HMGCS2 encodes the mitochondrial isoform of 3-hydroxy-3-methylglutaryl-CoA synthase (mitochondrial HMG-CoA synthase, mHS; EC 2.3.3.10), a homodimeric enzyme of the thiolase-like superfamily that catalyzes the first, committed and rate-limiting step of ketogenesis. Using an active-site cysteine (Cys166) to form an acyl-thioester intermediate, it condenses acetyl-CoA with acetoacetyl-CoA (and water) to yield (3S)-3-hydroxy-3-methylglutaryl-CoA (HMG-CoA), CoA and a proton; the HMG-CoA product is subsequently cleaved by mitochondrial HMG-CoA lyase (HMGCL) to acetoacetate, the first ketone body. The enzyme resides in the mitochondrial matrix and is expressed at very high levels in liver (roughly 200-fold above other tissues), with lower expression in colon, kidney, testis and pancreas. It is strongly induced during fasting/starvation, chiefly through PPAR-alpha/FGF21 signaling, and provides the ketone bodies that serve as an alternative fuel for the brain and peripheral tissues. Loss-of-function mutations cause mitochondrial HMG-CoA synthase deficiency (HMGCS2D; MIM 605911), an inborn error of metabolism presenting with fasting hypoketotic hypoglycemia, encephalopathy and hepatomegaly. HMGCS2 is distinct from the cytosolic paralog HMGCS1, which supplies HMG-CoA to the mevalonate/cholesterol biosynthetic pathway; unlike HMGCS1 and prokaryotic HMG-CoA synthases, mitochondrial HMGCS2 does not function in isoprenoid/sterol biosynthesis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004421 hydroxymethylglutaryl-CoA synthase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assignment of the defining molecular function of HMGCS2, HMG-CoA synthase activity (EC 2.3.3.10). This is the enzyme's core, experimentally established catalytic activity and the term is at the correct level of specificity. Reason: HMG-CoA synthase activity is the primary molecular function of HMGCS2 and is independently supported by direct experimental evidence in human (EXP/IMP). The IBA call is consistent across the orthologous panel including the human, mouse and rat mitochondrial enzymes. Supporting Evidence: PMID:29597274 catalyzes the condensation reaction between acetyl-CoA and acetoacetyl-CoA in ketone body synthesis |
| GO:0006084 acetyl-CoA metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) involvement in acetyl-CoA metabolism. Acetyl-CoA is a direct substrate of the HMG-CoA synthase reaction, so this broad metabolic-process term is biologically correct, though generic relative to the enzyme's specific role in ketone body biosynthesis. Reason: The enzyme consumes acetyl-CoA (and acetoacetyl-CoA) in its condensation reaction, so involvement in acetyl-CoA metabolic process is accurate. It is a broad parent term and is non-core relative to ketone body biosynthetic process, but not incorrect. Supporting Evidence: PMID:29597274 catalyzes the condensation reaction between acetyl-CoA and acetoacetyl-CoA in ketone body synthesis |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assignment of mitochondrial localization/activity. HMGCS2 carries an N-terminal mitochondrial transit peptide (residues 1-37) and functions in the mitochondrial matrix; this is consistent with the mitochondrial isoform. Reason: Correct compartment for the mitochondrial isoform. The more precise term (mitochondrial matrix, GO:0005759) is also annotated; mitochondrion is an accurate parent and the is_active_in qualifier is appropriate for an active matrix enzyme. Supporting Evidence: file:human/HMGCS2/HMGCS2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0004421 hydroxymethylglutaryl-CoA synthase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (UniProt/ARBA + RHEA/EC:2.3.3.10) assignment of HMG-CoA synthase activity. Redundant with the experimental, IBA and ISS calls for the same term and at the correct specificity. Reason: Matches the experimentally established catalytic activity (RHEA:10188, EC 2.3.3.10). Duplication across evidence codes is acceptable. Supporting Evidence: file:human/HMGCS2/HMGCS2-uniprot.txt EC=2.3.3.10 |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of mitochondrial localization (UniProt SubCell SL-0173, ortholog transfer). Correct compartment for the mitochondrial isoform. Reason: Consistent with the transit peptide and matrix localization; redundant with other mitochondrion/matrix annotations. Supporting Evidence: file:human/HMGCS2/HMGCS2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0006084 acetyl-CoA metabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO electronic assignment of acetyl-CoA metabolic process. Biologically correct (acetyl-CoA is a substrate), though broad; redundant with the IBA/IMP calls for the same term. Reason: Accurate broad metabolic-process term; acetyl-CoA is consumed by the reaction. Supporting Evidence: PMID:29597274 catalyzes the condensation reaction between acetyl-CoA and acetoacetyl-CoA in ketone body synthesis |
