIDED pending physiological flux evidence and clarification of the ancestral assertion; do not manufacture a NOT annotation. GO:0010142 is itself obsolete in the GO release 2026-07-26 (consider GO:0019287 or GO:0045337); no replacement is proposed because native mevalonate-pathway participation is the unresolved question. Supporting Evidence: PMID:7961793 The prototroph cell line Mev-SM can incorporate labeled acetate into cholesterol in the absence of mevalonate. |
| GO:0016746 acyltransferase activity | IEA GO_REF:0000002 | ACCEPT | Summary: HMG-CoA synthase catalyzes acyl transfer during condensation of acetyl-CoA and acetoacetyl-CoA. Reason: The EC 2.3.3.10 reaction belongs to the acyltransferase class and satisfies GO:0016746. This broad catalytic label is not an erroneous function merely because a more specific synthase annotation is present. |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Hmgcs2 is inferred to form a homodimer, supporting identical-protein association. Reason: UniProt records a homodimer by similarity to P54868. The identical-protein-binding annotation captures that structural association and is more informative than unrestricted protein binding. Retain as non-core relative to the synthase reaction rather than remove it merely because it is broad. |
| GO:0046951 ketone body biosynthetic process | IEA GO_REF:0000107 | ACCEPT | Summary: Core function. Hmgcs2 catalyzes the rate-limiting step of ketogenesis. Automated Ensembl transfer is consistent with extensive experimental evidence. Supporting Evidence: file:rat/Hmgcs2/Hmgcs2-deep-research-falcon.md HMGCS2 performs the **rate-limiting / first irreversible step of mitochondrial ketogenesis**, generating the precursor used for ketone body production |
| GO:0042802 identical protein binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Hmgcs2 is inferred to form a homodimer, supporting identical-protein association. Reason: UniProt records a homodimer by similarity to P54868. The identical-protein-binding annotation captures that structural association and is more informative than unrestricted protein binding. Retain as non-core relative to the synthase reaction rather than remove it merely because it is broad. |
| GO:0042802 identical protein binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Hmgcs2 is inferred to form a homodimer, supporting identical-protein association. Reason: UniProt records a homodimer by similarity to P54868. The identical-protein-binding annotation captures that structural association and is more informative than unrestricted protein binding. Retain as non-core relative to the synthase reaction rather than remove it merely because it is broad. |
| GO:0004421 hydroxymethylglutaryl-CoA synthase activity | ISO GO_REF:0000121 | ACCEPT | Summary: Correct ISO transfer from human ortholog. Consistent with IDA evidence. |
| GO:0006084 acetyl-CoA metabolic process | ISO GO_REF:0000121 | ACCEPT | Summary: Acetyl-CoA metabolism is a core process for Hmgcs2 because the enzyme directly consumes acetyl-CoA to synthesize HMG-CoA. Reason: The gene product catalyzes a chemical step involving acetyl-CoA rather than merely responding to its concentration. The broad metabolic-process annotation is accurate alongside the more specific ketogenesis annotation. |
| GO:0046951 ketone body biosynthetic process | ISO GO_REF:0000121 | ACCEPT | Summary: Core function. Consistent with experimental evidence. |
| GO:0005739 mitochondrion | ISO GO_REF:0000121 | ACCEPT | Summary: Hmgcs2 is a mitochondrial enzyme, with its catalytic pool localized in the matrix. Reason: The broader mitochondrion annotation is experimentally and phylogenetically compatible with matrix localization. The specific matrix term adds precision without making this existing parent-compartment annotation incorrect. |
| GO:0030324 lung development | IEP PMID:7911291 Effect of squalene synthase inhibition on the expression of ... | UNDECIDED | Summary: The available source does not resolve the particular lung development evidence recorded by the experimental annotation. Reason: The cached source is abstract-only. Its foregrounded tissues or stimuli cannot establish that the full paper omitted the curated lung development experiment. Withdraw the over-annotation judgment pending the relevant full text; neither a generic expression observation nor absence from the abstract is sufficient to resolve this specific claim. |
