ACACB (acetyl-CoA carboxylase 2; ACC2, ACC-beta) is a large multidomain, biotin-dependent carboxylase that catalyzes the ATP-dependent carboxylation of acetyl-CoA to malonyl-CoA (EC 6.4.1.2), the first committed step of fatty-acid metabolism. It is one of the two mammalian acetyl-CoA carboxylases; it shares the same catalytic reaction with the cytosolic paralog ACACA/ACC1 but is distinguished by a hydrophobic N-terminal targeting sequence that anchors it to the mitochondrial outer membrane. The reaction proceeds in two half-reactions: the biotin carboxylase (BC) domain ATP-dependently carboxylates a biotin cofactor covalently attached to the central biotin-carboxyl-carrier (BCC) domain, and the carboxyl transferase (CT) domain then transfers the carboxyl group to acetyl-CoA to form malonyl-CoA. At the mitochondrial outer membrane the malonyl-CoA produced by ACC2 allosterically inhibits carnitine palmitoyltransferase 1 (CPT1), thereby limiting mitochondrial long-chain fatty-acid uptake and negatively regulating fatty-acid beta-oxidation; this contrasts with ACC1, whose cytosolic malonyl-CoA feeds de novo lipogenesis. ACC2 is most abundant in oxidative tissues (heart, skeletal muscle, liver, adipose tissue). Its activity is acutely controlled by phosphorylation at Ser222 by AMPK (which disrupts the active oligomer), by allosteric activation by citrate, by product inhibition by malonyl-CoA, and by citrate-dependent polymerization into active filaments promoted by MID1IP1/MIG12. Requiring Mg2+/Mn2+ and biotin, ACC2 is a well-studied metabolic drug target for obesity, type 2 diabetes, and fatty liver disease.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006633 fatty acid biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation to fatty acid biosynthetic process. ACC2 produces malonyl-CoA, the committed precursor for fatty-acid synthesis, shared across the ACC family; the class-level process is correct for this family even though ACC2's dedicated physiological role is regulation of beta-oxidation rather than lipogenesis. Accept as a correct broad process. Supporting Evidence: file:human/ACACB/ACACB-uniprot.txt which is involved in de novo fatty acid |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) is_active_in mitochondrion. Consistent with the experimentally established mitochondrial localization of ACC2. The more precise term is mitochondrial outer membrane (GO:0005741), also annotated; accept this broader parent as correct. Supporting Evidence: PMID:10677481 ACC2 was associated with the mitochondria |
| GO:0003989 acetyl-CoA carboxylase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation to the core catalytic activity. This is the defining molecular function of ACC2 and is independently supported by multiple direct experimental assays on the human protein. Accept as core. Supporting Evidence: PMID:19236960 Acetyl-CoA carboxylase (ACC) catalyzes the carboxylation of acetyl-CoA to |
| GO:0003989 acetyl-CoA carboxylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (ARBA/InterPro/RHEA/EC) annotation to the core catalytic activity, redundant with the experimental annotations. This is ACC2's own correct core function, so accept rather than flag as over-annotation. Supporting Evidence: file:human/ACACB/ACACB-uniprot.txt Mitochondrial enzyme that catalyzes the carboxylation of |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based ATP binding, consistent with the ATP-grasp fold of the biotin carboxylase domain (UniProt DOMAIN ATP-grasp 414..609; ATP binding site 458..463). ATP is a substrate of the carboxylase reaction. Accept as a correct supporting molecular function. Supporting Evidence: file:human/ACACB/ACACB-uniprot.txt starting with the ATP-dependent carboxylation of the biotin |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation (UniProt SubCell/Ensembl) to mitochondrion, redundant with the experimental IDA and the more specific mitochondrial outer membrane term. Correct core localization; accept. Supporting Evidence: file:human/ACACB/ACACB-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0006633 fatty acid biosynthetic process | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based electronic annotation duplicating the IBA fatty acid biosynthetic process annotation. Correct at the family/class level. Accept. Supporting Evidence: file:human/ACACB/ACACB-uniprot.txt plays a central role in fatty acid |