| GO:0008299 isoprenoid biosynthetic process | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO electronic assignment of isoprenoid biosynthetic process, transferred from the pan-HMGCS InterPro families (IPR000590, IPR010122). This role belongs to the cytosolic/prokaryotic HMG-CoA synthases that feed the mevalonate/isoprenoid pathway, NOT to the mitochondrial ketogenic isoform HMGCS2. Reason: HMGCS2 is the mitochondrial isoform whose product HMG-CoA is committed to ketogenesis (cleaved by HMGCL to acetoacetate), not to mevalonate/isoprenoid synthesis. The isoprenoid role is a paralog function of HMGCS1 (cytosolic) and of prokaryotic HMGCS; the InterPro family term is over-propagated across all HMG-CoA synthases. PMID:20346956 explicitly separates the mitochondrial isoform (ketone body formation) from the cytosolic isoform (mevalonate pathway, end product cholesterol). Supporting Evidence: PMID:20346956 Mammals also contain a mitochondrial isoform; its PMID:7851882 whereas the cytoplasmic HS isozyme (cHS) mediates an early step |
| GO:0016746 acyltransferase activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro electronic assignment of the broad acyltransferase-activity term based on the thiolase-like fold (IPR016039). This is a distant parent of the specific and experimentally established HMG-CoA synthase activity. Reason: Too general. The enzyme's actual acyl-transfer chemistry is captured precisely by GO:0004421 (hydroxymethylglutaryl-CoA synthase activity), which is already annotated with experimental support. Replace with the specific term. Proposed replacements: hydroxymethylglutaryl-CoA synthase activity Supporting Evidence: PMID:29597274 catalyzes the condensation reaction between acetyl-CoA and acetoacetyl-CoA in ketone body synthesis |
| GO:0001822 kidney development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl-Compara electronic transfer from the rat ortholog (RGD phenotype/expression annotation) of kidney development. HMGCS2 is expressed at low levels in kidney but there is no evidence its catalytic activity drives kidney organogenesis. Reason: Automatic phenotype/expression transfer that conflates tissue expression with a developmental role. HMGCS2 is a ketogenic metabolic enzyme; a specific function in kidney development is not supported and this term over-annotates the gene. |
| GO:0001889 liver development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl-Compara electronic transfer of liver development from the rat ortholog. HMGCS2 is very highly expressed in liver, but its role there is ketogenesis, not driving liver organogenesis. Reason: Reflects high hepatic expression rather than a demonstrated developmental function. Over-annotation for a metabolic enzyme. |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl-Compara electronic transfer of mitochondrial matrix localization from the rat ortholog. This is the precise, correct subcellular compartment for HMGCS2. Reason: Matrix localization is correct for this matrix-soluble ketogenic enzyme and is corroborated by Reactome TAS annotations to the same term. Supporting Evidence: file:human/HMGCS2/HMGCS2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0007494 midgut development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl-Compara electronic transfer of midgut development from the rat ortholog. Not supported by any evidence of a developmental role for HMGCS2. Reason: Automatic ortholog transfer that over-annotates a metabolic enzyme with an unrelated developmental process. |
| GO:0007584 response to nutrient | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara electronic transfer of response to nutrient. HMGCS2 expression and activity are indeed nutritionally regulated (fasting induction), so a nutrient-response annotation is biologically plausible, though it captures regulation of the gene rather than a distinct process the protein carries out. Reason: Consistent with the well-documented nutritional/fasting regulation of ketogenesis, but peripheral to the enzyme's core catalytic function. |
| GO:0009266 response to temperature stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl-Compara electronic transfer of response to temperature stimulus from the rat ortholog. No specific evidence links HMGCS2 catalytic function to temperature responses. Reason: Non-specific ortholog phenotype transfer; over-annotation for this enzyme. |
| GO:0009410 response to xenobiotic stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl-Compara electronic transfer of response to xenobiotic stimulus. Not substantiated for HMGCS2's molecular function. Reason: Automatic ortholog transfer without evidence of a direct role; over-annotation. |