| GO:0009410 response to xenobiotic stimulus | IEP PMID:11323196 Cholesterol biosynthesis regulation and protein changes in r... | KEEP AS NON CORE | Summary: PMID:11323196 shows Hmgcs2 is among the proteins altered by fluvastatin (a statin drug) treatment in rat liver. Fluvastatin is a xenobiotic, and Hmgcs2 expression changes are part of the compensatory upregulation of the cholesterol biosynthesis pathway. Valid IEP. Supporting Evidence: PMID:11323196 it is suggested that HMG-CoA synthase and isopentenyl-diphosphate delta-isomerase may be explored as alternative drug targets |
| GO:0032869 cellular response to insulin stimulus | IEP PMID:12027802 Down-regulation of the mitochondrial 3-hydroxy-3-methylgluta... | ACCEPT | Summary: PMID:12027802 demonstrates that insulin represses HMGCS2 transcription via the forkhead transcription factor FKHRL1/FOXO3a. This is a well-characterized regulatory mechanism directly relevant to Hmgcs2. Strong IEP evidence. Supporting Evidence: PMID:12027802 insulin rapidly inhibiting the expression of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (HMGCS2) gene |
| GO:0034696 response to prostaglandin F | IEP PMID:11517196 Opposite effect of prolactin and prostaglandin F(2 alpha) on... | KEEP AS NON CORE | Summary: PMID:11517196 uses cDNA arrays to show PGF2alpha inhibits HMG-CoA synthase expression in rat corpus luteum. Valid IEP showing expression change. Non-core regulatory response. Supporting Evidence: PMID:11517196 It also inhibited genes involved in estradiol (P-450(AROM)) and cholesterol biosynthesis (HMG-CoA synthase) |
| GO:0001822 kidney development | IEP PMID:8099282 Developmental changes in mitochondrial 3-hydroxy-3-methylglu... | KEEP AS NON CORE | Summary: PMID:8099282 shows developmental changes in Hmgcs2 mRNA in rat kidney, with expression increasing postnatally and declining at weaning on high-carbohydrate diet. Valid IEP showing developmental regulation. The gene is expressed during kidney maturation but this likely reflects metabolic adaptation rather than a role in kidney organogenesis. Supporting Evidence: PMID:8099282 Kidney-cortex mitochondria from suckling rats were able to produce low amounts of ketone bodies from oleate |
| GO:0004421 hydroxymethylglutaryl-CoA synthase activity | IDA PMID:1971108 Rat mitochondrial and cytosolic 3-hydroxy-3-methylglutaryl-C... | ACCEPT | Summary: The defining IDA evidence. PMID:1971108 cloned the rat mitochondrial HMG-CoA synthase cDNA and showed the E. coli expression product has HMG-CoA synthase activity. This is the core molecular function. Supporting Evidence: PMID:1971108 The expression product of the cDNA in Escherichia coli has HMG-CoA synthase activity |
| GO:0010038 response to metal ion | IEP PMID:8100835 Vanadate treatment restores the expression of genes for key ... | KEEP AS NON CORE | Summary: PMID:8100835 shows vanadate treatment of diabetic rats restores Hmgcs2 gene expression to normal levels. Vanadate acts as an insulin mimetic, so the effect is likely through insulin signaling rather than a direct metal ion response. The annotation is technically valid as IEP (expression changes with metal treatment) but somewhat misleading. Reason: Vanadate is an insulin mimetic; the effect on Hmgcs2 is likely mediated through insulin signaling pathways rather than direct metal ion response. Supporting Evidence: PMID:8100835 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 |
| GO:0032870 cellular response to hormone stimulus | IEP PMID:9025717 Post-transcriptional induction of beta 1-adrenergic receptor... | KEEP AS NON CORE | Summary: PMID:9025717 shows T3 (triiodothyronine) induces mitochondrial HMG-CoA synthase expression in C6 glioma cells engineered to express thyroid hormone receptors. Valid IEP but this is a broad term. More specific hormone-response annotations exist. Supporting Evidence: PMID:9025717 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 |
| GO:0033555 multicellular organismal response to stress | IEP PMID:16962226 Restraint stress alters the duodenal expression of genes imp... | KEEP AS NON CORE | Summary: PMID:16962226 shows restraint stress (2-week immobilization) upregulates Hmgcs2 expression in rat duodenum, likely mediated by glucocorticoids. Valid IEP. The term is broad but appropriate for a whole-organism stress paradigm. Supporting Evidence: PMID:16962226 immobilization preferentially stimulated the expression of genes related to lipid metabolism, including genes encoding mitochondrial HMG-CoA synthase |