| GO:0006637 acyl-CoA metabolic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA electronic annotation to acyl-CoA metabolic process. Acetyl-CoA and malonyl-CoA are acyl-CoAs, so this is technically true but generic and less informative than the specific process terms already present. Keep as non-core. |
| GO:0016874 ligase activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based general ligase activity, a high-level parent of the specific acetyl-CoA carboxylase activity (EC 6.4.1.2 is a ligase). Correct but uninformative; the specific MF term is annotated. Keep as non-core. |
| GO:0046872 metal ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based metal ion binding, consistent with the 2 Mg2+/Mn2+ ions bound per subunit in the biotin carboxylase domain. Correct but generic. Keep as non-core. Supporting Evidence: file:human/ACACB/ACACB-uniprot.txt Binds 2 magnesium or manganese ions per subunit |
| GO:0005515 protein binding | IPI PMID:20085763 The N-terminal domain of human holocarboxylase synthetase fa... | MARK AS OVER ANNOTATED | Summary: Bare protein binding IPI capturing the interaction with holocarboxylase synthetase (HLCS, P50747), the enzyme that biotinylates ACC2. The interaction is real (ACC2 is an HLCS substrate; Reactome R-HSA-4167511) but the term is uninformative. Retain the annotation but mark as over-annotated per policy (do not remove an IPI); the informative facts are captured elsewhere. |
| GO:0005515 protein binding | IPI PMID:20457939 Induced polymerization of mammalian acetyl-CoA carboxylase b... | MARK AS OVER ANNOTATED | Summary: Bare protein binding IPI for the interaction with MID1IP1/MIG12 (Q9CQ20), which promotes ACC polymerization and activation. The interaction is genuine and functionally important, but the term is uninformative. Retain but mark as over-annotated; a specific adaptor/activator MF would be preferable. Supporting Evidence: PMID:20457939 MIG12, a 22 kDa cytosolic protein of |
| GO:0042802 identical protein binding | IPI PMID:20457939 Induced polymerization of mammalian acetyl-CoA carboxylase b... | KEEP AS NON CORE | Summary: Identical protein binding (self-association), reflecting ACC2 homo-oligomerization into dimers/tetramers/filaments that underlies its activity regulation. Supported by the polymerization data. Keep as non-core. Supporting Evidence: PMID:20457939 induced polymerization of ACC |
| GO:0006098 pentose-phosphate shunt | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl orthology transfer from a rat isoform (A0A0G2K1F2). The pentose-phosphate shunt is unrelated to ACC2's carboxylase function; a spurious over-transfer. Mark as over-annotated (IEA). |
| GO:0006163 purine nucleotide metabolic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl orthology transfer (rat A0A0G2K1F2). ACC2 uses ATP as a substrate but is not part of purine nucleotide metabolism; an inappropriate ortholog transfer. Mark as over-annotated. |
| GO:0007584 response to nutrient | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl orthology transfer to a generic response to nutrient process. ACC2 activity is nutritionally/hormonally regulated, so a nutrient-response role is plausible but this generic term adds little. Keep as non-core. |
| GO:0009374 biotin binding | IEA GO_REF:0000107 | ACCEPT | Summary: Biotin binding, a genuine and essential molecular function: ACC2 covalently binds biotin (N6-biotinyllysine at Lys929) as the cofactor for its carboxylase reaction. Although annotated by Ensembl orthology, this is a correct core cofactor-binding MF. Accept. Supporting Evidence: file:human/ACACB/ACACB-uniprot.txt The biotin cofactor is covalently attached to the central |
| GO:0009410 response to xenobiotic stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl orthology transfer (rat A0A0G2K1F2) to response to xenobiotic stimulus. Not a function of ACC2; likely reflects a drug/treatment context in the rat source study rather than an intrinsic role. Mark as over-annotated. |
| GO:0010884 positive regulation of lipid storage | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl orthology transfer (mouse E9Q4Z2). Consistent with UniProt (promotes lipid storage): by restraining beta-oxidation, ACC2 favors net lipid storage. Plausible downstream physiological role. Keep as non-core. Supporting Evidence: file:human/ACACB/ACACB-uniprot.txt promotes lipid storage |