| GO:0009617 response to bacterium | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl-Compara electronic transfer of response to bacterium. Not supported for HMGCS2. Reason: Non-specific ortholog phenotype transfer; over-annotation. |
| GO:0010038 response to metal ion | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl-Compara electronic transfer of response to metal ion. Not supported for HMGCS2. Reason: Non-specific ortholog phenotype transfer; over-annotation. |
| GO:0030324 lung development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl-Compara electronic transfer of lung development from the rat ortholog. No evidence of a developmental role for HMGCS2 in lung. Reason: Automatic ortholog transfer that over-annotates a metabolic enzyme with an unrelated developmental process. |
| GO:0032868 response to insulin | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara electronic transfer of response to insulin. HMGCS2 transcription is reciprocally regulated by insulin/glucagon (suppressed in the fed state), so a response-to-insulin annotation reflects known regulation of the gene rather than a distinct molecular activity. Reason: Plausible given hormonal (insulin) regulation of ketogenic gene expression; peripheral to the enzyme's catalytic function. |
| GO:0032869 cellular response to insulin stimulus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara electronic transfer of cellular response to insulin stimulus. As with response to insulin, reflects hormonal regulation of the gene. Reason: Consistent with insulin regulation of ketogenic gene expression; non-core. |
| GO:0032870 cellular response to hormone stimulus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara electronic transfer of cellular response to hormone stimulus. HMGCS2 is regulated by several hormones (glucagon, insulin, glucocorticoids), so this broad term captures regulation of expression rather than the protein's own function. Reason: Broad hormone-response term consistent with documented hormonal regulation of the ketogenic program; peripheral to catalytic function. |
| GO:0033555 multicellular organismal response to stress | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl-Compara electronic transfer of a very broad organism-level stress-response term. Not informative for the enzyme's molecular role. Reason: Overly general organism-level term from automatic ortholog transfer; over-annotation. |
| GO:0033574 response to testosterone | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl-Compara electronic transfer of response to testosterone. Not substantiated for HMGCS2. Reason: Non-specific ortholog phenotype transfer; over-annotation. |
| GO:0033762 response to glucagon | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara electronic transfer of response to glucagon. Glucagon (via cAMP) is a principal inducer of hepatic ketogenesis and HMGCS2 transcription during fasting, so this annotation reflects a well-established regulatory input. Reason: Consistent with glucagon/cAMP induction of ketogenic gene expression during fasting; peripheral to the enzyme's catalytic function but biologically grounded. |
| GO:0034014 response to triglyceride | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl-Compara electronic transfer of response to triglyceride. Not specifically supported for HMGCS2's function. Reason: Non-specific ortholog phenotype transfer; over-annotation. |
| GO:0034284 response to monosaccharide | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara electronic transfer of response to monosaccharide (e.g., glucose). Glucose availability reciprocally regulates ketogenesis, so this is a plausible regulatory annotation but peripheral to function. Reason: Consistent with glucose/carbohydrate regulation of ketogenic gene expression; non-core. |
| GO:0034696 response to prostaglandin F | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl-Compara electronic transfer of response to prostaglandin F. Not substantiated for HMGCS2. Reason: Non-specific ortholog phenotype transfer; over-annotation. |
| GO:0042594 response to starvation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara electronic transfer of response to starvation. Fasting/starvation is the central physiological trigger for HMGCS2-driven ketogenesis and induces HMGCS2 expression, so this is among the most biologically relevant of the response-to-X terms. Reason: Well-grounded in the fasting physiology of ketogenesis (HMGCS2 is induced during starvation), but describes the physiological context rather than the enzyme's molecular activity, so it is retained as non-core. |
| GO:0043434 response to peptide hormone | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara electronic transfer of response to peptide hormone (broad parent of the insulin/glucagon responses). Reflects hormonal regulation of ketogenic gene expression. Reason: Broad hormone-response term consistent with documented hormonal regulation; non-core. |
