ACAA1 (peroxisomal 3-ketoacyl-CoA thiolase; peroxisomal thiolase 1) is a peroxisomal-matrix enzyme that catalyzes the final, thiolytic-cleavage step of the peroxisomal fatty-acid beta-oxidation spiral. Using coenzyme A, it cleaves a 3-oxoacyl-CoA (3-ketoacyl-CoA) into an acyl-CoA shortened by two carbons plus acetyl-CoA (acetyl-CoA C-acyltransferase / 3-ketoacyl-CoA thiolase, EC 2.3.1.16). It acts on straight-chain substrates across short, medium, long, and very-long chain lengths in the ACOX1/EHHADH-HSD17B4 spiral, whereas the branched-chain and bile-acid thiolytic step is carried by the separate SCPx/SCP2 thiolase. Through this activity ACAA1 supports degradation of very-long-chain fatty acids and contributes to peroxisomal chain-shortening reactions in polyunsaturated fatty acid metabolism, including the retroconversion of C24:6n-3 to docosahexaenoic acid (DHA). ACAA1 is synthesized in the cytosol with a cleavable N-terminal PTS2 targeting signal that is recognized by the receptor PEX7 (with co-receptor PEX5L) and mediates import into the peroxisomal matrix, where the signal is removed and the enzyme functions as a homodimer. It is expressed broadly with enrichment in liver and kidney, and its deficiency impairs peroxisomal beta-oxidation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003988 acetyl-CoA C-acyltransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assignment of the core 3-ketoacyl-CoA thiolase (EC 2.3.1.16) activity. This is the defining, evolutionarily conserved molecular function of ACAA1: cleaving a 3-oxoacyl-CoA with CoA to give an acyl-CoA shortened by two carbons plus acetyl-CoA. Reason: Correct and well-supported across all evidence lines (IBA, ISS from rat P21775, Reactome TAS). This is the primary core molecular function of the protein. |
| GO:0005777 peroxisome | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) placement of ACAA1 activity in the peroxisome. ACAA1 is a peroxisomal-matrix enzyme imported via a PTS2 signal. Reason: Correct core localization, corroborated by multiple experimental IDA studies and UniProt SUBCELL. |
| GO:0006635 fatty acid beta-oxidation | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assignment to fatty acid beta-oxidation, the core biological process ACAA1 participates in as the thiolase (final) step of the peroxisomal beta-oxidation spiral. Reason: Core process, supported experimentally (IMP) in human thiolase-deficiency studies and by UniProt PATHWAY. |
| GO:0010124 phenylacetate catabolic process | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA propagation of a phenylacetate catabolic process from the thiolase phylogenetic family. Phenylacetate degradation via a beta-oxidation-like route is a bacterial/plant pathway; there is no evidence that human ACAA1 functions in phenylacetate catabolism. Reason: Over-propagated from distant family members; not a demonstrated human ACAA1 function. Retained (not removed) as it derives from an evolutionary model, but flagged as an over-annotation. Propagation Review Root cause: PROPAGATION BAD Failure modes: LINEAGE OR TAXON MISMATCH FUNCTIONAL DIVERGENCE |
| GO:0003985 acetyl-CoA C-acetyltransferase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic (RHEA/EC 2.3.1.9) assignment of acetoacetyl-CoA thiolase activity (2 acetyl-CoA = acetoacetyl-CoA + CoA). UniProt lists this reaction only by similarity to rat (P21775); it is a minor/ancestral short-chain condensation activity, not the principal function of ACAA1. Reason: Chemically plausible for a thiolase-family enzyme but non-core; the principal activity is the 3-ketoacyl-CoA thiolase (GO:0003988) direction of degradative chain shortening. |
| GO:0003988 acetyl-CoA C-acyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (RHEA/EC 2.3.1.16) assignment of the core 3-ketoacyl-CoA thiolase activity, matching the many curated catalytic-activity reactions in UniProt. Reason: Correct core molecular function, redundant with the IBA/ISS/TAS calls to the same term. |
| GO:0005777 peroxisome | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (UniProt SubCell SL-0204 / ARBA) peroxisome localization, consistent with the experimentally established localization. Reason: Correct core localization. |
