SOD1

UniProt ID: P00441
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

SOD1 encodes Cu/Zn superoxide dismutase, a highly abundant homodimeric metalloenzyme that catalyzes the dismutation of superoxide radical (O2.-) into molecular oxygen and hydrogen peroxide (EC 1.15.1.1), providing a first line of antioxidant defense. Each ~16 kDa subunit adopts an eight-stranded Greek-key beta-barrel and binds one catalytic copper ion and one structural zinc ion; an intrasubunit disulfide bond (Cys58-Cys147) and zinc binding stabilize the unusually robust dimer. Catalytic copper is delivered by the copper chaperone CCS, which also promotes intramolecular disulfide formation during maturation. SOD1 is predominantly cytosolic, with a functional minor pool in the mitochondrial intermembrane space (imported with CCS) that detoxifies mitochondria-derived superoxide, and additional pools detected in the nucleus and extracellularly. Beyond its dismutase activity, SOD1 has been reported to oxidize hydrogen sulfide to sulfate (a reactive-sulfur-species detoxifying activity) and to act as a redox sensor that binds Rac1 to modulate NADPH oxidase. Loss of SOD1 activity causes a recessive neurological syndrome (STAHP), whereas dominant missense variants cause familial amyotrophic lateral sclerosis through a toxic gain-of-function involving destabilization, misfolding, and aggregation of the protein.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005634 nucleus
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: IBA across the Cu/Zn-SOD family annotates SOD1 active in the nucleus; SOD1 has a reproducible secondary nuclear pool that participates in the oxidative stress response and has been linked to roles in transcription and ribosome biogenesis.
Reason: Nuclear localization is genuine but secondary to the predominant cytosolic site of catalysis; kept as non-core.
Supporting Evidence:
PMID:1332049
Cu,Zn-SOD was found widely distributed in the cell cytosol and in the cell nucleus
file:human/SOD1/SOD1-deep-research-falcon.md
substantial nuclear localization of SOD1 under both normal and pathological conditions, where it participates in oxidative stress response and may have regulatory roles in transcription and ribosome biogenesis
GO:0019430 removal of superoxide radicals
IBA
GO_REF:0000033 		ACCEPT
Summary: IBA: removal of superoxide radicals; the direct process consequence of dismutase activity.
Reason: Strongly phylogenetically supported and equivalent to the core enzymatic role.
Supporting Evidence:
PMID:16790527
Superoxide dismutases (SODs) represent the first line of defense against oxidative stress
GO:0005739 mitochondrion
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: IBA: SOD1 active in mitochondrion; reflects the intermembrane-space pool.
Reason: The functional mitochondrial pool is specifically the intermembrane space (GO:0005758); the generic 'mitochondrion' is a broader, non-core localization.
Supporting Evidence:
PMID:24026195
both localize to the cytosol and the mitochondrial intermembrane space where they specifically counteract mitochondria-derived superoxide
GO:0005507 copper ion binding
IBA
GO_REF:0000033 		ACCEPT
Summary: IBA: copper ion binding, the catalytic metal of SOD1.
Reason: Phylogenetically well-supported; copper is the catalytic cofactor.
Supporting Evidence:
PMID:31292775
Copper-zinc superoxide dismutase (Sod1) is a critical antioxidant enzyme that rids the cell of reactive oxygen through the redox cycling of a catalytic copper ion provided by its copper chaperone (Ccs).
GO:0005777 peroxisome
IBA
GO_REF:0000033 		MARK AS OVER ANNOTATED
Summary: IBA: SOD1 active in peroxisome; weakly supported in human cells.
Reason: Peroxisomal localization is poorly supported; EM immunocytochemistry found SOD1 primarily cytosolic with peroxisome labeling near background. Likely over-annotation.
Supporting Evidence:
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells.
GO:0005829 cytosol
IBA
GO_REF:0000033 		ACCEPT
Summary: IBA: cytosol; SOD1 is principally cytosolic.
Reason: Core compartment; matches direct human-cell localization.
Supporting Evidence:
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells.
GO:0004784 superoxide dismutase activity
IEA
GO_REF:0000120 		ACCEPT
Summary: SOD1 catalyzes dismutation of superoxide to O2 + H2O2 (EC 1.15.1.1); the defining molecular function.
Reason: IEA mapping from RHEA/EC is correct and matches direct experimental evidence.
Supporting Evidence:
PMID:24140062
Cu/Zn superoxide dismutase (SOD1) is a key antioxidant enzyme.
GO:0005507 copper ion binding
IEA
GO_REF:0000120 		ACCEPT
Summary: Copper ion binding (IEA); the catalytic copper cofactor.
Reason: Correct metal-binding mapping.
Supporting Evidence:
PMID:31292775
Copper-zinc superoxide dismutase (Sod1) is a critical antioxidant enzyme that rids the cell of reactive oxygen through the redox cycling of a catalytic copper ion provided by its copper chaperone (Ccs).
GO:0005634 nucleus
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: Nucleus (IEA, SubCell).
Reason: Secondary nuclear pool; non-core.
Supporting Evidence:
PMID:1332049
Cu,Zn-SOD was found widely distributed in the cell cytosol and in the cell nucleus
GO:0005737 cytoplasm
IEA
GO_REF:0000120 		ACCEPT
Summary: Cytoplasm (IEA, SubCell).
Reason: Consistent with predominant cytosolic localization.
Supporting Evidence:
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells.
GO:0006801 superoxide metabolic process
IEA
GO_REF:0000120 		ACCEPT
Summary: Superoxide metabolic process (IEA); core process parent of dismutation.
Reason: Correct broad parent of the reaction.
GO:0046872 metal ion binding
IEA
GO_REF:0000002 		KEEP AS NON CORE
Summary: Broad 'metal ion binding' (IEA, InterPro).
Reason: Correct but less informative than the specific copper (GO:0005507) and zinc (GO:0008270) ion binding annotations; retained as a broader parent.
GO:1904115 axon cytoplasm
IEA
GO_REF:0000108 		MARK AS OVER ANNOTATED
Summary: Axon cytoplasm (IEA), inferred from axonal-transport annotations of the rodent ortholog.
Reason: Derived computationally from ortholog axonal-transport annotations; not a core human SOD1 localization.
GO:0005515 protein binding
IPI
PMID:12968035
The copper toxicosis gene product Murr1 directly interacts w... 		MARK AS OVER ANNOTATED
Summary: Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets.
Reason: Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding).
GO:0005515 protein binding
IPI
PMID:16369483
Chromogranin-mediated secretion of mutant superoxide dismuta... 		MARK AS OVER ANNOTATED
Summary: Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets.
Reason: Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding).
GO:0005515 protein binding
IPI
PMID:16595634
Spinal cord endoplasmic reticulum stress associated with a m... 		MARK AS OVER ANNOTATED
Summary: Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets.
Reason: Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding).
GO:0005515 protein binding
IPI
PMID:19171884
Progressive aggregation despite chaperone associations of a ... 		MARK AS OVER ANNOTATED
Summary: Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets.
Reason: Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding).
GO:0005515 protein binding
IPI
PMID:20195357
A comprehensive resource of interacting protein regions for ... 		MARK AS OVER ANNOTATED
Summary: Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets.
Reason: Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding).
GO:0005515 protein binding
IPI
PMID:21252941
BAG3 mediates chaperone-based aggresome-targeting and select... 		MARK AS OVER ANNOTATED
Summary: Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets.
Reason: Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding).
GO:0005515 protein binding
IPI
PMID:22508683
Molecular and biochemical characterization of a unique mutat... 		MARK AS OVER ANNOTATED
Summary: Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets.
Reason: Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding).
GO:0005515 protein binding
IPI
PMID:24234043
Cystatin B and SOD1: protein–protein interaction and possibl... 		MARK AS OVER ANNOTATED
Summary: Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets.
Reason: Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding).
GO:0005515 protein binding
IPI
PMID:24981860
Human-chromatin-related protein interactions identify a deme... 		MARK AS OVER ANNOTATED
Summary: Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets.
Reason: Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding).
GO:0005515 protein binding
IPI
PMID:26643113
alpha-synuclein interacts with SOD1 and promotes its oligome... 		MARK AS OVER ANNOTATED
Summary: Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets.
Reason: Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding).
Supporting Evidence:
PMID:26643113
α-synuclein interacts with SOD1 and promotes its oligomerization.
GO:0005515 protein binding
IPI
PMID:28514442
Architecture of the human interactome defines protein commun... 		MARK AS OVER ANNOTATED
Summary: Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets.
Reason: Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding).
GO:0005515 protein binding
IPI
PMID:29128334
A Map of Human Mitochondrial Protein Interactions Linked to ... 		MARK AS OVER ANNOTATED
Summary: Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets.
Reason: Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding).
GO:0005515 protein binding
IPI
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative ... 		MARK AS OVER ANNOTATED
Summary: Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets.
Reason: Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding).
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		MARK AS OVER ANNOTATED
Summary: Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets.
Reason: Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding).
GO:0042802 identical protein binding
IPI
PMID:17592131
Metal-free superoxide dismutase forms soluble oligomers unde... 		ACCEPT