| GO:0010906 regulation of glucose metabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl orthology transfer (mouse E9Q4Z2). ACC2/malonyl-CoA is linked to glucose-fatty-acid crosstalk and insulin sensitivity, so glucose-metabolism regulation is a plausible systemic effect. Downstream/indirect; keep as non-core. |
| GO:0016507 mitochondrial fatty acid beta-oxidation multienzyme complex | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl orthology transfer asserting ACC2 is part_of the mitochondrial fatty-acid beta-oxidation multienzyme complex. ACC2 regulates beta-oxidation indirectly (via malonyl-CoA/CPT1) but is not a structural subunit of the beta-oxidation trifunctional complex. This is an incorrect cellular-component assignment from ortholog transfer. Mark as over-annotated (IEA). |
| GO:0019395 fatty acid oxidation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl orthology transfer to fatty acid oxidation. ACC2 does not itself oxidize fatty acids; it negatively regulates the process. The correctly directional negative-regulation terms are also present. This unqualified involvement is less precise. Keep as non-core. |
| GO:0031667 response to nutrient levels | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic annotation (UniProt combined IEA) to response to nutrient levels. ACC2 is regulated by nutritional/energy status (AMPK, citrate), so a nutrient-level response is plausible but generic. Keep as non-core. |
| GO:0031999 negative regulation of fatty acid beta-oxidation | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl orthology transfer to negative regulation of fatty acid beta-oxidation. This is precisely the physiological role that distinguishes ACC2 from ACC1: its malonyl-CoA inhibits CPT1, restraining mitochondrial beta-oxidation. Although IEA, it captures the key process for ACC2. Accept as core. Supporting Evidence: file:human/ACACB/ACACB-uniprot.txt carnitine palmitoyltransferase 1 at the mitochondria, negatively |
| GO:0046322 negative regulation of fatty acid oxidation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl orthology transfer, the more general sibling of negative regulation of fatty acid beta-oxidation. Correct for ACC2's malonyl-CoA/CPT1 mechanism. Keep as non-core (redundant with the more specific beta-oxidation term marked core). Supporting Evidence: file:human/ACACB/ACACB-uniprot.txt negatively |
| GO:0046722 lactic acid secretion | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl orthology transfer (rat A0A0G2K1F2). Lactic acid secretion is unrelated to ACC2's carboxylase function; a spurious ortholog transfer. Mark as over-annotated. |
| GO:0050995 negative regulation of lipid catabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl orthology transfer (mouse E9Q4Z2). Consistent with ACC2 suppressing fatty-acid oxidation and thus lipid catabolism. A more general phrasing of the beta-oxidation regulatory role. Keep as non-core. |
| GO:0060421 positive regulation of heart growth | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl orthology transfer (mouse E9Q4Z2). ACC2 is highly expressed in heart and cardiac malonyl-CoA metabolism is important, but a direct role in positive regulation of heart growth is a systemic/indirect ortholog inference. Keep as non-core. |
| GO:0072350 tricarboxylic acid metabolic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl orthology transfer (rat A0A0G2K1F2). ACC2 is allosterically activated by citrate (a tricarboxylic acid) but does not metabolize TCA-cycle acids; an inappropriate process assignment. Mark as over-annotated. |
| GO:0090459 intracellular aspartate homeostasis | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl orthology transfer (rat A0A0G2K1F2). Aspartate homeostasis is unrelated to ACC2's function; a spurious ortholog transfer. Mark as over-annotated. |
| GO:0090461 intracellular glutamate homeostasis | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl orthology transfer (rat A0A0G2K1F2). Glutamate homeostasis is unrelated to ACC2's carboxylase function; a spurious ortholog transfer. Mark as over-annotated. |
| GO:0097009 energy homeostasis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl orthology transfer (mouse E9Q4Z2). ACC2 sits at the fatty-acid oxidation/synthesis switch and contributes to whole-body energy balance, so an energy-homeostasis role is plausible but broad and indirect. Keep as non-core. |