| GO:0033762 response to glucagon | IEP PMID:1967579 Glucagon activates mitochondrial 3-hydroxy-3-methylglutaryl-... | ACCEPT | Summary: PMID:1967579 directly demonstrates glucagon activates mitochondrial HMG-CoA synthase by decreasing succinylation. This is both an expression and activity response -- glucagon is a key physiological activator of ketogenesis through this enzyme. Core regulatory response. Supporting Evidence: PMID:1967579 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 |
| GO:0034284 response to monosaccharide | IEP PMID:1967579 Glucagon activates mitochondrial 3-hydroxy-3-methylglutaryl-... | KEEP AS NON CORE | Summary: PMID:1967579 used mannoheptulose (a glucose antagonist) to activate HMG-CoA synthase. The enzyme response reflects the metabolic shift from fed to fasted state. Valid IEP. Supporting Evidence: PMID:1967579 The enzyme is less active in extracts of whole liver from control rats than from rats treated with glucagon or mannoheptulose |
| GO:0051591 response to cAMP | IEP PMID:7902069 Regulation of mitochondrial 3-hydroxy-3-methylglutaryl-coenz... | ACCEPT | Summary: PMID:7902069 shows mitochondrial HMG-CoA synthase protein rapidly increases in response to cyclic AMP. cAMP is a downstream mediator of glucagon signaling, so this is mechanistically linked to the core ketogenic regulation. Supporting Evidence: PMID:7902069 The amount of mitochondrial HMG-CoA synthase protein rapidly increased in response to cyclic AMP, dexamethasone, starvation, fat feeding, and diabetes |
| GO:0070543 response to linoleic acid | IEP PMID:16216487 Differential action of 13-HPODE on PPARalpha downstream gene... | KEEP AS NON CORE | Summary: PMID:16216487 tests 13-HPODE (a linoleic acid oxidation product) on PPARalpha target genes including mitochondrial HMG-CoA synthase. The paper found 13-HPODE activated PPARalpha in rat Fao cells (increasing expression of some target genes) but specifically tested HMG-CoA synthase only in HepG2 cells where no effect was seen. Valid IEP but marginal evidence. Supporting Evidence: PMID:16216487 no remarkable induction of the PPARalpha target genes ACO, CPT1A, mitochondrial HMG-CoA synthase and delta9-desaturase was observed |
| GO:0001889 liver development | IEP PMID:8620869 The expression of mitochondrial 3-hydroxy-3-methylglutaryl-c... | KEEP AS NON CORE | Summary: PMID:8620869 shows developmental regulation of Hmgcs2 in neonatal rat liver with transcriptional control. Expression increases postnatally and follows a pattern consistent with metabolic maturation. Valid IEP showing developmental expression changes. Supporting Evidence: PMID:8620869 hepatic pre-mRNA of mitochondrial HOMeGlt-CoA synthase from suckling rats follows a pattern of expression identical to that of mature hepatic mRNA, which also suggests a transcriptional modulation of this gene in the liver of neonatal rats |
| GO:0005759 mitochondrial matrix | IDA PMID:17971398 Identification of palmitoylated mitochondrial proteins using... | ACCEPT | Summary: PMID:17971398 identified palmitoylated mitochondrial proteins using azido-palmitate and confirmed Hmgcs2 as a mitochondrial matrix protein. This provides direct localization evidence. Supporting Evidence: PMID:17971398 confirmed the palmitoylation of newly identified mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase. file:rat/Hmgcs2/Hmgcs2-deep-research-falcon.md 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 |
| GO:0007494 midgut development | IEP PMID:8620869 The expression of mitochondrial 3-hydroxy-3-methylglutaryl-c... | KEEP AS NON CORE | Summary: PMID:8620869 shows developmental expression of Hmgcs2 in neonatal rat intestine under transcriptional control. Expression in intestinal enterocytes reflects metabolic maturation. Valid IEP. Supporting Evidence: PMID:8620869 Enterocytes are the only intestinal cells that express this ketogenic enzyme, as deduced from immunolocalization experiments |