| GO:0045471 response to ethanol | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl-Compara electronic transfer of response to ethanol. Not specifically supported for HMGCS2's molecular function. Reason: Non-specific ortholog phenotype transfer; over-annotation. |
| GO:0046951 ketone body biosynthetic process | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl-Compara electronic transfer of ketone body biosynthetic process. This is the core biological process of HMGCS2 and is independently supported by human IMP and Reactome TAS evidence. Reason: Ketone body biosynthesis is the defining physiological role of HMGCS2 (the rate-limiting step of ketogenesis). Correct and well-supported; redundant with the IMP/TAS calls. Supporting Evidence: PMID:23751782 that affects ketone-body synthesis. |
| GO:0051384 response to glucocorticoid | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara electronic transfer of response to glucocorticoid. Glucocorticoids contribute to induction of the fasting/ketogenic program, so this is a plausible regulatory annotation. Reason: Consistent with hormonal (glucocorticoid) regulation of ketogenic gene expression; peripheral to catalytic function. |
| GO:0051591 response to cAMP | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara electronic transfer of response to cAMP. cAMP is the second messenger of glucagon signaling that induces hepatic ketogenesis and HMGCS2 expression, so this term reflects a genuine regulatory pathway. Reason: Consistent with cAMP/glucagon induction of the ketogenic program; non-core relative to the enzyme's activity. |
| GO:0060416 response to growth hormone | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl-Compara electronic transfer of response to growth hormone. Not specifically substantiated for HMGCS2. Reason: Non-specific ortholog phenotype transfer; over-annotation. |
| GO:0060612 adipose tissue development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl-Compara electronic transfer of adipose tissue development from the rat ortholog. No evidence of a developmental role for HMGCS2 in adipose tissue. Reason: Automatic ortholog transfer that over-annotates a metabolic enzyme with an unrelated developmental process. |
| GO:0070542 response to fatty acid | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara electronic transfer of response to fatty acid. Fatty acids (via PPAR-alpha) induce the ketogenic program including HMGCS2, so this is a biologically grounded regulatory annotation. Reason: Consistent with fatty-acid/PPAR-alpha induction of HMGCS2 during fasting; peripheral to the catalytic function. |
| GO:0070543 response to linoleic acid | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl-Compara electronic transfer of response to a specific fatty acid (linoleic acid). More specific than can be justified for HMGCS2 beyond the general fatty-acid response. Reason: Overly specific ortholog transfer; the general response to fatty acid already captures the relevant regulatory input. |
| GO:0071222 cellular response to lipopolysaccharide | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl-Compara electronic transfer of cellular response to lipopolysaccharide. Not specifically supported for HMGCS2's function. Reason: Non-specific ortholog phenotype transfer; over-annotation. |
| GO:0071230 cellular response to amino acid stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl-Compara electronic transfer of cellular response to amino acid stimulus. Not specifically substantiated for HMGCS2. Reason: Non-specific ortholog phenotype transfer; over-annotation. |
| GO:0071385 cellular response to glucocorticoid stimulus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara electronic transfer of cellular response to glucocorticoid stimulus. Reflects glucocorticoid regulation of the ketogenic program. Reason: Consistent with hormonal (glucocorticoid) regulation of HMGCS2 expression; non-core. |
| GO:0071398 cellular response to fatty acid | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara electronic transfer of cellular response to fatty acid. Reflects fatty-acid/PPAR-alpha induction of the ketogenic program. Reason: Consistent with fatty-acid regulation of HMGCS2; peripheral to catalytic function. |
| GO:0046951 ketone body biosynthetic process | TAS Reactome:R-HSA-77111 | ACCEPT | Summary: Reactome traceable-author-statement placing HMGCS2 in the Synthesis of Ketone Bodies pathway. This is the core biological process of the enzyme. Reason: Reactome curates HMGCS2 as the enzyme catalyzing the committed step of ketone body synthesis, consistent with all experimental and phylogenetic evidence. Supporting Evidence: PMID:23751782 that affects ketone-body synthesis. |