| GO:0016746 acyltransferase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO (IEA) generic acyltransferase activity from the thiolase-like superfamily signature. Correct at the family level but far more general than the specific EC 2.3.1.16 thiolase activity. Reason: Uninformative parent of the specific acetyl-CoA C-acyltransferase activity (GO:0003988); superseded by the specific term. |
| GO:0016747 acyltransferase activity, transferring groups other than amino-acyl groups | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO (IEA) generic acyltransferase activity from thiolase InterPro signatures. Correct but overly broad relative to the specific 3-ketoacyl-CoA thiolase activity. Reason: Uninformative parent term superseded by GO:0003988. |
| GO:0050633 acetyl-CoA C-myristoyltransferase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic (RHEA/EC 2.3.1.155) assignment of a specific-chain-length instance of the thiolase reaction (tetradecanoyl-CoA + acetyl-CoA = 3-oxohexadecanoyl-CoA + CoA). This is a legitimate substrate of ACAA1 but overly specific; it is one instance of the general straight-chain thiolase activity captured by GO:0003988. Reason: Correct chemistry but an unnecessarily narrow, chain-length-specific term; subsumed by the core acetyl-CoA C-acyltransferase activity. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" IPI from a high-throughput binary interactome screen (HuRI, Y2H), reporting an interaction with TFCP2 (Q12800). No functional/mechanistic context is provided and the interaction has no established relationship to ACAA1's thiolase function. Reason: Uninformative bare protein-binding call from a systematic screen; not indicative of a specific molecular function. Retained per policy (not removed). |
| GO:0033540 fatty acid beta-oxidation using acyl-CoA oxidase | TAS Reactome:R-HSA-390247 | ACCEPT | Summary: Reactome (TAS) assignment to the peroxisomal (acyl-CoA-oxidase-initiated) branch of fatty acid beta-oxidation, via the "Beta-oxidation of very long chain fatty acids" pathway. This is the correct peroxisomal specialization of the beta-oxidation process, of which ACAA1 catalyzes the thiolase step. Reason: Accurately captures the peroxisomal (H2O2-generating, oxidase-initiated) beta-oxidation pathway that ACAA1 completes. |
| GO:0036109 alpha-linolenic acid metabolic process | TAS Reactome:R-HSA-2046106 | KEEP AS NON CORE | Summary: Reactome (TAS) assignment to alpha-linolenic acid (ALA, C18:3n-3) metabolism. ACAA1 participates in the peroxisomal beta-oxidation chain-shortening of the C24:6n-3 intermediate to DHA within n-3 PUFA metabolism derived from ALA. Reason: A specific downstream pathway context of the core beta-oxidation function; correct but a specialized process rather than the enzyme's primary annotated role. |
| GO:0033540 fatty acid beta-oxidation using acyl-CoA oxidase | IEA GO_REF:0000041 | ACCEPT | Summary: UniPathway (IEA) mapping to the peroxisomal acyl-CoA-oxidase-initiated beta-oxidation pathway. Same correct process as the Reactome TAS call to this term. Reason: Correct peroxisomal beta-oxidation process; redundant with the TAS annotation. |
| GO:0003988 acetyl-CoA C-acyltransferase activity | TAS Reactome:R-HSA-390250 | ACCEPT | Summary: Reactome (TAS) assignment of the 3-ketoacyl-CoA thiolase activity to the specific reaction 3-ketohexacosanoyl-CoA + CoA => tetracosanoyl-CoA + acetyl-CoA, an instance of the core thiolase step. Reason: Core molecular function, redundant with the IBA/ISS/IEA calls to GO:0003988. |
| GO:0008775 acetate CoA-transferase activity | EXP PMID:11734571 Identification of the peroxisomal beta-oxidation enzymes inv... | MARK AS OVER ANNOTATED | Summary: "Acetate CoA-transferase activity" (acyl-CoA + acetate = fatty acid + acetyl-CoA) is a CoA-transferase reaction, which is NOT the thiolytic reaction ACAA1 catalyzes (acyl-CoA + acetyl-CoA = 3-oxoacyl-CoA + CoA). PMID:11734571 identifies 3-ketoacyl-CoA thiolase and SCPx as the thiolases in DHA-forming peroxisomal beta-oxidation; it does not establish a CoA-transferase activity for ACAA1. This is a mis-typed molecular function (a Reactome-derived EXP call). Reason: Wrong molecular-function class (CoA-transferase rather than thiolase). Per policy, an EXP annotation is not removed; flagged as over-annotation. The correct activity is acetyl-CoA C-acyltransferase (GO:0003988). Supporting Evidence: PMID:11734571 SCOX, DBP, and both 3-ketoacyl-CoA thiolase and SCPx. These findings are of |