| GO:0098708 D-glucose import across plasma membrane | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl orthology transfer (rat A0A0G2K1F2). ACC2 is a mitochondrial-outer-membrane carboxylase and does not mediate glucose import across the plasma membrane; a spurious/mislocalized ortholog transfer. Mark as over-annotated. |
| GO:1903242 regulation of cardiac muscle hypertrophy in response to stress | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl orthology transfer (rat A0A0G2K1F2). A specific cardiac stress-hypertrophy role is a downstream/indirect physiological inference, not attributable to ACC2's molecular activity. Keep as non-core. |
| GO:2001295 malonyl-CoA biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation (UniProt/UniPathway) to malonyl-CoA biosynthetic process, the direct product-forming process of ACC2's carboxylase reaction (UniProt PATHWAY: malonyl-CoA from acetyl-CoA, step 1/1). Core biological process. Accept. Supporting Evidence: file:human/ACACB/ACACB-uniprot.txt malonyl-CoA biosynthesis; malonyl-CoA from |
| GO:0055089 fatty acid homeostasis | TAS Reactome:R-HSA-8876889 | KEEP AS NON CORE | Summary: Reactome TAS to fatty acid homeostasis, from the pathway in which biotinylated ACC2 carboxylates acetyl-CoA to malonyl-CoA. Consistent with ACC2's role in balancing fatty-acid synthesis and oxidation. Keep as non-core. |
| GO:0003989 acetyl-CoA carboxylase activity | TAS Reactome:R-HSA-8876889 | ACCEPT | Summary: Reactome TAS to the core acetyl-CoA carboxylase activity, from the reaction in which the biotinylated ACACB polymer carboxylates acetyl-CoA to malonyl-CoA. Correct core function. Accept. |
| GO:0003989 acetyl-CoA carboxylase activity | EXP PMID:16854592 Expression, purification, and characterization of human and ... | ACCEPT | Summary: Direct experimental (EXP) annotation of acetyl-CoA carboxylase activity. Recombinant human ACC2 was purified with high specific activity and proper biotinylation. Core catalytic function; accept. Supporting Evidence: PMID:16854592 The resultant human ACC2, human ACC1, and rat ACC2 possess high |
| GO:0003989 acetyl-CoA carboxylase activity | EXP PMID:19900410 Molecular mechanism for the regulation of human ACC2 through... | ACCEPT | Summary: Experimental (EXP) annotation of acetyl-CoA carboxylase activity, from the study of the human ACC2 BC domain and its AMPK phospho-regulation. Core catalytic function; accept. Supporting Evidence: PMID:19900410 the crystal structures of the biotin |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-200423 | ACCEPT | Summary: Reactome TAS localizing ACC2 to the mitochondrial outer membrane (reaction where pAMPK inactivates ACACB). This is ACC2's defining, physiologically critical location. Accept as core. Supporting Evidence: file:human/ACACB/ACACB-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion |
| GO:0003989 acetyl-CoA carboxylase activity | IDA PMID:26976583 Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic ... | ACCEPT | Summary: Direct assay (IDA) of acetyl-CoA carboxylase activity: ND-630 inhibits the enzymatic activity of both ACC isozymes. Core catalytic function; accept. Supporting Evidence: PMID:26976583 inhibit the enzymatic activity of both ACC |
| GO:0003989 acetyl-CoA carboxylase activity | IDA PMID:19236960 Characterization of recombinant human acetyl-CoA carboxylase... | ACCEPT | Summary: Direct assay (IDA) of acetyl-CoA carboxylase activity using a purified recombinant human ACC2 and LC/MS/MS measurement of malonyl-CoA formation. Core catalytic function; accept. Supporting Evidence: PMID:19236960 LC/MS/MS assay to directly measure malonyl-CoA formation |
| GO:0003989 acetyl-CoA carboxylase activity | IDA PMID:20457939 Induced polymerization of mammalian acetyl-CoA carboxylase b... | ACCEPT | Summary: Direct assay (IDA) of ACC activity in the context of MIG12-induced polymerization, which increased ACC activity more than 50-fold. Core catalytic function; accept. Supporting Evidence: PMID:20457939 increased ACC activity by > 50-fold in the presence of |
| GO:0005634 nucleus | IDA PMID:10677481 The subcellular localization of acetyl-CoA carboxylase 2. | MARK AS OVER ANNOTATED | Summary: IDA nuclear localization from the ACC2 subcellular-localization study. The cached abstract supports mitochondrial (and cytosolic ACC1) localization but not a nuclear pool for ACC2; nuclear localization is inconsistent with ACC2's mitochondrial-outer-membrane biology and likely reflects background/artefact. Per policy, retain the experimental annotation but mark as over-annotated rather than remove. |