| GO:0004421 hydroxymethylglutaryl-CoA synthase activity | TAS Reactome:R-HSA-73918 | ACCEPT | Summary: Reactome TAS for the HMG-CoA synthase reaction (acetoacetyl-CoA + acetyl-CoA => HMG-CoA + CoASH). Core molecular function. Reason: Directly describes the enzyme's catalyzed reaction; consistent with experimental evidence and the correct level of specificity. Supporting Evidence: PMID:20346956 condensation of acetyl-CoA and acetoacetyl-CoA into 3-hydroxy-3-methylglutaryl |
| GO:0004421 hydroxymethylglutaryl-CoA synthase activity | EXP PMID:11228257 Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase defici... | ACCEPT | Summary: Direct experimental (EXP) evidence for HMG-CoA synthase activity. This study characterized wild-type and the F174L disease variant of human mHS by bacterial expression and activity assay, establishing the catalytic function. Reason: Experimental characterization of the human enzyme's HMG-CoA synthase activity, with the F174L patient variant abolishing detectable activity. This is a definitive, core MF annotation. Supporting Evidence: PMID:11228257 F174L-mHS produces a low level of mHS polypeptide with no detectable activity. |
| GO:0004421 hydroxymethylglutaryl-CoA synthase activity | EXP PMID:29597274 Human Mitochondrial HMG-CoA Synthase Deficiency: Role of Enz... | ACCEPT | Summary: Direct experimental (EXP) evidence for HMG-CoA synthase activity. This study expressed wild-type human mHS and measured its activity relative to numerous disease variants, confirming the condensation reaction of ketone body synthesis. Reason: Experimental measurement of human mHS enzymatic activity; core MF annotation supported by quantitative enzyme assays. Supporting Evidence: PMID:29597274 catalyzes the condensation reaction between acetyl-CoA and acetoacetyl-CoA in ketone body synthesis |
| GO:0005739 mitochondrion | ISS GO_REF:0000024 | ACCEPT | Summary: ISS (sequence-similarity) assignment of mitochondrial localization, transferred from the rat ortholog P22791. Correct compartment for the mitochondrial isoform bearing an N-terminal transit peptide. Reason: Consistent with the mitochondrial transit peptide and matrix localization; redundant with the mitochondrion/matrix annotations from other sources. Supporting Evidence: file:human/HMGCS2/HMGCS2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput mass-spectrometry evidence (MitoCoP high-confidence human mitochondrial proteome) placing HMGCS2 in mitochondria. Consistent with its established matrix localization. Reason: Large-scale proteomic detection in the high-confidence mitochondrial proteome supports mitochondrial localization, corroborating the manual/ISS/IBA annotations. Supporting Evidence: file:human/HMGCS2/HMGCS2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0042802 identical protein binding | IDA PMID:20346956 Crystal structures of human HMG-CoA synthase isoforms provid... | KEEP AS NON CORE | Summary: IDA annotation of identical protein binding based on the crystal structure of human HMGCS2 (PDB 2WYA), which shows the enzyme is a homodimer. The homodimeric assembly is a real structural property, but "identical protein binding" is an uninformative molecular function term relative to the enzyme's catalytic role. Reason: The homodimer is structurally established (self-association is genuine), so per curation policy this experimental self-binding annotation is retained rather than removed, but it is uninformative about the enzyme's function and is therefore marked non-core. Supporting Evidence: PMID:29597274 Previous studies have already pointed out that mHS is a homodimeric enzyme PMID:29597274 which was subsequently confirmed by the crystallization of the enzyme |
| GO:0004421 hydroxymethylglutaryl-CoA synthase activity | IMP PMID:23751782 New case of mitochondrial HMG-CoA synthase deficiency. Funct... | ACCEPT | Summary: IMP evidence for HMG-CoA synthase activity: the study developed a method to express human mHS and measured the effect of eight disease mutations on catalytic activity, demonstrating the enzyme's function through loss-of-activity variants. Reason: Functional analysis of patient mutations (total loss or reduced catalytic efficiency) directly demonstrates HMGCS2's HMG-CoA synthase activity. Core MF annotation. Supporting Evidence: PMID:23751782 an enzyme with a catalytic efficiency of 11.5%. |
| GO:0006084 acetyl-CoA metabolic process | IMP PMID:23751782 New case of mitochondrial HMG-CoA synthase deficiency. Funct... | ACCEPT | Summary: IMP involvement in acetyl-CoA metabolic process, inferred from mutation analysis of the HMG-CoA synthase reaction (which consumes acetyl-CoA). Correct but broad. Reason: Acetyl-CoA is a direct substrate of the reaction assayed in this mutation study; the broad metabolic-process term is accurate though non-core relative to ketogenesis. Supporting Evidence: PMID:29597274 catalyzes the condensation reaction between acetyl-CoA and acetoacetyl-CoA in ketone body synthesis |