| GO:0005777 peroxisome | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence-based (HPA, IDA) peroxisome localization. Consistent with the established peroxisomal-matrix localization of ACAA1. Reason: Correct core localization supported by direct imaging. |
| GO:0003985 acetyl-CoA C-acetyltransferase activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer (from rat P21775) of acetoacetyl-CoA thiolase activity (EC 2.3.1.9). A minor/ancestral short-chain condensation activity of the thiolase family; not the principal ACAA1 function. Reason: Non-core; the core degradative activity is captured by GO:0003988. |
| GO:0005777 peroxisome | IDA PMID:22057399 Structural requirements for interaction of peroxisomal targe... | ACCEPT | Summary: Direct (IDA) peroxisomal localization from a PTS2/PEX7 import study, in which ACAA1 (acyl-CoA thiolase) is treated as a mammalian PTS2-carrying peroxisomal matrix protein that exerts the last step of fatty acid beta-oxidation. Reason: Correct core localization with mechanistic import support. Supporting Evidence: PMID:22057399 acyl-CoA thiolase exerting the last step of fatty acid |
| GO:0005777 peroxisome | IDA PMID:25538232 Mechanistic insights into PTS2-mediated peroxisomal protein ... | ACCEPT | Summary: Direct (IDA) peroxisomal localization from a PTS2-mediated import study (PEX7-PEX5L-cargo trimeric complex), using thiolase as the prototypical PTS2 cargo. Reason: Correct core localization; redundant with other IDA/IBA peroxisome calls. |
| GO:0003988 acetyl-CoA C-acyltransferase activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer (from rat P21775) of the core 3-ketoacyl-CoA thiolase (EC 2.3.1.16) activity. Reason: Core molecular function; redundant with IBA/IEA/TAS calls to GO:0003988. |
| GO:0006635 fatty acid beta-oxidation | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer (from rat P21775) of the fatty acid beta-oxidation process. Core biological process for ACAA1. Reason: Core process; redundant with IBA/IMP support. |
| GO:0008206 bile acid metabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer (from rat P21775) of bile acid metabolic process. The peroxisomal thiolytic step of bile-acid (di/trihydroxycholestanoyl-CoA) chain shortening is now attributed principally to the separate SCPx/SCP2 thiolase; the ACAA1 bile-acid link derives from early human thiolase-deficiency patients that predate that assignment. Reason: A secondary/peripheral process for ACAA1 relative to straight-chain beta-oxidation; the branched-chain bile-acid thiolase role is carried by SCPx. Retained as non-core rather than removed. |
| GO:0050633 acetyl-CoA C-myristoyltransferase activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer (from rat P21775) of a chain-length-specific instance (EC 2.3.1.155) of the thiolase reaction. Overly specific; subsumed by the core acetyl-CoA C-acyltransferase activity. Reason: Correct chemistry but unnecessarily narrow; non-core relative to GO:0003988. |
| GO:0005777 peroxisome | IDA PMID:19479899 Pex3p-dependent peroxisomal biogenesis initiates in the endo... | ACCEPT | Summary: Direct (IDA) peroxisome localization from a peroxisomal-biogenesis study in human fibroblasts. Consistent with the established peroxisomal-matrix localization. Reason: Correct core localization; one of several redundant IDA peroxisome calls. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9033232 | MARK AS OVER ANNOTATED | Summary: Reactome (TAS) cytosol localization corresponding to the pre-import state, when PEX7 binds the PTS2-containing cytosolic cargo (thiolase) prior to translocation into peroxisomes. Reason: Reflects a transient trafficking intermediate rather than the compartment where ACAA1 functions; the mature, active enzyme is in the peroxisomal matrix. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9033514 | MARK AS OVER ANNOTATED | Summary: Reactome (TAS) cytosol localization for the cytosolic cargo state prior to PEX5L:PEX7-mediated translocation into the peroxisomal matrix. Reason: Transient pre-import localization, not the functional compartment; superseded by the peroxisomal-matrix annotation. |