Summary: SOD1 self-association (identical protein binding); SOD1 functions as a homodimer.
Reason: SOD1 is an obligate homodimer; identical protein binding (homodimerization) is a genuine and informative molecular function supported by structural and interaction studies.
GO:0042802 identical protein binding
IPI
PMID:19022905
Initiation and elongation in fibrillation of ALS-linked supe... 		ACCEPT
Summary: SOD1 self-association (identical protein binding); SOD1 functions as a homodimer.
Reason: SOD1 is an obligate homodimer; identical protein binding (homodimerization) is a genuine and informative molecular function supported by structural and interaction studies.
GO:0042802 identical protein binding
IPI
PMID:19171884
Progressive aggregation despite chaperone associations of a ... 		ACCEPT
Summary: SOD1 self-association (identical protein binding); SOD1 functions as a homodimer.
Reason: SOD1 is an obligate homodimer; identical protein binding (homodimerization) is a genuine and informative molecular function supported by structural and interaction studies.
Supporting Evidence:
PMID:19171884
superoxide dismutase 1 (SOD1)-linked amyotrophic
GO:0042802 identical protein binding
IPI
PMID:19369197
Structural and dynamic aspects related to oligomerization of... 		ACCEPT
Summary: SOD1 self-association (identical protein binding); SOD1 functions as a homodimer.
Reason: SOD1 is an obligate homodimer; identical protein binding (homodimerization) is a genuine and informative molecular function supported by structural and interaction studies.
GO:0042802 identical protein binding
IPI
PMID:19828437
Transient structural distortion of metal-free Cu/Zn superoxi... 		ACCEPT
Summary: SOD1 self-association (identical protein binding); SOD1 functions as a homodimer.
Reason: SOD1 is an obligate homodimer; identical protein binding (homodimerization) is a genuine and informative molecular function supported by structural and interaction studies.
GO:0042802 identical protein binding
IPI
PMID:21257910
Decreased stability and increased formation of soluble aggre... 		ACCEPT
Summary: SOD1 self-association (identical protein binding); SOD1 functions as a homodimer.
Reason: SOD1 is an obligate homodimer; identical protein binding (homodimerization) is a genuine and informative molecular function supported by structural and interaction studies.
GO:0042802 identical protein binding
IPI
PMID:23831581
Intracellular seeded aggregation of mutant Cu,Zn-superoxide ... 		ACCEPT
Summary: SOD1 self-association (identical protein binding); SOD1 functions as a homodimer.
Reason: SOD1 is an obligate homodimer; identical protein binding (homodimerization) is a genuine and informative molecular function supported by structural and interaction studies.
GO:0042802 identical protein binding
IPI
PMID:26643113
alpha-synuclein interacts with SOD1 and promotes its oligome... 		ACCEPT
Summary: SOD1 self-association (identical protein binding); SOD1 functions as a homodimer.
Reason: SOD1 is an obligate homodimer; identical protein binding (homodimerization) is a genuine and informative molecular function supported by structural and interaction studies.
GO:0042802 identical protein binding
IPI
PMID:31999698
Tryptophan residue 32 in human Cu-Zn superoxide dismutase mo... 		ACCEPT
Summary: SOD1 self-association (identical protein binding); SOD1 functions as a homodimer.
Reason: SOD1 is an obligate homodimer; identical protein binding (homodimerization) is a genuine and informative molecular function supported by structural and interaction studies.
GO:0001975 response to amphetamine
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Response to amphetamine (IEA, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0005576 extracellular region
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: Extracellular region (IEA).
Reason: A minor secreted/extracellular pool of SOD1 (including exosomes) exists but is peripheral to the cytosolic antioxidant function.
GO:0005764 lysosome
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Lysosome (IEA, ortholog).
Reason: Minor/ortholog-transferred localization; non-core.
GO:0005777 peroxisome
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: Peroxisome (IEA, ortholog).
Reason: Weakly supported in human; same concern as the IBA peroxisome call.
Supporting Evidence:
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells.
GO:0006979 response to oxidative stress
IEA
GO_REF:0000107 		ACCEPT
Summary: Response to oxidative stress (IEA, ortholog); SOD1 is a first-line antioxidant defense.
Reason: Core defensive role against oxidative stress.
Supporting Evidence:
PMID:16790527
Superoxide dismutases (SODs) represent the first line of defense against oxidative stress
GO:0008089 anterograde axonal transport
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Anterograde axonal transport (IEA, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0008090 retrograde axonal transport
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Retrograde axonal transport (IEA, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0019430 removal of superoxide radicals
IEA
GO_REF:0000107 		ACCEPT
Summary: Removal of superoxide radicals (IEA, ortholog); core process.
Reason: Equivalent to the core enzymatic role.
Supporting Evidence:
PMID:16790527
Superoxide dismutases (SODs) represent the first line of defense against oxidative stress
GO:0019899 enzyme binding
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Enzyme binding (IEA, ortholog).
Reason: Generic and uninformative; more specific informative binding (e.g. calcineurin/PP2B, Rac1, CCS) is captured elsewhere. Non-core.
GO:0030141 secretory granule
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Secretory granule (IEA, ortholog).
Reason: Minor ortholog-transferred localization; non-core.
GO:0030346 protein phosphatase 2B binding
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Protein phosphatase 2B (calcineurin) binding (IEA, ortholog).
Reason: SOD1 directly binds and activates calcineurin (protein phosphatase 2B); a specific, experimentally supported interaction, though peripheral to the core antioxidant function.
GO:0031045 dense core granule
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Dense core granule (IEA, ortholog).
Reason: Minor ortholog-transferred localization; non-core.
GO:0031667 response to nutrient levels
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Response to nutrient levels (IEA, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0032991 protein-containing complex
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Protein-containing complex (IEA, ortholog).
Reason: Very generic; SOD1's specific complexes (homodimer, CCS chaperone complex) are captured by more precise terms. Non-core.
GO:0034465 response to carbon monoxide
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Response to carbon monoxide (IEA, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0034599 cellular response to oxidative stress
IEA
GO_REF:0000107 		ACCEPT
Summary: Cellular response to oxidative stress (IEA, ortholog).
Reason: Consistent with SOD1's antioxidant defense role.
Supporting Evidence:
PMID:16790527
Superoxide dismutases (SODs) represent the first line of defense against oxidative stress
GO:0035865 cellular response to potassium ion
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Cellular response to potassium ion (IEA, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0043025 neuronal cell body
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Neuronal cell body (IEA, ortholog).
Reason: Cell-type-specific localization; non-core.
GO:0043066 negative regulation of apoptotic process
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Negative regulation of apoptotic process (IEA, ortholog).
Reason: SOD1 is broadly cytoprotective/anti-apoptotic via ROS removal; this downstream process is non-core.
GO:0046688 response to copper ion
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Response to copper ion (IEA, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0050665 hydrogen peroxide biosynthetic process
IEA
GO_REF:0000120 		ACCEPT
Summary: Hydrogen peroxide biosynthetic process (IEA); H2O2 is the SOD reaction product.
Reason: H2O2 is the direct product of dismutation; correct consequence of SOD1 activity.
GO:0050728 negative regulation of inflammatory response
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Negative regulation of inflammatory response (IEA, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0050766 positive regulation of phagocytosis
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Positive regulation of phagocytosis (IEA, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0071276 cellular response to cadmium ion
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Cellular response to cadmium ion (IEA, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0071318 cellular response to ATP
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Cellular response to ATP (IEA, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0097332 response to antipsychotic drug
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Response to antipsychotic drug (IEA, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0005758 mitochondrial intermembrane space
IDA
PMID:24026195
Human copper chaperone for superoxide dismutase 1 mediates i... 		ACCEPT
Summary: Mitochondrial intermembrane space as active location (IDA).
Reason: Direct evidence for a functional IMS pool dismutating mitochondria-derived superoxide.
Supporting Evidence:
PMID:24026195
both localize to the cytosol and the mitochondrial intermembrane space where they specifically counteract mitochondria-derived superoxide
GO:0005829 cytosol
TAS
PMID:24026195
Human copper chaperone for superoxide dismutase 1 mediates i... 		ACCEPT
Summary: Cytosol as active location (TAS).
Reason: Core compartment.
Supporting Evidence:
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells.
GO:0019430 removal of superoxide radicals
NAS
PMID:31292775
Copper-zinc superoxide dismutase (Sod1) activation terminate... 		ACCEPT