| GO:0009266 response to temperature stimulus | IEP PMID:10357839 Atypical expression of mitochondrial 3-hydroxy-3-methylgluta... | MARK AS OVER ANNOTATED | Summary: PMID:10357839 tested mtHMG-CoA synthase expression in subcutaneous adipose tissue at 24C vs 4C and found expression is independent of thermic environment. The annotation is technically valid (expression was measured under different temperatures) but the result was negative -- no change observed. Reason: The cited study (PMID:10357839) specifically found that mtHMG-CoA synthase expression in subcutaneous adipose tissue is independent of temperature. Supporting Evidence: PMID:10357839 the expression of mtHMG-CoA synthase in SC adipose deposit is independent of the nutritional state (fed versus starved) or of the thermic environment (24 degrees C versus 4 degrees C) |
| GO:0009617 response to bacterium | IEP PMID:14686922 Expression of mitochondrial HMGCoA synthase and glutaminase ... | KEEP AS NON CORE | Summary: PMID:14686922 shows colonic Hmgcs2 expression is modulated by bacterial colonization, particularly butyrate-producing species. Valid IEP showing that the intestinal microbiome regulates this ketogenic enzyme. Supporting Evidence: PMID:14686922 the intestinal flora, through butyrate production, could control the expression of colonic mHMGCoA synthase and glutaminase |
| GO:0032868 response to insulin | IEP PMID:9143333 The effect of fasting/refeeding and insulin treatment on the... | ACCEPT | Summary: PMID:9143333 shows insulin decreases Hmgcs2 mRNA and activity in suckling rat liver and intestine. Strong evidence for insulin regulation of ketogenesis via this enzyme. Core regulatory response. Supporting Evidence: PMID:9143333 Long-term insulin treatment had little effect on the mRNA levels for CPT I or mit. HMG-CoA synthase, but both the expressed and total activities of mit. HMG-CoA synthase were reduced by half in both intestine and liver |
| GO:0033574 response to testosterone | IEP PMID:10357839 Atypical expression of mitochondrial 3-hydroxy-3-methylgluta... | KEEP AS NON CORE | Summary: PMID:10357839 shows testosterone controls atypical Hmgcs2 expression in subcutaneous adipose tissue. Castration suppresses expression; testosterone replacement restores it. Valid IEP. Supporting Evidence: PMID:10357839 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 |
| GO:0034014 response to triglyceride | IEP PMID:11551854 Effects of fatty acids and growth hormone on liver fatty aci... | KEEP AS NON CORE | Summary: PMID:11551854 shows dietary triglycerides (10% corn oil) increase Hmgcs2 mRNA in hypophysectomized rats, but only in the presence of growth hormone. Valid IEP showing nutrient-hormone interaction. Supporting Evidence: PMID:11551854 Dietary triglycerides increased mitochondrial hydroxymethylglutaryl-CoA synthase mRNA only in the presence of GH |
| GO:0042594 response to starvation | IEP PMID:10357839 Atypical expression of mitochondrial 3-hydroxy-3-methylgluta... | ACCEPT | Summary: PMID:10357839 tested starvation effects on Hmgcs2 in adipose tissue and found expression is independent of nutritional state in subcutaneous fat. However, starvation induction of Hmgcs2 in liver is one of the best-established responses (PMID:7902069). The annotation is valid but this specific reference shows no effect in adipose tissue. Reason: While the specific cited reference shows no starvation response in adipose tissue, Hmgcs2 starvation induction in liver is extensively documented and is the core physiological context. Supporting Evidence: PMID:7902069 The amount of mitochondrial HMG-CoA synthase protein rapidly increased in response to cyclic AMP, dexamethasone, starvation, fat feeding, and diabetes |
| GO:0045471 response to ethanol | IEP PMID:17964421 Effects of 4-hydroxynonenal on mitochondrial 3-hydroxy-3-met... | KEEP AS NON CORE | Summary: PMID:17964421 shows chronic ethanol consumption increases 4-hydroxynonenal (4-HNE) adduct formation on Hmgcs2, with compensatory increase in protein levels. Valid IEP. Supporting Evidence: PMID:17964421 ethanol consumption increases the formation of a 4-HNE adduct with mitochondrial HMG-CoA synthase, which has the potential to inactivate the enzyme in situ |
| GO:0046951 ketone body biosynthetic process | IEP PMID:12399220 Impaired ketogenesis is a major mechanism for disturbed hepa... | ACCEPT | Summary: PMID:12399220 shows impaired ketogenesis in cholestatic rats with reduced HMG-CoA synthase mRNA and protein. After bile flow restoration, HMG-CoA synthase recovers slowly (3 months). Directly demonstrates Hmgcs2 as the rate-limiting factor in ketogenesis. Core function. Supporting Evidence: PMID:12399220 reduced activity of HMG-CoA synthase is the major factor |
