ACOX3 is a peroxisomal, FAD-dependent acyl-CoA oxidase (EC 1.3.3.6) of the acyl-CoA oxidase family that catalyzes the first and rate-limiting dehydrogenation step of peroxisomal fatty-acid beta-oxidation, converting a 2,3-saturated acyl-CoA to the corresponding (2E)-enoyl-CoA while reducing O2 to H2O2. Its preferred physiological substrates are 2-methyl-branched (multi-methyl branched) fatty acyl-CoA esters, in particular (2S)-pristanoyl-CoA, which is derived from alpha-oxidation of dietary phytanic acid; ACOX3 thus functions as a pristanoyl-CoA / branched-chain acyl-CoA oxidase. It can also oxidize straight-chain and dicarboxylyl acyl-CoAs with lower efficiency. The mature protein is a soluble matrix enzyme imported into the peroxisome via a C-terminal PTS1 (SKL) targeting signal. In humans, branched-chain acyl-CoA oxidase activity is shared with the paralog ACOX2; ACOX3 was long thought to be nearly silent but is expressed at mRNA and protein level in several normal tissues including liver, kidney, lung, brain and heart.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005504 fatty acid binding | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Phylogenetically-propagated generic MF. ACOX3 binds and oxidizes fatty acyl-CoA thioesters, not free fatty acids, so "fatty acid binding" does not capture its actual ligand or function; it is at best incidental to the catalytic activity captured by GO:0016402/GO:0003997. Reason: The substrate is a fatty acyl-CoA ester, not a free fatty acid; the specific acyl-CoA oxidase MF terms already cover the real function. Generic "fatty acid binding" is an over-annotation for an acyl-CoA oxidase. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN000097533 Acyl-CoA oxidase family node; "fatty acid binding" propagates across the family but conflates the acyl-CoA-ester substrate with free fatty acid. |
| GO:0033540 fatty acid beta-oxidation using acyl-CoA oxidase | IBA GO_REF:0000033 | ACCEPT | Summary: Correct core biological process. ACOX3 catalyzes the initial, acyl-CoA-oxidase-dependent (H2O2-generating) step of peroxisomal fatty-acid beta-oxidation, consistent with UniProt PATHWAY and experimental substrate studies. Supporting Evidence: file:human/ACOX3/ACOX3-uniprot.txt PATHWAY: Lipid metabolism; peroxisomal fatty acid beta-oxidation. PMID:29287774 both ACOX2 and ACOX3 are involved in the degradation |
| GO:0005777 peroxisome | IBA GO_REF:0000033 | ACCEPT | Summary: Correct core localization. ACOX3 is a peroxisomal enzyme with a C-terminal PTS1 (SKL) targeting signal, supported by UniProt SUBCELLULAR LOCATION and experimental IDA (PMID:8993592). Supporting Evidence: file:human/ACOX3/ACOX3-uniprot.txt SUBCELLULAR LOCATION: Peroxisome PMID:9271077 harbouring a peroxisomal C-terminal-targeting |
| GO:0050660 flavin adenine dinucleotide binding | IBA GO_REF:0000033 | ACCEPT | Summary: Correct core cofactor-binding function. ACOX3 is a flavoprotein oxidoreductase that uses FAD as prosthetic group; UniProt records the FAD cofactor. GO:0050660 and GO:0071949 are equivalent descriptions of FAD binding. Supporting Evidence: file:human/ACOX3/ACOX3-uniprot.txt Name=FAD; Xref=ChEBI:CHEBI:57692 |
| GO:0016402 pristanoyl-CoA oxidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Correct core molecular function and the most specific well-supported MF for ACOX3. The enzyme oxidizes (2S)-pristanoyl-CoA and other 2-methyl-branched acyl-CoA esters; supported by the UniProt catalytic activity and by experimental substrate-specificity studies. Supporting Evidence: file:human/ACOX3/ACOX3-uniprot.txt Reaction=(2S)-pristanoyl-CoA + O2 = (2E)-pristenoyl-CoA + H2O2 file:human/ACOX3/ACOX3-uniprot.txt Oxidizes the CoA-esters of 2-methyl-branched fatty acids. |
| GO:0003997 acyl-CoA oxidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Correct parent molecular function (EC 1.3.3.6). ACOX3 catalyzes a 2,3-saturated acyl-CoA + O2 = a (2E)-enoyl-CoA + H2O2. Retained as core; the more specific GO:0016402 (pristanoyl-CoA oxidase activity) better captures the physiological substrate preference. Supporting Evidence: file:human/ACOX3/ACOX3-uniprot.txt Reaction=a 2,3-saturated acyl-CoA + O2 = a (2E)-enoyl-CoA + H2O2 |