Summary: Removal of superoxide radicals asserted for the SOD1/CCS complex (NAS).
Reason: Equivalent to the core process.
Supporting Evidence:
PMID:31292775
Copper-zinc superoxide dismutase (Sod1) is a critical antioxidant enzyme that rids the cell of reactive oxygen through the redox cycling of a catalytic copper ion provided by its copper chaperone (Ccs).
GO:1902694 superoxide dismutase copper chaperone complex
IPI
PMID:30735496
Molecular recognition and maturation of SOD1 by its evolutio... 		ACCEPT
Summary: SOD1 is part of the superoxide dismutase copper chaperone complex (with CCS).
Reason: Directly supported: hCCS recognizes and matures SOD1 (copper insertion, disulfide formation) via a defined heterocomplex.
Supporting Evidence:
PMID:30735496
Molecular recognition and maturation of SOD1 by its evolutionarily destabilised cognate chaperone hCCS.
GO:0005654 nucleoplasm
IDA
GO_REF:0000052 		KEEP AS NON CORE
Summary: Nucleoplasm (IDA, HPA).
Reason: Secondary nuclear pool; non-core.
Supporting Evidence:
PMID:1332049
Cu,Zn-SOD was found widely distributed in the cell cytosol and in the cell nucleus
GO:0005829 cytosol
IDA
GO_REF:0000052 		ACCEPT
Summary: Cytosol (IDA, HPA immunofluorescence).
Reason: Core compartment.
Supporting Evidence:
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells.
GO:0005739 mitochondrion
HTP
PMID:34800366
Quantitative high-confidence human mitochondrial proteome an... 		KEEP AS NON CORE
Summary: Mitochondrion (HTP proteomics).
Reason: High-throughput; consistent with IMS pool but non-specific.
GO:0019430 removal of superoxide radicals
IDA
PMID:24567322
DJ-1 is a copper chaperone acting on SOD1 activation. 		ACCEPT
Summary: DJ-1/PARK7 copper chaperone activates SOD1, restoring superoxide removal.
Reason: Direct demonstration of SOD1 activation and superoxide removal.
Supporting Evidence:
PMID:24567322
DJ-1 is a copper chaperone acting on SOD1 activation.
GO:0042803 protein homodimerization activity
IPI
PMID:24567322
DJ-1 is a copper chaperone acting on SOD1 activation. 		ACCEPT
Summary: Protein homodimerization activity (IPI); SOD1 is an obligate homodimer.
Reason: Homodimerization is a core structural property required for activity.
Supporting Evidence:
PMID:24567322
DJ-1 is a copper chaperone acting on SOD1 activation.
GO:0019430 removal of superoxide radicals
IDA
PMID:16254550
Expression of superoxide dismutase in whole lens prevents ca... 		ACCEPT
Summary: SOD1 expression in lens prevents oxidative cataract via superoxide removal.
Reason: Functional demonstration of antioxidant protection.
Supporting Evidence:
PMID:16254550
overexpression of superoxide dismutase (SOD) in intact lenses could prevent cataract formation induced by oxidative stress
GO:0005515 protein binding
IPI
PMID:31292775
Copper-zinc superoxide dismutase (Sod1) activation terminate... 		KEEP AS NON CORE
Summary: Protein-binding interaction with CCS (IPI).
Reason: Bare 'protein binding', but the partner (copper chaperone CCS) is functionally central; the informative aspect is captured by the copper chaperone complex and chaperone-binding annotations. Kept non-core.
Supporting Evidence:
PMID:31292775
provided by its copper chaperone (Ccs)
GO:0043410 positive regulation of MAPK cascade
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Positive regulation of MAPK cascade (ISS, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0005737 cytoplasm
IDA
PMID:24784232
A new transcriptional role for matrix metalloproteinase-12 i... 		ACCEPT
Summary: Cytoplasm (IDA).
Reason: Core compartment.
Supporting Evidence:
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells.
GO:0005515 protein binding
IPI
PMID:24023695
Molecular chaperone mediated late-stage neuroprotection in t... 		KEEP AS NON CORE
Summary: Protein-binding interaction with the chaperone HSJ1/DNAJB2 (IPI).
Reason: Disease-context chaperone interaction (mutant SOD1 aggregation); bare protein binding, non-core.
Supporting Evidence:
PMID:24023695
HSJ1a preferentially bound to mutant SOD1
GO:0005634 nucleus
IDA
PMID:24023695
Molecular chaperone mediated late-stage neuroprotection in t... 		KEEP AS NON CORE
Summary: Nucleus (IDA).
Reason: Secondary nuclear pool; non-core.
Supporting Evidence:
PMID:1332049
Cu,Zn-SOD was found widely distributed in the cell cytosol and in the cell nucleus
GO:0005737 cytoplasm
IDA
PMID:24023695
Molecular chaperone mediated late-stage neuroprotection in t... 		ACCEPT
Summary: Cytoplasm (IDA).
Reason: Core compartment.
Supporting Evidence:
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells.
GO:0005634 nucleus
IDA
PMID:22496122
Endothelial cell palmitoylproteomic identifies novel lipid-m... 		KEEP AS NON CORE
Summary: Nucleus (IDA); Cys7 palmitoylation promotes nuclear targeting.
Reason: Genuine secondary nuclear pool regulated by palmitoylation; non-core.
Supporting Evidence:
PMID:22496122
palmitoylproteins identified is superoxide dismutase-1, an intensively studied enzyme that protects all cells from oxidative damage
GO:0005739 mitochondrion
IDA
PMID:19741096
Mitochondrial ubiquitin ligase MITOL ubiquitinates mutant SO... 		KEEP AS NON CORE
Summary: Mitochondrion (IDA); ALS-mutant SOD1 accumulates in mitochondria.
Reason: Derives from mutant SOD1 aggregation/accumulation in mitochondria, a disease context rather than the core wild-type location.
GO:0070062 extracellular exosome
HDA
PMID:23533145
In-depth proteomic analyses of exosomes isolated from expres... 		KEEP AS NON CORE
Summary: Extracellular exosome (HDA proteomics).
Reason: A minor secreted/extracellular pool of SOD1 (including exosomes) exists but is peripheral to the cytosolic antioxidant function.
GO:0004784 superoxide dismutase activity
IDA
PMID:24567322
DJ-1 is a copper chaperone acting on SOD1 activation. 		ACCEPT
Summary: Direct SOD activity assay (DJ-1/SOD1 study).
Reason: Confirms the core molecular function.
Supporting Evidence:
PMID:24567322
DJ-1 is a copper chaperone acting on SOD1 activation.
GO:0005634 nucleus
HDA
PMID:21630459
Proteomic characterization of the human sperm nucleus. 		KEEP AS NON CORE
Summary: Nucleus (HDA proteomics).
Reason: Secondary nuclear pool; non-core.
Supporting Evidence:
PMID:1332049
Cu,Zn-SOD was found widely distributed in the cell cytosol and in the cell nucleus
GO:0004784 superoxide dismutase activity
IDA
PMID:24140062
SIRT5 desuccinylates and activates SOD1 to eliminate ROS. 		ACCEPT
Summary: Direct SOD activity assay; succinylation/SIRT5 regulation study.
Reason: Confirms core function.
Supporting Evidence:
PMID:24140062
Cu/Zn superoxide dismutase (SOD1) is a key antioxidant enzyme.
GO:0072593 reactive oxygen species metabolic process
IDA
PMID:24140062
SIRT5 desuccinylates and activates SOD1 to eliminate ROS. 		ACCEPT
Summary: Reactive oxygen species metabolic process (IDA). Beyond consuming superoxide, SOD1-derived H2O2 itself acts as a diffusible redox-signaling species, reinforcing SOD1's central role in cellular ROS metabolism.
Reason: SOD1 directly governs cellular ROS levels; it both removes superoxide and generates H2O2, which functions in redox signaling, so the broad ROS metabolic process term is well supported.
Supporting Evidence:
PMID:24140062
SOD1-mediated ROS reduction is increased when SIRT5 is co-expressed.
file:human/SOD1/SOD1-deep-research-falcon.md
H2O2 generated by SOD1 can diffuse across cellular membranes and oxidize specific protein thiols, thereby regulating enzyme activities, transcription factors, and signaling pathways
GO:0070062 extracellular exosome
HDA
PMID:19056867
Large-scale proteomics and phosphoproteomics of urinary exos... 		KEEP AS NON CORE
Summary: Extracellular exosome (HDA proteomics).
Reason: A minor secreted/extracellular pool of SOD1 (including exosomes) exists but is peripheral to the cytosolic antioxidant function.
GO:0005758 mitochondrial intermembrane space
TAS
Reactome:R-HSA-3777112 		ACCEPT
Summary: Mitochondrial IMS (TAS, Reactome) dismutation.
Reason: Functional IMS pool.
Supporting Evidence:
PMID:24026195
both localize to the cytosol and the mitochondrial intermembrane space where they specifically counteract mitochondria-derived superoxide
GO:0005758 mitochondrial intermembrane space
TAS
Reactome:R-HSA-8950771 		ACCEPT
Summary: Mitochondrial IMS (TAS, Reactome) detoxification of ROS.
Reason: Functional IMS pool.
Supporting Evidence:
PMID:24026195
both localize to the cytosol and the mitochondrial intermembrane space where they specifically counteract mitochondria-derived superoxide
GO:0005829 cytosol
TAS
Reactome:R-HSA-3299691 		ACCEPT
Summary: Cytosol (TAS, Reactome).
Reason: Core compartment.
Supporting Evidence:
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells.
GO:0005829 cytosol
TAS
Reactome:R-HSA-3299753 		ACCEPT
Summary: Cytosol (TAS, Reactome).
Reason: Core compartment.
Supporting Evidence:
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells.
GO:0004784 superoxide dismutase activity
IDA
PMID:12551919
Differential effects of superoxide dismutase isoform express... 		ACCEPT
Summary: Direct SOD activity (CuZn-SOD overexpression in PC-12).
Reason: Confirms core function.
Supporting Evidence:
PMID:12551919
stably overexpress the human mitochondrial or cytoplasmic forms of superoxide
GO:0006801 superoxide metabolic process
IDA
PMID:12551919
Differential effects of superoxide dismutase isoform express... 		ACCEPT
Summary: Superoxide metabolic process (IDA).
Reason: SOD1 governs superoxide handling.
Supporting Evidence:
PMID:12551919
Stable overexpression of SOD isoforms
GO:1902177 positive regulation of oxidative stress-induced intrinsic apoptotic signaling pathway
IMP
PMID:12551919
Differential effects of superoxide dismutase isoform express... 		MARK AS OVER ANNOTATED
Summary: Positive regulation of oxidative-stress-induced intrinsic apoptotic signaling (IMP).
Reason: Derived from SOD isoform overexpression effects on hydroperoxide-induced apoptosis; SOD1 is canonically cytoprotective/antioxidant, so a 'positive regulation of apoptosis' process annotation is a context-specific over-annotation.
Supporting Evidence:
PMID:12551919
hydroperoxide-induced apoptosis
GO:0031267 small GTPase binding
IDA