| GO:0046951 ketone body biosynthetic process | IMP PMID:23751782 New case of mitochondrial HMG-CoA synthase deficiency. Funct... | ACCEPT | Summary: IMP involvement in ketone body biosynthetic process, based on functional analysis of disease mutations that impair ketogenesis. This is the core biological process of HMGCS2. Reason: The study links HMGCS2 mutations to a disorder that affects ketone-body synthesis and characterizes the associated loss of enzyme activity, directly supporting the ketogenesis annotation. Core BP annotation. Supporting Evidence: PMID:23751782 that affects ketone-body synthesis. |
| GO:0004421 hydroxymethylglutaryl-CoA synthase activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS assignment of HMG-CoA synthase activity, transferred from the human cytosolic paralog HMGCS1 (P54869). Redundant with the experimental evidence for the same term at the correct specificity. Reason: The catalytic activity is correct and experimentally established for HMGCS2; the ISS transfer converges on the right molecular function despite being based on the paralog. Supporting Evidence: file:human/HMGCS2/HMGCS2-uniprot.txt EC=2.3.3.10 |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-1989760 | ACCEPT | Summary: Reactome TAS for mitochondrial matrix localization (Expression of HMGCS2 pathway). This is the precise, correct compartment for the enzyme. Reason: Matrix localization is correct for this matrix-soluble ketogenic enzyme; consistent with the transit peptide and other matrix/mitochondrion annotations. Supporting Evidence: file:human/HMGCS2/HMGCS2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-73918 | ACCEPT | Summary: Reactome TAS for mitochondrial matrix localization, associated with the HMG-CoA synthase reaction. Correct compartment. Reason: Matrix localization corroborated across multiple Reactome events and the transit peptide. Supporting Evidence: file:human/HMGCS2/HMGCS2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838081 | ACCEPT | Summary: Reactome TAS for mitochondrial matrix localization, in the context of LONP1-mediated degradation of matrix proteins. Correct compartment; annotation reflects HMGCS2 being a matrix substrate of the LONP1 quality-control machinery. Reason: The matrix localization is correct. The associated pathway (LONP1 degrades matrix proteins) concerns turnover of HMGCS2 rather than its ketogenic function, but the cellular-component call is accurate. Supporting Evidence: file:human/HMGCS2/HMGCS2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838093 | ACCEPT | Summary: Reactome TAS for mitochondrial matrix localization, in the context of LONP1 binding matrix proteins. Correct compartment. Reason: Matrix localization is accurate; the pathway concerns HMGCS2 as a LONP1 client, not its catalytic role, but the compartment annotation is correct. Supporting Evidence: file:human/HMGCS2/HMGCS2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0005739 mitochondrion | TAS PMID:7851882 Human mitochondrial HMG CoA synthase: liver cDNA and partial... | ACCEPT | Summary: TAS (from the original human liver mHS cloning paper) for mitochondrial localization. The paper established mHS as the first enzyme of ketogenesis, distinct from the cytosolic cholesterol-synthesis isozyme, and mitochondrial localization is intrinsic to that distinction. Reason: Foundational reference identifying the mitochondrial HMG-CoA synthase; the mitochondrion annotation is correct and consistent with all downstream evidence. Supporting Evidence: PMID:7851882 whereas the cytoplasmic HS isozyme (cHS) mediates an early step |
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Download this section (compressed HTML)Q: Do the acetylation/succinylation PTMs of HMGCS2 (e.g., at Lys-83/Lys-310) and their reversal by SIRT3/SIRT5 provide physiologically significant control of ketogenic flux in human liver, beyond transcriptional (PPAR-alpha/FGF21) regulation?
Q: What, if any, is the function of the muscle/heart-enriched isoform 3 (HMGCS2delta4), and does it retain HMG-CoA synthase activity?
Experiment: Quantify ketogenic flux (labeled acetyl-CoA to beta-hydroxybutyrate) in primary human hepatocytes with HMGCS2 knockdown/knockout versus rescue with wild-type and PTM-site mutants to test the contribution of acetylation/succinylation to activity control.
Experiment: Express and assay HMGCS2 isoform 3 (HMGCS2delta4) in parallel with isoform 1 to determine whether the muscle/heart-enriched splice variant retains catalytic activity or has a distinct role.
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