| GO:0005504 fatty acid binding | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro-propagated duplicate of the "fatty acid binding" annotation. Same reasoning: ACOX3 binds fatty acyl-CoA esters, not free fatty acids. Reason: Generic InterPro2GO transfer that mischaracterizes the ligand; the acyl-CoA oxidase MF terms already describe the real substrate binding/turnover. |
| GO:0005777 peroxisome | IEA GO_REF:0000120 | ACCEPT | Summary: Correct localization, electronically inferred and consistent with the experimental IDA and UniProt SUBCELLULAR LOCATION. Redundant with the IBA and IDA peroxisome annotations. Supporting Evidence: file:human/ACOX3/ACOX3-uniprot.txt SUBCELLULAR LOCATION: Peroxisome |
| GO:0005782 peroxisomal matrix | IEA GO_REF:0000117 | ACCEPT | Summary: More specific and correct localization. ACOX3 is a soluble matrix enzyme imported via its PTS1 signal; the peroxisomal matrix is the compartment where it acts. Consistent with Reactome TAS matrix annotations. Supporting Evidence: file:human/ACOX3/ACOX3-uniprot.txt SUBCELLULAR LOCATION: Peroxisome PMID:9271077 harbouring a peroxisomal C-terminal-targeting |
| GO:0006631 fatty acid metabolic process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Correct but very general parent BP. The specific process (peroxisomal fatty-acid beta-oxidation) is captured by GO:0033540 / GO:0006635, which are the informative annotations to retain. Reason: High-level parent of the more specific beta-oxidation terms already present; not wrong but uninformative as a standalone. |
| GO:0006635 fatty acid beta-oxidation | IEA GO_REF:0000002 | ACCEPT | Summary: Correct core biological process describing the beta-oxidation pathway ACOX3 initiates. Consistent with the UniProt PATHWAY annotation and the peroxisomal acyl-CoA-oxidase branch (GO:0033540). Supporting Evidence: file:human/ACOX3/ACOX3-uniprot.txt PATHWAY: Lipid metabolism; peroxisomal fatty acid beta-oxidation. |
| GO:0016402 pristanoyl-CoA oxidase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Rhea-mapped duplicate of the core pristanoyl-CoA oxidase MF, mapped from RHEA:40459 ((2S)-pristanoyl-CoA + O2 = (2E)-pristenoyl-CoA + H2O2). Correct and core. Supporting Evidence: file:human/ACOX3/ACOX3-uniprot.txt Reaction=(2S)-pristanoyl-CoA + O2 = (2E)-pristenoyl-CoA + H2O2 |
| GO:0016627 oxidoreductase activity, acting on the CH-CH group of donors | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Correct but general grandparent MF. This is the EC-class-level description of an acyl-CoA oxidase/dehydrogenase; the specific acyl-CoA oxidase terms are the informative ones to retain. Reason: High-level parent of GO:0003997/GO:0016402; not wrong but uninformative. |
| GO:0033540 fatty acid beta-oxidation using acyl-CoA oxidase | IEA GO_REF:0000120 | ACCEPT | Summary: Electronically-inferred duplicate of the core IBA BP annotation. Correct and core: ACOX3 initiates the acyl-CoA-oxidase (H2O2-generating) branch of peroxisomal beta-oxidation. Supporting Evidence: file:human/ACOX3/ACOX3-uniprot.txt PATHWAY: Lipid metabolism; peroxisomal fatty acid beta-oxidation. |
| GO:0044535 very-long-chain fatty acyl-CoA oxidase activity | IEA GO_REF:0000116 | KEEP AS NON CORE | Summary: Rhea-mapped from a By-similarity straight-chain reaction (tetracosanoyl-CoA, RHEA:40319). ACOX3 can oxidize straight/very-long-chain acyl-CoAs but only with lower efficiency; this is not its physiological (branched-chain) role. Plausible but non-core. Reason: Reflects lower-efficiency, By-similarity straight-chain activity, not the branched-chain specialization that defines ACOX3. Supporting Evidence: file:human/ACOX3/ACOX3-uniprot.txt Can oxidize straight-chain mono- and dicarboxylyl |
| GO:0071949 FAD binding | IEA GO_REF:0000002 | ACCEPT | Summary: Correct core cofactor-binding function; equivalent to the IBA GO:0050660 annotation. ACOX3 is a FAD-dependent flavoprotein oxidase. Supporting Evidence: file:human/ACOX3/ACOX3-uniprot.txt Name=FAD; Xref=ChEBI:CHEBI:57692 |
| GO:0120523 medium-chain fatty acyl-CoA oxidase activity | IEA GO_REF:0000116 | KEEP AS NON CORE | Summary: Rhea-mapped from a straight-chain reaction (decanoyl-CoA, RHEA:40179). Represents lower-efficiency straight-chain activity rather than the physiological branched-chain role; retained as non-core. Reason: Lower-efficiency straight-chain activity; not the defining branched-chain function. Supporting Evidence: file:human/ACOX3/ACOX3-uniprot.txt Can oxidize straight-chain mono- and dicarboxylyl |