PMID:18219391
SOD1 mutations disrupt redox-sensitive Rac regulation of NAD... 		KEEP AS NON CORE
Summary: Small GTPase (Rac1) binding (IDA).
Reason: SOD1 directly binds Rac1 as a redox sensor regulating NADPH oxidase; specific and experimentally supported but a specialized moonlighting role, non-core.
Supporting Evidence:
PMID:18219391
SOD1 is not just a catabolic enzyme, but can also directly regulate NADPH oxidase-dependent (Nox-dependent) O(2)(*-) production by binding Rac1 and inhibiting its GTPase activity.
GO:0032930 positive regulation of superoxide anion generation
IDA
PMID:18219391
SOD1 mutations disrupt redox-sensitive Rac regulation of NAD... 		KEEP AS NON CORE
Summary: Positive regulation of superoxide anion generation (IDA), via Rac1/Nox regulation.
Reason: Paradoxical relative to SOD1's superoxide-consuming activity; reflects the specialized Rac1/Nox redox-sensor role rather than the core function. Non-core.
Supporting Evidence:
PMID:18219391
SOD1 is not just a catabolic enzyme, but can also directly regulate NADPH oxidase-dependent (Nox-dependent) O(2)(*-) production by binding Rac1 and inhibiting its GTPase activity.
GO:0043087 regulation of GTPase activity
IDA
PMID:18219391
SOD1 mutations disrupt redox-sensitive Rac regulation of NAD... 		KEEP AS NON CORE
Summary: Regulation of GTPase activity (IDA); SOD1 inhibits Rac1 GTPase.
Reason: Specialized Rac1/Nox redox-sensor moonlighting role; non-core.
Supporting Evidence:
PMID:18219391
SOD1 is not just a catabolic enzyme, but can also directly regulate NADPH oxidase-dependent (Nox-dependent) O(2)(*-) production by binding Rac1 and inhibiting its GTPase activity.
GO:0005634 nucleus
IDA
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic pr... 		KEEP AS NON CORE
Summary: Nucleus (IDA, EM immunocytochemistry).
Reason: Secondary nuclear pool; non-core.
Supporting Evidence:
PMID:1332049
Cu,Zn-SOD was found widely distributed in the cell cytosol and in the cell nucleus
GO:0005777 peroxisome
IDA
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic pr... 		MARK AS OVER ANNOTATED
Summary: Peroxisome (IDA, EM immunocytochemistry).
Reason: The original EM immunocytochemistry study found SOD1 primarily cytosolic with peroxisome labeling only slightly above background; peroxisomal localization is weakly supported and treated as an over-annotation, consistent with the IBA/IEA/ISS peroxisome calls.
Supporting Evidence:
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells.
GO:0005576 extracellular region
TAS
Reactome:R-HSA-482772 		KEEP AS NON CORE
Summary: Extracellular region (TAS, Reactome).
Reason: A minor secreted/extracellular pool of SOD1 (including exosomes) exists but is peripheral to the cytosolic antioxidant function.
GO:0005829 cytosol
TAS
Reactome:R-HSA-3697860 		ACCEPT
Summary: Cytosol (TAS, Reactome).
Reason: Core compartment.
Supporting Evidence:
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells.
GO:0005829 cytosol
TAS
Reactome:R-HSA-482772 		ACCEPT
Summary: Cytosol (TAS, Reactome).
Reason: Core compartment.
Supporting Evidence:
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8951723 		ACCEPT
Summary: Cytosol (TAS, Reactome).
Reason: Core compartment.
Supporting Evidence:
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells.
GO:0008089 anterograde axonal transport
ISS
PMID:20510358
Effects of ALS-related SOD1 mutants on dynein- and KIF5-medi... 		KEEP AS NON CORE
Summary: Anterograde axonal transport (ISS, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0008090 retrograde axonal transport
ISS
PMID:20510358
Effects of ALS-related SOD1 mutants on dynein- and KIF5-medi... 		KEEP AS NON CORE
Summary: Retrograde axonal transport (ISS, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0005737 cytoplasm
IDA
PMID:19741096
Mitochondrial ubiquitin ligase MITOL ubiquitinates mutant SO... 		ACCEPT
Summary: Cytoplasm (IDA).
Reason: Core compartment.
Supporting Evidence:
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells.
GO:0005777 peroxisome
ISS
GO_REF:0000024 		MARK AS OVER ANNOTATED
Summary: Peroxisome (ISS, ortholog).
Reason: Weakly supported in human; over-annotation.
Supporting Evidence:
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells.
GO:0005737 cytoplasm
IDA
PMID:18809582
Nucleophosmin serves as a rate-limiting nuclear export chape... 		ACCEPT
Summary: Cytoplasm (IDA).
Reason: Core compartment.
Supporting Evidence:
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells.
GO:0001541 ovarian follicle development
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Ovarian follicle development (ISS, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0001890 placenta development
NAS
PMID:12485882
Implication of copper zinc superoxide dismutase (SOD-1) in h... 		KEEP AS NON CORE
Summary: Placenta development (NAS).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0001895 retina homeostasis
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Retina homeostasis (ISS, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0002262 myeloid cell homeostasis
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Myeloid cell homeostasis (ISS, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0005737 cytoplasm
IDA
PMID:11527942
Superoxide dismutase isoenzymes in the normal and diseased h... 		ACCEPT
Summary: Cytoplasm (IDA).
Reason: Core compartment.
Supporting Evidence:
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells.
GO:0006749 glutathione metabolic process
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Glutathione metabolic process (ISS, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0006801 superoxide metabolic process
ISS
GO_REF:0000024 		ACCEPT
Summary: Superoxide metabolic process (ISS, ortholog); core process.
Reason: Equivalent to the core role.
GO:0006879 intracellular iron ion homeostasis
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Intracellular iron ion homeostasis (ISS, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0007283 spermatogenesis
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Spermatogenesis (ISS, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0007566 embryo implantation
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Embryo implantation (ISS, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0007566 embryo implantation
NAS
PMID:10920331
Differential localization of placental extracellular superox... 		KEEP AS NON CORE
Summary: Embryo implantation (NAS).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0007605 sensory perception of sound
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Sensory perception of sound (ISS, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0007626 locomotory behavior
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Locomotory behavior (ISS, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0008217 regulation of blood pressure
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Regulation of blood pressure (ISS, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0008270 zinc ion binding
IDA
PMID:17381088
Binding of a single zinc ion to one subunit of copper-zinc s... 		ACCEPT
Summary: SOD1 binds one structural zinc ion per subunit (IDA).
Reason: Direct biochemical evidence; zinc is the structural cofactor stabilizing the dimer/active site.
Supporting Evidence:
PMID:17381088
Binding of a single zinc ion to one subunit of copper-zinc superoxide dismutase apoprotein substantially influences the structure and stability of the entire homodimeric protein.
GO:0009408 response to heat
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Response to heat (ISS, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0019226 transmission of nerve impulse
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Transmission of nerve impulse (ISS, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0019430 removal of superoxide radicals
ISS
GO_REF:0000024 		ACCEPT
Summary: Removal of superoxide radicals (ISS, ortholog); core process.
Reason: Equivalent to the core role.
GO:0032287 peripheral nervous system myelin maintenance
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Peripheral nervous system myelin maintenance (ISS, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0033081 regulation of T cell differentiation in thymus
NAS
PMID:16716898
Early thymic T cell development in young transgenic mice ove... 		KEEP AS NON CORE
Summary: Regulation of T cell differentiation in thymus (NAS).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0040014 regulation of multicellular organism growth
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Regulation of multicellular organism growth (ISS, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0042542 response to hydrogen peroxide
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Response to hydrogen peroxide (ISS, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0043524 negative regulation of neuron apoptotic process
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Negative regulation of neuron apoptotic process (ISS, ortholog).
Reason: SOD1 is broadly neuroprotective via ROS removal; downstream process, non-core.
GO:0045471 response to ethanol
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Response to ethanol (ISS, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0046620 regulation of organ growth
NAS
PMID:16716898
Early thymic T cell development in young transgenic mice ove... 		KEEP AS NON CORE
Summary: Regulation of organ growth (NAS).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0046716 muscle cell cellular homeostasis
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Muscle cell cellular homeostasis (ISS, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0048538 thymus development
NAS
PMID:16716898
Early thymic T cell development in young transgenic mice ove... 		KEEP AS NON CORE
Summary: Thymus development (NAS).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0048678 response to axon injury
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Response to axon injury (ISS, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0050665 hydrogen peroxide biosynthetic process