| GO:0005782 peroxisomal matrix | TAS Reactome:R-HSA-9033514 | ACCEPT | Summary: Reactome (TAS) peroxisomal-matrix localization, the compartment where the mature ACAA1 enzyme resides and functions after PTS2 cleavage. Reason: Correct, most-specific core localization. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798749 | MARK AS OVER ANNOTATED | Summary: Reactome (TAS) extracellular-region localization from the neutrophil-degranulation pathway ("Exocytosis of specific granule lumen proteins"). ACAA1 has been detected in neutrophil granule proteomes, but as a peroxisomal-matrix beta-oxidation enzyme an extracellular localization is not a biologically meaningful site of action. Reason: Bystander/secretome-proteomics-derived localization; not where ACAA1 performs its molecular function. |
| GO:0035580 specific granule lumen | TAS Reactome:R-HSA-6798749 | MARK AS OVER ANNOTATED | Summary: Reactome (TAS) specific-granule-lumen localization from the neutrophil-degranulation pathway. Based on detection of ACAA1 in neutrophil granule proteomes rather than a functional role there. Reason: Proteomics co-detection in neutrophil granules; not the functional peroxisomal compartment. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: High-throughput (HDA) membrane-proteome detection (NK-cell membrane proteome). ACAA1 is a soluble peroxisomal-matrix enzyme; a "membrane" assignment most likely reflects co-fractionation/contamination in a large-scale proteomic dataset. Reason: Spurious/high-throughput localization inconsistent with the soluble matrix biology of ACAA1. |
| GO:0005782 peroxisomal matrix | TAS Reactome:R-HSA-2066788 | ACCEPT | Summary: Reactome (TAS) peroxisomal-matrix localization from the "Formation of DHA-CoA catalysed by 3-ketoacyl-CoA thiolase" reaction, i.e. the matrix compartment where ACAA1 acts. Reason: Correct, most-specific core localization. |
| GO:0005782 peroxisomal matrix | TAS Reactome:R-HSA-390250 | ACCEPT | Summary: Reactome (TAS) peroxisomal-matrix localization associated with a specific VLCFA thiolase reaction. Reason: Correct core localization; redundant with other matrix calls. |
| GO:0005777 peroxisome | IDA PMID:9053548 Immunocytochemical localization of peroxisomal proteins in h... | ACCEPT | Summary: Direct (IDA) peroxisome localization by immunocytochemistry in human liver and kidney. Reason: Correct core localization; one of several redundant experimental peroxisome calls. |
| GO:0000038 very long-chain fatty acid metabolic process | IMP PMID:2318981 Bile acid profiles in peroxisomal 3-oxoacyl-coenzyme A thiol... | ACCEPT | Summary: IMP from a patient lacking immunoreactive peroxisomal thiolase, in whom accumulation of C27 bile-acid intermediates and impaired peroxisomal chain shortening implicate ACAA1 in the metabolism of very-long-chain (and cholestanoic) acyl chains. Consistent with the thiolase completing VLCFA beta-oxidation. Reason: Correct, experimentally supported process directly downstream of the core thiolase activity. Supporting Evidence: PMID:2318981 liver contained no immunoreactive peroxisomal 3-oxoacyl-CoA thiolase |
| GO:0008206 bile acid metabolic process | IMP PMID:2318981 Bile acid profiles in peroxisomal 3-oxoacyl-coenzyme A thiol... | KEEP AS NON CORE | Summary: IMP from bile-acid profiling of a thiolase-deficient patient showing accumulation of C27 bile-acid intermediates (varanic acid, THCA). The peroxisomal bile-acid (branched-chain cholestanoyl-CoA) thiolytic step is now attributed principally to SCPx/SCP2; this early single-patient link predates that assignment. Reason: Secondary process relative to straight-chain beta-oxidation; the branched-chain/bile-acid thiolase role is carried by SCPx. Retained (experimental) as non-core. Supporting Evidence: PMID:2318981 liver contained no immunoreactive peroxisomal 3-oxoacyl-CoA thiolase |