| GO:0005739 mitochondrion | IDA PMID:10677481 The subcellular localization of acetyl-CoA carboxylase 2. | ACCEPT | Summary: IDA mitochondrial localization, the key experimental finding of this study (ACC2 associates with mitochondria via its N-terminal targeting sequence; colocalizes with CPT1). Core localization; accept. The more precise term is mitochondrial outer membrane. Supporting Evidence: PMID:10677481 ACC2 was associated with the mitochondria |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-4167501 | ACCEPT | Summary: Reactome TAS to mitochondrial outer membrane (ACACB degradation reaction). ACC2's defining location. Accept as core. |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-4167511 | ACCEPT | Summary: Reactome TAS to mitochondrial outer membrane (HLCS biotinylates ACACB reaction). ACC2's defining location. Accept as core. |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-8876889 | ACCEPT | Summary: Reactome TAS to mitochondrial outer membrane (Btn-ACACB polymer carboxylates Ac-CoA reaction). ACC2's defining location. Accept as core. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1655830 | KEEP AS NON CORE | Summary: Reactome TAS to cytosol, from the ACACB expression reaction. This reflects the transcription/expression context rather than a functional cytosolic pool; ACC2 is targeted to the mitochondrial outer membrane. Keep as non-core. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9856605 | KEEP AS NON CORE | Summary: Reactome TAS to cytosol, from the ChREBP:MLX transcriptional-activation reaction. As with the other cytosol annotation, this reflects an expression/regulation context, not ACC2's functional mitochondrial-outer-membrane localization. Keep as non-core. |
| GO:0003989 acetyl-CoA carboxylase activity | IDA PMID:20952656 Crystal structure of Spot 14, a modulator of fatty acid synt... | ACCEPT | Summary: Direct assay (IDA) of acetyl-CoA carboxylase activity in the S14/MIG12 study (MIG12 induces ACC polymerization and activity; S14 attenuates it). Core catalytic function; accept. Supporting Evidence: PMID:20952656 the polymerization and activity of acetyl-CoA carboxylase |
| GO:0005515 protein binding | IPI PMID:20952656 Crystal structure of Spot 14, a modulator of fatty acid synt... | MARK AS OVER ANNOTATED | Summary: Bare protein binding IPI (with MID1IP1/MIG12, Q9CQ20). The interaction is genuine and functionally important for ACC polymerization/activation, but the term is uninformative. Retain but mark as over-annotated per policy (do not remove an IPI). Supporting Evidence: PMID:20952656 S14 can |
| GO:0006084 acetyl-CoA metabolic process | IDA PMID:20952656 Crystal structure of Spot 14, a modulator of fatty acid synt... | KEEP AS NON CORE | Summary: IDA involvement in acetyl-CoA metabolic process: ACC2 consumes acetyl-CoA in the carboxylase reaction. Directly consistent with the catalytic function, though broader than the specific malonyl-CoA biosynthetic process. Keep as non-core. Supporting Evidence: PMID:20952656 acetyl-CoA carboxylase, the first committed |
| GO:0051289 protein homotetramerization | IDA PMID:20952656 Crystal structure of Spot 14, a modulator of fatty acid synt... | KEEP AS NON CORE | Summary: IDA protein homotetramerization, reflecting the self-association of ACC2 into higher-order oligomers/filaments that is central to its activity regulation (promoted by MIG12, disrupted by AMPK phosphorylation). Keep as non-core. Supporting Evidence: PMID:20952656 the polymerization and activity of acetyl-CoA carboxylase |
| GO:0005515 protein binding | IPI PMID:16794074 TRB3 links the E3 ubiquitin ligase COP1 to lipid metabolism. | MARK AS OVER ANNOTATED | Summary: Bare protein binding IPI (with mouse Trib3/TRB3, Q8K4K2; assigned by BHF-UCL) from the TRB3-COP1 study, in which TRB3 triggers ubiquitination/degradation of ACC during fasting. The interaction underlies regulated degradation of ACC, but the term is uninformative. Retain but mark as over-annotated per policy. Supporting Evidence: PMID:16794074 stimulates lipolysis by triggering the degradation of ACC |
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