ISS
GO_REF:0000024 		ACCEPT
Summary: Hydrogen peroxide biosynthetic process (ISS); H2O2 is the SOD reaction product.
Reason: H2O2 is the direct product of dismutation.
GO:0060047 heart contraction
IDA
PMID:9539776
Overexpression of human copper, zinc-superoxide dismutase (S... 		KEEP AS NON CORE
Summary: Heart contraction (IDA, ortholog/physiology).
Reason: Organ-physiology phenotype downstream of antioxidant protection; non-core.
GO:0060052 neurofilament cytoskeleton organization
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Neurofilament cytoskeleton organization (ISS, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0060087 relaxation of vascular associated smooth muscle
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Relaxation of vascular associated smooth muscle (ISS, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0060088 auditory receptor cell stereocilium organization
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Auditory receptor cell stereocilium organization (ISS, ortholog).
Reason: Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core.
GO:0001819 positive regulation of cytokine production
IDA
PMID:15544046
Gene transfer of CuZn superoxide dismutase enhances the synt... 		KEEP AS NON CORE
Summary: Positive regulation of cytokine production (IDA).
Reason: Single-study immunomodulatory effect; downstream/peripheral, non-core.
Supporting Evidence:
PMID:15544046
Gene transfer of CuZn superoxide dismutase enhances the synthesis of vascular endothelial growth factor.
GO:0004784 superoxide dismutase activity
IDA
PMID:15544046
Gene transfer of CuZn superoxide dismutase enhances the synt... 		ACCEPT
Summary: Direct SOD activity assay.
Reason: Confirms core function.
Supporting Evidence:
PMID:15544046
dismutase (CuZnSOD, SOD1). Overexpression of human SOD1
GO:0004784 superoxide dismutase activity
IDA
PMID:17324120
Activation of brain calcineurin (Cn) by Cu-Zn superoxide dis... 		ACCEPT
Summary: Direct SOD activity assay (calcineurin study).
Reason: Confirms core function.
Supporting Evidence:
PMID:17324120
Cu-Zn superoxide dismutase (SOD1)
GO:0005507 copper ion binding
IDA
PMID:17008312
Mitochondrial matrix copper complex used in metallation of c... 		ACCEPT
Summary: Copper ion binding (IDA); SOD1 metallation in mitochondrial IMS.
Reason: Direct evidence SOD1 acquires its catalytic copper.
Supporting Evidence:
PMID:31292775
Copper-zinc superoxide dismutase (Sod1) is a critical antioxidant enzyme that rids the cell of reactive oxygen through the redox cycling of a catalytic copper ion provided by its copper chaperone (Ccs).
GO:0005759 mitochondrial matrix
NAS
PMID:17008312
Mitochondrial matrix copper complex used in metallation of c... 		REMOVE
Summary: Mitochondrial matrix (NAS).
Reason: The functional and metallation pools of SOD1 are in the cytosol and mitochondrial intermembrane space, not the matrix; the matrix call appears to be a misassignment.
Supporting Evidence:
PMID:24026195
both localize to the cytosol and the mitochondrial intermembrane space where they specifically counteract mitochondria-derived superoxide
GO:0005886 plasma membrane
IDA
PMID:17324120
Activation of brain calcineurin (Cn) by Cu-Zn superoxide dis... 		KEEP AS NON CORE
Summary: Plasma membrane colocalization (IDA).
Reason: Colocalization observed on endocytosis/specialized contexts; peripheral, non-core.
GO:0030346 protein phosphatase 2B binding
IDA
PMID:17324120
Activation of brain calcineurin (Cn) by Cu-Zn superoxide dis... 		KEEP AS NON CORE
Summary: Protein phosphatase 2B (calcineurin) binding (IDA).
Reason: SOD1 directly binds and activates calcineurin (protein phosphatase 2B); a specific, experimentally supported interaction, though peripheral to the core antioxidant function.
Supporting Evidence:
PMID:17324120
Activation of brain calcineurin (Cn) by Cu-Zn superoxide dismutase (SOD1) depends on direct SOD1-Cn protein interactions occurring in vitro and in vivo.
GO:0032839 dendrite cytoplasm
IDA
PMID:17324120
Activation of brain calcineurin (Cn) by Cu-Zn superoxide dis... 		KEEP AS NON CORE
Summary: Dendrite cytoplasm (IDA).
Reason: Cell-type-specific cytoplasmic localization; non-core.
GO:0032991 protein-containing complex
IDA
PMID:17324120
Activation of brain calcineurin (Cn) by Cu-Zn superoxide dis... 		KEEP AS NON CORE
Summary: Protein-containing complex (IDA).
Reason: Generic; SOD1's specific complexes are captured by precise terms. Non-core.
GO:0043025 neuronal cell body
IDA
PMID:17324120
Activation of brain calcineurin (Cn) by Cu-Zn superoxide dis... 		KEEP AS NON CORE
Summary: Neuronal cell body (IDA).
Reason: Cell-type-specific localization; non-core.
GO:0050665 hydrogen peroxide biosynthetic process
IDA
PMID:15544046
Gene transfer of CuZn superoxide dismutase enhances the synt... 		ACCEPT
Summary: Hydrogen peroxide biosynthetic process (IDA); H2O2 produced by SOD1.
Reason: H2O2 is the direct product of dismutation.
Supporting Evidence:
PMID:15544046
Overexpression of human SOD1
GO:0000303 response to superoxide
IDA
PMID:16790527
Mitochondrial damage due to SOD1 deficiency in SH-SY5Y neuro... 		KEEP AS NON CORE
Summary: Response to superoxide (IDA); SOD1 deficiency raises steady-state superoxide.
Reason: Real, but a downstream cellular-response framing; the core process is removal of superoxide.
Supporting Evidence:
PMID:16790527
The steady-state concentration of superoxide was significantly increased
GO:0005515 protein binding
IPI
PMID:16790527
Mitochondrial damage due to SOD1 deficiency in SH-SY5Y neuro... 		MARK AS OVER ANNOTATED
Summary: Generic protein-binding interaction (IPI).
Reason: Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding).
GO:0005576 extracellular region
IDA
PMID:9453566
CuZn-superoxide dismutase, extracellular superoxide dismutas... 		KEEP AS NON CORE
Summary: Extracellular region (IDA); SOD1 detected extracellularly.
Reason: A minor secreted/extracellular pool of SOD1 (including exosomes) exists but is peripheral to the cytosolic antioxidant function.
GO:0005634 nucleus
IDA
PMID:17504823
Mutation of SOD1 in ALS: a gain of a loss of function. 		KEEP AS NON CORE
Summary: Nucleus (IDA).
Reason: Secondary nuclear pool; non-core.
Supporting Evidence:
PMID:1332049
Cu,Zn-SOD was found widely distributed in the cell cytosol and in the cell nucleus
GO:0005634 nucleus
IDA
PMID:9726962
The copper chaperone CCS directly interacts with copper/zinc... 		KEEP AS NON CORE
Summary: Nucleus (IDA); SOD1/CCS study.
Reason: Secondary nuclear pool; non-core.
Supporting Evidence:
PMID:1332049
Cu,Zn-SOD was found widely distributed in the cell cytosol and in the cell nucleus
GO:0005737 cytoplasm
IDA
PMID:17077646
Rapid endocytosis of copper-zinc superoxide dismutase into h... 		ACCEPT
Summary: Cytoplasm (IDA).
Reason: Core compartment.
Supporting Evidence:
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells.
GO:0005737 cytoplasm
IDA
PMID:17504823
Mutation of SOD1 in ALS: a gain of a loss of function. 		ACCEPT
Summary: Cytoplasm (IDA).
Reason: Core compartment.
Supporting Evidence:
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells.
GO:0005737 cytoplasm
IDA
PMID:9726962
The copper chaperone CCS directly interacts with copper/zinc... 		ACCEPT
Summary: Cytoplasm (IDA).
Reason: Core compartment.
Supporting Evidence:
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells.
GO:0005739 mitochondrion
IDA
PMID:16790527
Mitochondrial damage due to SOD1 deficiency in SH-SY5Y neuro... 		KEEP AS NON CORE
Summary: Mitochondrion (IDA); SOD1 deficiency causes mitochondrial damage.
Reason: Reflects functional impact on mitochondria; the specific functional pool is the IMS.
Supporting Evidence:
PMID:16790527
Mitochondrial damage due to SOD1 deficiency in SH-SY5Y neuroblastoma cells
GO:0005829 cytosol
IDA
PMID:16790527
Mitochondrial damage due to SOD1 deficiency in SH-SY5Y neuro... 		ACCEPT
Summary: Cytosol (IDA).
Reason: Core compartment.
Supporting Evidence:
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells.
GO:0005886 plasma membrane
IDA
PMID:17077646
Rapid endocytosis of copper-zinc superoxide dismutase into h... 		KEEP AS NON CORE
Summary: Plasma membrane colocalization (IDA); endocytic uptake context.
Reason: Colocalization on endocytosis into endothelial cells; peripheral, non-core.
GO:0031410 cytoplasmic vesicle
IDA
PMID:17077646
Rapid endocytosis of copper-zinc superoxide dismutase into h... 		KEEP AS NON CORE
Summary: Cytoplasmic vesicle (IDA); endocytic uptake context.
Reason: Vesicular localization in an uptake/endocytosis context; non-core.
GO:0043065 positive regulation of apoptotic process
IC
PMID:16790527
Mitochondrial damage due to SOD1 deficiency in SH-SY5Y neuro... 		MARK AS OVER ANNOTATED
Summary: Positive regulation of apoptotic process (IC, chained off protein binding).
Reason: Inferred (IC) from a protein-binding annotation; SOD1 is canonically anti-apoptotic/cytoprotective, so a positive-apoptosis process annotation is a context-specific over-annotation.
GO:0051087 protein-folding chaperone binding
IPI
PMID:9726962
The copper chaperone CCS directly interacts with copper/zinc... 		ACCEPT
Summary: Protein-folding chaperone binding (IPI); SOD1 binds its CCS chaperone.
Reason: Direct, informative interaction with the copper chaperone CCS that matures SOD1.
Supporting Evidence:
PMID:30735496
maturation of SOD1 by its evolutionarily destabilised cognate chaperone hCCS
GO:0051881 regulation of mitochondrial membrane potential
IMP
PMID:16790527
Mitochondrial damage due to SOD1 deficiency in SH-SY5Y neuro... 		KEEP AS NON CORE
Summary: Regulation of mitochondrial membrane potential (IMP).
Reason: SOD1 knockdown impairs mitochondrial membrane potential; a downstream consequence of lost antioxidant protection, non-core.
Supporting Evidence:
PMID:16790527
impairment of the mitochondrial transmembrane potential
GO:0005737 cytoplasm
IDA
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic pr... 		ACCEPT
Summary: Cytoplasm (IDA, EM immunocytochemistry).
Reason: Core compartment.
Supporting Evidence:
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells.