| GO:0120524 long-chain fatty acyl-CoA oxidase activity | IEA GO_REF:0000116 | KEEP AS NON CORE | Summary: Rhea-mapped from a straight-chain reaction (hexadecanoyl-CoA, RHEA:40167; ECO:0000305 in UniProt). Lower-efficiency straight-chain activity rather than the physiological branched-chain role; retained as non-core. Reason: Lower-efficiency straight-chain activity; not the defining branched-chain function. Supporting Evidence: file:human/ACOX3/ACOX3-uniprot.txt Can oxidize straight-chain mono- and dicarboxylyl |
| GO:0003997 acyl-CoA oxidase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Correct core molecular function, transferred by sequence similarity from the rat ortholog (Q63448, pristanoyl-CoA oxidase). Consistent with the human catalytic-activity evidence; retained as core parent MF. Supporting Evidence: file:human/ACOX3/ACOX3-uniprot.txt Reaction=a 2,3-saturated acyl-CoA + O2 = a (2E)-enoyl-CoA + H2O2 |
| GO:0016402 pristanoyl-CoA oxidase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Correct core molecular function, transferred by sequence similarity from the rat pristanoyl-CoA oxidase ortholog (Q63448). Duplicate of the IBA/IEA/Rhea pristanoyl-CoA oxidase annotations; core. Supporting Evidence: file:human/ACOX3/ACOX3-uniprot.txt Reaction=(2S)-pristanoyl-CoA + O2 = (2E)-pristenoyl-CoA + H2O2 PMID:9271077 the human homologue of rat |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9033235 | KEEP AS NON CORE | Summary: Reactome annotation reflecting the transient cytosolic stage of PEX5-mediated peroxisomal matrix import (cargo translocates from the cytosol to the peroxisomal matrix), not a steady-state cytosolic localization. Keep as non-core; the steady-state compartment is the peroxisomal matrix. Reason: Captures the import intermediate (newly synthesized enzyme in the cytosol before PEX5-dependent matrix translocation), not the functional location. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9033236 | KEEP AS NON CORE | Summary: Duplicate Reactome cytosol annotation from the PEX5 docking/translocation step. As above, an import intermediate rather than the functional localization. Reason: Reflects PTS1-cargo binding to the docking module during import, not steady-state cytosolic residence. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: High-throughput membrane-proteome dataset from an NK-like cell line (YTS) that identified >1800 proteins; ACOX3 is a soluble peroxisomal matrix enzyme, so this generic "membrane" localization is almost certainly non-specific co-purification rather than a genuine membrane association. Not removed (experimental HDA), but flagged as over-annotation. Reason: Bulk membrane-proteome study; ACOX3 has no transmembrane domain and is a matrix-soluble enzyme, so "membrane" is not an informative or reliable localization for it. |
| GO:0005782 peroxisomal matrix | TAS Reactome:R-HSA-389891 | ACCEPT | Summary: Correct, specific localization. Reactome models ACOX3 as the matrix enzyme catalyzing (2S)-pristanoyl-CoA oxidation. Consistent with the PTS1 import pathway and UniProt peroxisome localization. Supporting Evidence: file:human/ACOX3/ACOX3-uniprot.txt SUBCELLULAR LOCATION: Peroxisome |
| GO:0005782 peroxisomal matrix | TAS Reactome:R-HSA-9033235 | ACCEPT | Summary: Duplicate peroxisomal-matrix annotation from the PEX5 import reaction (cargo released into the peroxisomal matrix). Correct steady-state localization. Supporting Evidence: file:human/ACOX3/ACOX3-uniprot.txt SUBCELLULAR LOCATION: Peroxisome |
| GO:0005777 peroxisome | IDA PMID:8993592 Mammalian peroxisomal acyl-CoA oxidases. III. Molecular char... | ACCEPT | Summary: Experimental (IDA) peroxisomal localization from the molecular characterization of human branched-chain fatty acyl-CoA oxidase. Correct core localization; consistent with the PTS1 (SKL) targeting signal and UniProt SUBCELLULAR LOCATION. Supporting Evidence: file:human/ACOX3/ACOX3-uniprot.txt SUBCELLULAR LOCATION: Peroxisome PMID:9271077 harbouring a peroxisomal C-terminal-targeting |
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