| GO:0051384 response to glucocorticoid | IEP PMID:9546617 The effect of dexamethasone treatment on the expression of t... | KEEP AS NON CORE | Summary: PMID:9546617 shows dexamethasone decreases Hmgcs2 mRNA and activity in suckling rat liver and intestine. Valid IEP showing glucocorticoid regulation. Supporting Evidence: PMID:9546617 Dexamethasone produced a 2 fold increase in mRNA and activity of CPT I in intestine, but led to a decrease in mit. HMG-CoA synthase |
| GO:0060416 response to growth hormone | IEP PMID:11551854 Effects of fatty acids and growth hormone on liver fatty aci... | KEEP AS NON CORE | Summary: PMID:11551854 shows growth hormone is required for dietary triglyceride-mediated induction of Hmgcs2 mRNA. Valid IEP showing GH-dependent regulation. Supporting Evidence: PMID:11551854 Dietary triglycerides increased mitochondrial hydroxymethylglutaryl-CoA synthase mRNA only in the presence of GH |
| GO:0060612 adipose tissue development | IEP PMID:10357839 Atypical expression of mitochondrial 3-hydroxy-3-methylgluta... | UNDECIDED | Summary: The available source does not resolve the particular adipose tissue development evidence recorded by the experimental annotation. Reason: The cached source is abstract-only. Its foregrounded tissues or stimuli cannot establish that the full paper omitted the curated adipose tissue development experiment. Withdraw the over-annotation judgment pending the relevant full text; neither a generic expression observation nor absence from the abstract is sufficient to resolve this specific claim. |
| GO:0071222 cellular response to lipopolysaccharide | IEP PMID:11578593 Analysis of genes differentially expressed in astrocytes sti... | KEEP AS NON CORE | Summary: PMID:11578593 shows Hmgcs2 is upregulated in LPS-stimulated astrocytes at 2h and 8h. Valid IEP showing inflammatory stimulus response. Supporting Evidence: PMID:11578593 In addition to these three, six other genes were also up-regulated at 2 and 8 h. They were genes encoding vascular cell adhesion protein 1 (VCAM-1), interferon regulatory factor 1 (IRF-1), mitochondrial hydroxymethylglutaryl-CoA synthase (HMG-CoA synthase), aldehyde dehydrogenase 2, macrophage inflammatory protein 1 (MIP-1) and neurotensin receptor 2. |
| GO:0071230 cellular response to amino acid stimulus | IEP PMID:20508999 Dissimilar properties of vaccenic versus elaidic acid in bet... | UNDECIDED | Summary: The available source does not resolve the particular amino-acid response evidence recorded by the experimental annotation. Reason: The cached source is abstract-only. Its foregrounded tissues or stimuli cannot establish that the full paper omitted the curated amino-acid response experiment. Withdraw the over-annotation judgment pending the relevant full text; neither a generic expression observation nor absence from the abstract is sufficient to resolve this specific claim. |
| GO:0071398 cellular response to fatty acid | IEP PMID:20508999 Dissimilar properties of vaccenic versus elaidic acid in bet... | KEEP AS NON CORE | Summary: PMID:20508999 shows elaidic acid (trans-9-C18:1) increases Hmgcs2 gene expression by >100% in rat hepatocytes compared to controls, while vaccenic acid does not. Valid IEP showing differential fatty acid regulation. Supporting Evidence: PMID:20508999 gene expression of CPT I, hydroxyacyl-CoA dehydrogenase and hydroxymethylglutaryl-CoA synthase was at least 100% increased |
| GO:0070542 response to fatty acid | IEP PMID:10796071 Mitochondrial 3-hydroxy-3-methylglutaryl coenzyme A synthase... | KEEP AS NON CORE | Summary: PMID:10796071 shows 3-thia fatty acids increase Hmgcs2 activity, protein, and mRNA in rat liver. Valid IEP showing fatty acid regulation of ketogenesis. Supporting Evidence: PMID:10796071 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 |
| GO:0071385 cellular response to glucocorticoid stimulus | IEP PMID:9798904 Hormonal regulation of the mRNA encoding the ketogenic enzym... | KEEP AS NON CORE | Summary: PMID:9798904 shows hydrocortisone causes a 4-fold increase in Hmgcs2 mRNA in neonatal cortical astrocytes and meningeal fibroblasts. Valid IEP. Note this contrasts with the dexamethasone effect in suckling rat liver (PMID:9546617), indicating tissue- specific glucocorticoid responses. Supporting Evidence: PMID:9798904 glucocorticoid hydrocortisone effects a selective fourfold increase in mHS mRNA abundances in both neonatal meningeal fibroblasts and neonatal cortical astrocytes |