| GO:0006635 fatty acid beta-oxidation | IMP PMID:2365812 Rhizomelic chondrodysplasia punctata. Deficiency of 3-oxoacy... | ACCEPT | Summary: IMP from RCDP fibroblasts with impaired maturation of peroxisomal 3-oxoacyl-CoA thiolase: reduced thiolase activity decreases the rate of peroxisomal beta-oxidation of palmitoyl-CoA, directly implicating ACAA1 in peroxisomal fatty acid beta-oxidation. Reason: Correct, experimentally supported core process. Supporting Evidence: PMID:2365812 results in a decrease in the rate of peroxisomal |
| GO:0005777 peroxisome | IDA PMID:1347505 Subcellular localisation and processing of non-specific lipi... | ACCEPT | Summary: Direct (IDA) peroxisome localization from a subcellular-fractionation study in fibroblasts. Reason: Correct core localization; redundant with other IDA peroxisome calls. |
| GO:0005777 peroxisome | IDA PMID:2365812 Rhizomelic chondrodysplasia punctata. Deficiency of 3-oxoacy... | ACCEPT | Summary: Direct (IDA) peroxisome localization: thiolase activity/protein detected in catalase-containing (peroxisomal) fractions in the RCDP-thiolase study. Reason: Correct core localization with fractionation support. Supporting Evidence: PMID:2365812 results in a decrease in the rate of peroxisomal |
| GO:0005777 peroxisome | IDA PMID:2895531 Immunocytochemical demonstration of peroxisomal enzymes in h... | ACCEPT | Summary: Direct (IDA) peroxisome localization by immunocytochemistry of peroxisomal enzymes in human kidney biopsies. Reason: Correct core localization; redundant with other IDA peroxisome calls. |
| GO:0005777 peroxisome | IDA PMID:17881773 Peroxisomes in human and mouse testis: differential expressi... | ACCEPT | Summary: Direct (IDA) peroxisome localization from a study of peroxisomal-protein expression in human and mouse testis. Reason: Correct core localization; redundant with other IDA peroxisome calls. |
| GO:0006635 fatty acid beta-oxidation | IMP PMID:2882519 Human peroxisomal 3-oxoacyl-coenzyme A thiolase deficiency. | ACCEPT | Summary: IMP from the first human peroxisomal 3-oxoacyl-CoA thiolase deficiency: peroxisomal beta-oxidation of [14C]palmitoyl-CoA was <10% of control and was restored by adding purified rat-liver peroxisomal thiolase, directly demonstrating ACAA1's role in peroxisomal fatty acid beta-oxidation. Reason: Definitive experimental support for the core beta-oxidation process. Supporting Evidence: PMID:2882519 the deficiency of peroxisomal 3-oxoacyl-CoA thiolase is responsible for the very low peroxisomal beta-oxidation activity |
| GO:0120524 long-chain fatty acyl-CoA oxidase activity | IMP PMID:2882519 Human peroxisomal 3-oxoacyl-coenzyme A thiolase deficiency. | MARK AS OVER ANNOTATED | Summary: "Long-chain fatty acyl-CoA oxidase activity" (acyl-CoA + O2 = enoyl-CoA + H2O2) is the acyl-CoA oxidase (ACOX1) step, not the thiolytic step ACAA1 catalyzes. PMID:2882519 measured a thiolase DEFICIENCY (and the resulting drop in overall beta-oxidation), not an oxidase activity of ACAA1. This is a mis-typed molecular function. Reason: Wrong molecular-function class (oxidase rather than thiolase). Per policy, an IMP annotation is not removed; flagged as over-annotation. The correct activity is acetyl-CoA C-acyltransferase (GO:0003988). Supporting Evidence: PMID:2882519 peroxisomal 3-oxoacyl-CoA thiolase (acyl-CoA:acetyl-CoA C-acyltransferase, EC 2.3.1.16) was |
| GO:0005515 protein binding | IPI PMID:18281296 Contribution of peroxisome-specific isoform of Lon protease ... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" IPI (with LONP2/pLon, Q86WA8). The cited study actually reports that pLon does NOT process the PTS2-containing 3-ketoacyl-CoA thiolase, i.e. it is largely a negative result for a functional pLon-thiolase interaction. No informative molecular function is conveyed. Reason: Uninformative bare protein-binding call with weak/negative supporting evidence; retained per policy (not removed) but flagged as over-annotation. Supporting Evidence: PMID:18281296 does not process PTS2-containing |
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