Core Functions

Cu/Zn superoxide dismutase that catalyzes dismutation of superoxide radical to molecular oxygen and hydrogen peroxide, the central antioxidant defense activity of the cytosol and mitochondrial intermembrane space.

Molecular Function:
superoxide dismutase activity
Directly Involved In:
removal of superoxide radicals superoxide metabolic process
Cellular Locations:
cytosol mitochondrial intermembrane space
Supporting Evidence:
  • PMID:24140062
    Cu/Zn superoxide dismutase (SOD1) is a key antioxidant enzyme.
  • PMID:16790527
    Superoxide dismutases (SODs) represent the first line of defense against oxidative stress
  • PMID:24026195
    both localize to the cytosol and the mitochondrial intermembrane space where they specifically counteract mitochondria-derived superoxide

Binds one catalytic copper ion and one structural zinc ion per subunit; metal binding is required for catalysis and for stability of the homodimer. Catalytic copper is delivered by the CCS copper chaperone.

Molecular Function:
copper ion binding
In Complex:
superoxide dismutase copper chaperone complex
Supporting Evidence:
  • PMID:31292775
    Copper-zinc superoxide dismutase (Sod1) is a critical antioxidant enzyme that rids the cell of reactive oxygen through the redox cycling of a catalytic copper ion provided by its copper chaperone (Ccs).
  • PMID:17381088
    Binding of a single zinc ion to one subunit of copper-zinc superoxide dismutase apoprotein substantially influences the structure and stability of the entire homodimeric protein.
  • PMID:30735496
    Molecular recognition and maturation of SOD1 by its evolutionarily destabilised cognate chaperone hCCS.

Functions as an obligate homodimer; subunit self-association (identical protein binding) is intrinsic to the active enzyme and its unusual stability.

Molecular Function:
identical protein binding
Supporting Evidence:

References

GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000108
Automatic assignment of GO terms using logical inference, based on on inter-ontology links
PMID:12968035
The copper toxicosis gene product Murr1 directly interacts with the Wilson disease protein.
PMID:16369483
Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis.
PMID:16595634
Spinal cord endoplasmic reticulum stress associated with a microsomal accumulation of mutant superoxide dismutase-1 in an ALS model.
PMID:19171884
Progressive aggregation despite chaperone associations of a mutant SOD1-YFP in transgenic mice that develop ALS.
PMID:20195357
A comprehensive resource of interacting protein regions for refining human transcription factor networks.
PMID:21252941
BAG3 mediates chaperone-based aggresome-targeting and selective autophagy of misfolded proteins.
PMID:22508683
Molecular and biochemical characterization of a unique mutation in CCS, the human copper chaperone to superoxide dismutase.
PMID:24234043
Cystatin B and SOD1: protein–protein interaction and possible relation to neurodegeneration.
PMID:24981860
Human-chromatin-related protein interactions identify a demethylase complex required for chromosome segregation.
PMID:26643113
alpha-synuclein interacts with SOD1 and promotes its oligomerization.
PMID:28514442
Architecture of the human interactome defines protein communities and disease networks.
PMID:29128334
A Map of Human Mitochondrial Protein Interactions Linked to Neurodegeneration Reveals New Mechanisms of Redox Homeostasis and NF-κB Signaling.
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:17592131
Metal-free superoxide dismutase forms soluble oligomers under physiological conditions: a possible general mechanism for familial ALS.
PMID:19022905
Initiation and elongation in fibrillation of ALS-linked superoxide dismutase.
PMID:19369197
Structural and dynamic aspects related to oligomerization of apo SOD1 and its mutants.
PMID:19828437
Transient structural distortion of metal-free Cu/Zn superoxide dismutase triggers aberrant oligomerization.
PMID:21257910
Decreased stability and increased formation of soluble aggregates by immature superoxide dismutase do not account for disease severity in ALS.
PMID:23831581
Intracellular seeded aggregation of mutant Cu,Zn-superoxide dismutase associated with amyotrophic lateral sclerosis.
PMID:31999698
Tryptophan residue 32 in human Cu-Zn superoxide dismutase modulates prion-like propagation and strain selection.
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs by Ensembl Compara
PMID:24026195
Human copper chaperone for superoxide dismutase 1 mediates its own oxidation-dependent import into mitochondria.
PMID:31292775
Copper-zinc superoxide dismutase (Sod1) activation terminates interaction between its copper chaperone (Ccs) and the cytosolic metal-binding domain of the copper importer Ctr1.
PMID:30735496
Molecular recognition and maturation of SOD1 by its evolutionarily destabilised cognate chaperone hCCS.
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
PMID:34800366
Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
PMID:24567322
DJ-1 is a copper chaperone acting on SOD1 activation.
PMID:16254550
Expression of superoxide dismutase in whole lens prevents cataract formation.
GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
PMID:24784232
A new transcriptional role for matrix metalloproteinase-12 in antiviral immunity.
PMID:24023695
Molecular chaperone mediated late-stage neuroprotection in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis.
PMID:22496122
Endothelial cell palmitoylproteomic identifies novel lipid-modified targets and potential substrates for protein acyl transferases.
PMID:19741096
Mitochondrial ubiquitin ligase MITOL ubiquitinates mutant SOD1 and attenuates mutant SOD1-induced reactive oxygen species generation.
PMID:23533145
In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
PMID:21630459
Proteomic characterization of the human sperm nucleus.
PMID:24140062
SIRT5 desuccinylates and activates SOD1 to eliminate ROS.
PMID:19056867
Large-scale proteomics and phosphoproteomics of urinary exosomes.
Reactome:R-HSA-3777112
Reactome pathway annotation
Reactome:R-HSA-8950771
Reactome pathway annotation
Reactome:R-HSA-3299691
Reactome pathway annotation
Reactome:R-HSA-3299753
Reactome pathway annotation
PMID:12551919
Differential effects of superoxide dismutase isoform expression on hydroperoxide-induced apoptosis in PC-12 cells.
PMID:18219391
SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model.
PMID:1332049
Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells.
Reactome:R-HSA-482772
Reactome pathway annotation
Reactome:R-HSA-3697860
Reactome pathway annotation
Reactome:R-HSA-8951723
Reactome pathway annotation
PMID:20510358
Effects of ALS-related SOD1 mutants on dynein- and KIF5-mediated retrograde and anterograde axonal transport.
PMID:18809582
Nucleophosmin serves as a rate-limiting nuclear export chaperone for the Mammalian ribosome.
PMID:12485882
Implication of copper zinc superoxide dismutase (SOD-1) in human placenta development.
PMID:11527942
Superoxide dismutase isoenzymes in the normal and diseased human cornea.
PMID:10920331
Differential localization of placental extracellular superoxide dismutase as pregnancy progresses.
PMID:17381088
Binding of a single zinc ion to one subunit of copper-zinc superoxide dismutase apoprotein substantially influences the structure and stability of the entire homodimeric protein.
PMID:16716898
Early thymic T cell development in young transgenic mice overexpressing human Cu/Zn superoxide dismutase, a model of Down syndrome.
PMID:9539776
Overexpression of human copper, zinc-superoxide dismutase (SOD1) prevents postischemic injury.
PMID:15544046
Gene transfer of CuZn superoxide dismutase enhances the synthesis of vascular endothelial growth factor.
PMID:17324120
Activation of brain calcineurin (Cn) by Cu-Zn superoxide dismutase (SOD1) depends on direct SOD1-Cn protein interactions occurring in vitro and in vivo.
PMID:17008312
Mitochondrial matrix copper complex used in metallation of cytochrome oxidase and superoxide dismutase.
PMID:16790527
Mitochondrial damage due to SOD1 deficiency in SH-SY5Y neuroblastoma cells: a rationale for the redundancy of SOD1.
PMID:9453566
CuZn-superoxide dismutase, extracellular superoxide dismutase, and glutathione peroxidase in blood from individuals homozygous for Asp90Ala CuZu-superoxide dismutase mutation.
PMID:17504823
Mutation of SOD1 in ALS: a gain of a loss of function.
PMID:9726962
The copper chaperone CCS directly interacts with copper/zinc superoxide dismutase.
PMID:17077646
Rapid endocytosis of copper-zinc superoxide dismutase into human endothelial cells: role for its vascular activity.
file:human/SOD1/SOD1-deep-research-falcon.md
Falcon deep research report for SOD1

Suggested Questions for Experts

Q: Is the hydrogen sulfide oxidase activity (EC 1.8.-.-) of SOD1 a physiologically significant function in human tissues, and should it be captured by a distinct molecular-function annotation alongside superoxide dismutase activity?

Suggested experts: Switzer CH, Eaton P

Q: To what extent does the mitochondrial intermembrane-space pool of SOD1 contribute to total cellular superoxide detoxification versus the cytosolic pool in human neurons?

Suggested experts: Riemer J

Suggested Experiments

Experiment: Use SOD1 separation-of-function variants (catalytically inactive but Rac1-binding competent, and vice versa) in human cells to dissociate dismutase activity from Rac1/Nox regulation, measuring superoxide flux and Rac1 GTPase activity.

Hypothesis: SOD1's Rac1-binding redox-sensor function modulates NADPH oxidase output independently of its bulk dismutase activity.

Type: structure-function mutagenesis with redox/GTPase readouts

Experiment: Compare superoxide levels, mitochondrial membrane potential, and viability in human iPSC-derived motor neurons with IMS-targeting-deficient versus wild-type SOD1, using CCS-dependent import mutants.