| GO:0007584 response to nutrient | IEP PMID:17103110 Chronic quercetin exposure affects fatty acid catabolism in ... | KEEP AS NON CORE | Summary: PMID:17103110 shows chronic dietary quercetin upregulates Hmgcs2 in rat lung. Valid IEP showing nutrient (flavonoid) regulation of fatty acid catabolism genes. Supporting Evidence: PMID:17103110 fatty acid catabolism pathways, like beta-oxidation and ketogenesis, are up-regulated by the long-term quercetin intervention |
| GO:0009410 response to xenobiotic stimulus | IEP PMID:15107969 Molecular mechanism investigation of phenobarbital-induced s... | KEEP AS NON CORE | Summary: PMID:15107969 shows phenobarbital treatment decreases Hmgcs2 mRNA in rat liver. Valid IEP. Supporting Evidence: PMID:15107969 it was only weakly observed after the repeated PB treatments, presumably owing to a decrease in HMG-CoA synthase mRNA content |
| GO:0043434 response to peptide hormone | IEP PMID:12027802 Down-regulation of the mitochondrial 3-hydroxy-3-methylgluta... | KEEP AS NON CORE | Summary: Hmgcs2 expression is responsive to peptide-hormone signaling in the cited experimental context. Reason: Retain the broad experimental hormone-response context as non-core relative to the catalytic ketogenesis function. Its overlap with specific insulin, glucagon or growth-hormone responses is not itself an argument against the annotation. Supporting Evidence: PMID:12027802 insulin rapidly inhibiting the expression of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (HMGCS2) gene, which is a key control site of ketogenesis |
| GO:0004421 hydroxymethylglutaryl-CoA synthase activity | TAS PMID:8097464 The rat mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme-A-... | ACCEPT | Summary: PMID:8097464 characterizes the gene structure and confirms liver-specific expression and multihormonal regulation. TAS for the enzymatic function. Consistent with IDA evidence. Supporting Evidence: PMID:8097464 Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) synthase, a liver-specific enzyme, is a constituent of the HMG-CoA cycle responsible for ketone-body synthesis |
| GO:0046951 ketone body biosynthetic process | TAS PMID:8097464 The rat mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme-A-... | ACCEPT | Summary: PMID:8097464 describes Hmgcs2 as a constituent of the HMG-CoA cycle responsible for ketone-body synthesis. Valid TAS. Supporting Evidence: PMID:8097464 a liver-specific enzyme, is a constituent of the HMG-CoA cycle responsible for ketone-body synthesis |
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Download this section (compressed HTML)Q: Does the palmitoylation of Hmgcs2 (identified in PMID:17971398) regulate its enzymatic activity or localization in vivo?
Q: What is the physiological significance of Hmgcs2 expression in the stromal vascular fraction of subcutaneous adipose tissue?
Suggested experts: Pegorier JP, Thumelin S
Q: How do the tissue-specific glucocorticoid effects on Hmgcs2 (stimulatory in astrocytes, inhibitory in suckling liver) arise mechanistically?
Suggested experts: Cullingford TE, Hegardt FG
Q: Does endogenous rat Hmgcs2 contribute measurable carbon flux to mevalonate/isoprenoids in any physiological tissue, and what evidence motivated removal of the earlier PTN000222418 FPP assertion? Mitochondrial-enzyme complementation (PMID:7961793) demonstrates capacity but does not settle native pathway participation.
Experiment: Site-directed mutagenesis of candidate palmitoylation sites on Hmgcs2, followed by in vitro activity assays and palmitoylation status assessment, to determine whether palmitoylation directly modulates catalytic activity.
Hypothesis: Palmitoylation of Hmgcs2 at specific cysteine residues inhibits enzymatic activity similar to succinylation.
Experiment: Isolate stromal vascular fraction from male rat subcutaneous adipose tissue, measure ketone body production rates, and assess whether ketone bodies affect nearby adipocyte differentiation or lipolysis.
Hypothesis: Hmgcs2 expression in subcutaneous adipose stromal cells represents a local ketogenic capacity for paracrine signaling.
Experiment: Comparative proteomics of Hmgcs2 post-translational modifications (succinylation, acetylation, palmitoylation, phosphorylation) under fed, fasted, and diabetic conditions to build an integrated map of activity regulation.
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