Hypothesis: The mitochondrial intermembrane-space SOD1 pool is required to protect against mitochondria-derived superoxide in human motor neurons.

Type: organelle-targeted rescue in iPSC-derived neurons

Deep Research

Falcon

(SOD1-deep-research-falcon.md)
Comprehensive Research Report: SOD1 (Superoxide Dismutase [Cu-Zn]) - Human Gene P00441 Falcon Edison Scientific Literature 16 citations 1 artifacts 2026-06-20T05:25:27.176338
Edison artifact artifact-00 (text/markdown)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive Research Report: SOD1 (Superoxide Dismutase [Cu-Zn]) - Human Gene P00441

Gene Identity Verification

The gene SOD1 (UniProt P00441) encodes human copper-zinc superoxide dismutase 1, confirmed as the correct target gene. This protein belongs to the Cu-Zn superoxide dismutase family and contains the conserved SOD_Cu_Zn_dom domain, matching the UniProt annotation for Homo sapiens (trist2021superoxidedismutase1 pages 1-3, trist2021superoxidedismutase1 pages 5-6).

Primary Enzymatic Function and Catalytic Mechanism

Core Enzymatic Activity

Human SOD1 catalyzes the dismutation of superoxide anion radicals (O2•−) to hydrogen peroxide (H2O2) and molecular oxygen (O2) via the reaction: 2O2•− + 2H+ → H2O2 + O2 (rosa2021superoxidedismutaseadministration pages 1-2, xu2022nuclearsod1in pages 1-2). The substrate specificity is highly selective for the superoxide anion radical, with the enzyme exhibiting exceptional catalytic efficiency at or near the diffusion limit (zheng2023theapplicationsand pages 1-2, boyd2020coppersourcesfor pages 1-3).

Catalytic Mechanism

The catalytic mechanism depends on copper redox cycling between Cu(I) and Cu(II) oxidation states at the active site (boyd2020coppersourcesfor pages 1-3). In the first half-reaction, Cu(II) is reduced to Cu(I) while oxidizing one superoxide molecule to molecular oxygen. In the second half-reaction, Cu(I) is reoxidized to Cu(II) while reducing a second superoxide molecule to hydrogen peroxide. This reaction is facilitated by an "electrostatic guidance system" comprising positively charged residues in the electrostatic loop, particularly Arg143, which attracts the anionic substrate and excludes non-substrate molecules (zheng2023theapplicationsand pages 1-2, boyd2020coppersourcesfor pages 1-3).

Substrate Recognition and Active Site Structure

Structural studies reveal that SOD1 is a homodimeric metalloprotein (~32 kDa) composed of two 153-amino acid monomers, each forming an eight-stranded β-barrel architecture (trist2021superoxidedismutase1 pages 5-6). The active site contains copper coordinated by four histidine residues (His46, His48, His63, His120) in a square-pyramidal geometry with a water ligand, while zinc is coordinated by His63, His71, His80, and Asp83 in a distorted tetrahedral arrangement (trist2021superoxidedismutase1 pages 5-6, boyd2020coppersourcesfor pages 1-3). Zinc binding stabilizes the active site architecture and is essential for proper protein folding and catalytic function, while copper performs the actual redox chemistry (boyd2020coppersourcesfor pages 1-3).

Subcellular Localization

SOD1 exhibits a multi-compartmental distribution pattern. The protein is predominantly cytosolic, where it carries out its primary antioxidant function (xu2022nuclearsod1in pages 1-2). However, SOD1 is also localized to the mitochondrial intermembrane space, providing antioxidant protection in this organelle (trist2021superoxidedismutase1 pages 1-3, xu2022nuclearsod1in pages 1-2). Recent studies have identified substantial nuclear localization of SOD1 under both normal and pathological conditions, where it participates in oxidative stress response and may have regulatory roles in transcription and ribosome biogenesis (xu2022nuclearsod1in pages 1-2). Additionally, SOD1 can be secreted via unconventional secretory pathways and circulates in blood bound to lipoproteins, suggesting paracrine functions (damiano2020metabolismregulationand pages 1-3).

Biochemical Pathways and Metabolic Regulation

SOD1-Mediated Metabolic Reprogramming

Beyond its classical antioxidant role, SOD1 functions as a key regulator integrating oxygen availability with cellular metabolism (montlloralbalate2022sod1integratesoxygen pages 1-2, montlloralbalate2022sod1integratesoxygen pages 3-4). A pivotal 2022 study demonstrated that SOD1 directly interacts with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and oxidizes its catalytic cysteine residue using SOD1-derived H2O2 (montlloralbalate2022sod1integratesoxygen pages 1-2, montlloralbalate2022sod1integratesoxygen pages 3-4). This oxidative inactivation of GAPDH reduces glycolytic flux and reroutes glucose metabolism toward the oxidative pentose phosphate pathway (oxPPP), thereby increasing NADPH production (montlloralbalate2022sod1integratesoxygen pages 1-2, montlloralbalate2022sod1integratesoxygen pages 3-4, chandel2021nadphtheforgottenreducing pages 1-3).

Mechanism of GAPDH Regulation

Experimental evidence from co-immunoprecipitation and thiol alkylation assays confirms physical interaction between SOD1 and GAPDH (montlloralbalate2022sod1integratesoxygen pages 1-2, montlloralbalate2022sod1integratesoxygen pages 3-4). The aerobic oxidation of GAPDH is both dependent on and rate-limited by SOD1, as demonstrated by dose-dependent increases in GAPDH oxidation with titrated SOD1 expression (montlloralbalate2022sod1integratesoxygen pages 3-4). Importantly, this regulatory mechanism requires the bulk of cellular SOD1 (~99%), distinguishing it from the direct superoxide scavenging function which requires less than 1% of total SOD1 (montlloralbalate2022sod1integratesoxygen pages 1-2).

NADPH Production and Antioxidant Defense

The SOD1-mediated redirection of metabolism to the pentose phosphate pathway maintains cellular NADPH pools, which are essential for regenerating reduced glutathione (GSH) and thioredoxin (TRX), the major cellular antioxidant systems (chandel2021nadphtheforgottenreducing pages 1-3, damiano2020metabolismregulationand pages 1-3). This mechanism positions SOD1 as a master regulator of both oxidative stress defense and metabolic adaptation to aerobic conditions (montlloralbalate2022sod1integratesoxygen pages 1-2, montlloralbalate2022sod1integratesoxygen pages 3-4). The pentose phosphate pathway generates NADPH through the oxidative phase catalyzed by glucose-6-phosphate dehydrogenase (G6PDH), providing reducing equivalents for biosynthetic reactions and antioxidant systems (chandel2021nadphtheforgottenreducing pages 1-3).

Post-Translational Maturation

SOD1 requires multiple post-translational modifications to achieve full catalytic activity and structural stability (trist2021superoxidedismutase1 pages 5-6, boyd2020coppersourcesfor pages 1-3). Immature apo-SOD1 monomers undergo three critical modifications: (1) zinc binding at the metal-binding loop, (2) copper insertion at the active site mediated by the copper chaperone for SOD1 (CCS), and (3) formation of an intramolecular disulfide bond between Cys57 and Cys146 (trist2021superoxidedismutase1 pages 5-6, boyd2020coppersourcesfor pages 1-3). These modifications promote homodimerization, burying approximately 640 Ų of hydrophobic surface area and creating an exceptionally stable enzyme with a melting temperature of 85-95°C (trist2021superoxidedismutase1 pages 5-6). In contrast, apo-SOD1 has a melting temperature of only ~43°C, near physiological temperature, making it susceptible to degradation by the proteasome and autophagy systems (trist2021superoxidedismutase1 pages 5-6).

Recent Discoveries: Hydrogen Sulfide Oxidase Activity

A novel non-canonical function of SOD1 has been identified in 2023, revealing that the enzyme can act as a hydrogen sulfide (H2S) oxidase (anwar2025therapeuticapplicationsand pages 1-3). The UniProt annotation for P00441 now includes the alternative name "Hydrogen sulfide oxidase" based on recent evidence showing that H2S binds at the copper active site of SOD1, where it functions as a micro-modulator regulating the enzyme's catalytic activity (anwar2025therapeuticapplicationsand pages 1-3). This finding expands our understanding of SOD1 beyond its traditional role in superoxide dismutation to include regulation by gaseous signaling molecules.

Structural Features and Protein Domains

The mature SOD1 homodimer exhibits several structurally and functionally important features (trist2021superoxidedismutase1 pages 5-6). Each monomer contains a metal-binding loop (residues 49-83) that coordinates both copper and zinc ions. The disulfide loop (residues 49-62) contains Cys57, which forms the rare cytosolic disulfide bond with Cys146. The electrostatic loop contains positively charged residues that create an electrostatic field to guide negatively charged superoxide substrates into the active site channel. The Greek key loop (residues 102-115) contributes to dimer interface stability (trist2021superoxidedismutase1 pages 5-6). These structural elements work in concert to achieve the enzyme's remarkable catalytic efficiency and stability.

Experimental Evidence and Methodological Approaches

The functional characterization of SOD1 has employed diverse experimental methodologies. Structural studies using X-ray crystallography and NMR spectroscopy have defined the atomic-level architecture and dynamics of SOD1 metalloforms (trist2021superoxidedismutase1 pages 5-6). Biochemical experiments using methoxypolyethylene glycol maleimide (mPEG-mal) thiol alkylation assays quantitatively measured GAPDH oxidation states in cells with varying SOD1 expression (montlloralbalate2022sod1integratesoxygen pages 1-2, montlloralbalate2022sod1integratesoxygen pages 3-4). Co-immunoprecipitation experiments confirmed direct protein-protein interactions between SOD1 and GAPDH (montlloralbalate2022sod1integratesoxygen pages 1-2). Metabolic flux studies using pH-sensitive fluorescent reporters (pHluorin) demonstrated SOD1's regulation of glycolytic activity and the pentose phosphate pathway (montlloralbalate2022sod1integratesoxygen pages 1-2, montlloralbalate2022sod1integratesoxygen pages 3-4). These precise, hypothesis-driven studies provide robust evidence for SOD1's multifaceted cellular roles.

Signaling and Redox Regulation

SOD1-derived hydrogen peroxide functions as a redox signaling molecule beyond its role as a metabolic byproduct (montlloralbalate2022sod1integratesoxygen pages 1-2, damiano2020metabolismregulationand pages 1-3). H2O2 generated by SOD1 can diffuse across cellular membranes and oxidize specific protein thiols, thereby regulating enzyme activities, transcription factors, and signaling pathways (damiano2020metabolismregulationand pages 1-3). This positions SOD1 at the intersection of oxygen sensing, metabolic regulation, and redox signaling. The enzyme participates in the NRF2-mediated oxidative stress response pathway, which coordinates the expression of antioxidant genes (anwar2025therapeuticapplicationsand pages 1-3, damiano2020metabolismregulationand pages 1-3).

Summary Table of Key Features

Feature Description Evidence/Citation
Protein structure Human SOD1 is a mature ~32 kDa homodimer composed of two 153-aa monomers (~16 kDa each). Each monomer forms an eight-stranded β-barrel with prominent metal-binding, disulfide, electrostatic, and Greek key loop elements. The electrostatic loop helps steer anionic substrate into the active site, and the dimer interface buries substantial hydrophobic surface, contributing to exceptional stability of holo-SOD1. (trist2021superoxidedismutase1 pages 5-6, boyd2020coppersourcesfor pages 1-3)
Metal cofactors SOD1 is a Cu/Zn metalloenzyme. Cu at the catalytic site is coordinated by His46, His48, His63, and His120, with a water ligand completing a square-pyramidal geometry; these residues support Cu(I)/Cu(II) redox cycling. Zn is coordinated in a distorted tetrahedral site by His63, His71, His80, and Asp83, stabilizing the active-site architecture and loop conformations required for function. (trist2021superoxidedismutase1 pages 5-6, boyd2020coppersourcesfor pages 1-3)
Primary enzymatic reaction The canonical reaction is superoxide dismutation: 2 O2•− + 2 H+ → H2O2 + O2. Thus, the substrate specificity is for the superoxide anion radical (O2•−), and the products are hydrogen peroxide and molecular oxygen. This reaction is a first-line antioxidant defense against intracellular superoxide. (rosa2021superoxidedismutaseadministration pages 1-2, xu2022nuclearsod1in pages 1-2, boyd2020coppersourcesfor pages 1-3)
Catalytic mechanism Catalysis depends on copper redox cycling between Cu(I) and Cu(II) at the active site. One superoxide is oxidized to O2 while reducing Cu(II) to Cu(I); a second superoxide is then reduced to H2O2 as Cu(I) is reoxidized to Cu(II). Catalysis occurs at or near the diffusion limit, aided by an electrostatic guidance system in the electrostatic loop; Arg143 is specifically important for substrate attraction and nonsubstrate exclusion. (zheng2023theapplicationsand pages 1-2, boyd2020coppersourcesfor pages 1-3)
Subcellular localization SOD1 is found primarily in the cytosol, but also in the mitochondrial intermembrane space and nucleus under normal and pathological conditions. Reviews also note extracellular/secreted SOD1 via unconventional secretion and circulation in blood-associated compartments, extending function beyond the strictly intracellular space. (rosa2021superoxidedismutaseadministration pages 1-2, xu2022nuclearsod1in pages 1-2, damiano2020metabolismregulationand pages 1-3)
Post-translational maturation requirements Functional maturation requires (1) Zn binding, (2) Cu insertion, (3) oxidation of the intramonomeric disulfide bond Cys57–Cys146, and (4) homodimerization. The mature enzyme is highly stable, whereas apo-SOD1 is markedly less stable. Copper incorporation is mediated by the copper chaperone for SOD1 (CCS), and proper metallation/disulfide formation are essential for catalytic activity and structural integrity. (trist2021superoxidedismutase1 pages 5-6, boyd2020coppersourcesfor pages 1-3)
Novel regulatory functions Beyond detoxifying superoxide, SOD1-derived H2O2 can function in redox signaling. Experimental work showed SOD1 interacts with GAPDH, promotes GAPDH thiol oxidation, lowers GAPDH activity, and thereby helps reroute carbon flux from glycolysis to the oxidative pentose phosphate pathway, increasing NADPH production and oxidative-stress resistance. This places SOD1 as a regulator of metabolic adaptation, not just a scavenger enzyme. (montlloralbalate2022sod1integratesoxygen pages 1-2, montlloralbalate2022sod1integratesoxygen pages 3-4, damiano2020metabolismregulationand pages 1-3)
Hydrogen sulfide oxidase activity Recent literature and UniProt-linked annotation indicate a non-canonical H2S-related activity for Cu/Zn-SOD1, including description as “hydrogen sulfide oxidase” and evidence that H2S binds at the copper active site to modulate catalytic behavior. Available accessible review sources describe this as a newly emerging role of SOD1 beyond classical superoxide dismutation; however, mechanistic depth is more limited in the presently available contexts than for canonical activity. (anwar2025therapeuticapplicationsand pages 1-3, boyd2020coppersourcesfor pages 1-3)

Table: This table compiles the main structural, catalytic, localization, maturation, and emerging regulatory properties of human SOD1. It is useful as a compact evidence-based reference for functional annotation of UniProt P00441.

Conclusion

Human SOD1 (UniProt P00441) is a highly conserved Cu-Zn metalloenzyme that serves as a critical first-line antioxidant defense by catalyzing superoxide dismutation to hydrogen peroxide and molecular oxygen. Beyond this canonical function, SOD1 acts as a metabolic regulator by oxidizing GAPDH to redirect glucose metabolism toward NADPH production via the pentose phosphate pathway. The enzyme exhibits multi-compartmental localization including cytosol, mitochondria, and nucleus, with emerging evidence for extracellular functions. Recent discoveries of H2S oxidase activity further expand SOD1's functional repertoire. The enzyme's structure, comprising an eight-stranded β-barrel homodimer with precisely coordinated copper and zinc ions, enables its exceptional catalytic efficiency and stability. These findings establish SOD1 as a multifunctional protein integrating antioxidant defense, metabolic regulation, and cellular signaling in response to oxygen availability and oxidative stress.

References

  1. (trist2021superoxidedismutase1 pages 1-3): Benjamin G. Trist, James B. Hilton, Dominic J. Hare, Peter J. Crouch, and Kay L. Double. Superoxide dismutase 1 in health and disease: how a frontline antioxidant becomes neurotoxic. Nov 2021. URL: https://doi.org/10.1002/anie.202000451, doi:10.1002/anie.202000451. This article has 260 citations.

  2. (trist2021superoxidedismutase1 pages 5-6): Benjamin G. Trist, James B. Hilton, Dominic J. Hare, Peter J. Crouch, and Kay L. Double. Superoxide dismutase 1 in health and disease: how a frontline antioxidant becomes neurotoxic. Nov 2021. URL: https://doi.org/10.1002/anie.202000451, doi:10.1002/anie.202000451. This article has 260 citations.

  3. (rosa2021superoxidedismutaseadministration pages 1-2): Arianna Carolina Rosa, Daniele Corsi, Niccolò Cavi, Natascia Bruni, and Franco Dosio. Superoxide dismutase administration: a review of proposed human uses. Molecules, 26:1844, Mar 2021. URL: https://doi.org/10.3390/molecules26071844, doi:10.3390/molecules26071844. This article has 338 citations.

  4. (xu2022nuclearsod1in pages 1-2): Joyce Xu, Xiaoyang Su, Stephen K. Burley, and X. F. Steven Zheng. Nuclear sod1 in growth control, oxidative stress response, amyotrophic lateral sclerosis, and cancer. Antioxidants, 11:427, Feb 2022. URL: https://doi.org/10.3390/antiox11020427, doi:10.3390/antiox11020427. This article has 95 citations.

  5. (zheng2023theapplicationsand pages 1-2): Mengli Zheng, Yating Liu, Guanfeng Zhang, Zhikang Yang, Weiwei Xu, and Qinghua Chen. The applications and mechanisms of superoxide dismutase in medicine, food, and cosmetics. Antioxidants, 12:1675, Aug 2023. URL: https://doi.org/10.3390/antiox12091675, doi:10.3390/antiox12091675. This article has 386 citations.

  6. (boyd2020coppersourcesfor pages 1-3): Stefanie D. Boyd, Morgan S. Ullrich, Amelie Skopp, and Duane D. Winkler. Copper sources for sod1 activation. Antioxidants, 9:500, Jun 2020. URL: https://doi.org/10.3390/antiox9060500, doi:10.3390/antiox9060500. This article has 87 citations.

  7. (damiano2020metabolismregulationand pages 1-3): Simona Damiano, Concetta Sozio, Giuliana La Rosa, Bruna Guida, Raffaella Faraonio, Mariarosaria Santillo, and Paolo Mondola. Metabolism regulation and redox state: insight into the role of superoxide dismutase 1. International Journal of Molecular Sciences, 21:6606, Sep 2020. URL: https://doi.org/10.3390/ijms21186606, doi:10.3390/ijms21186606. This article has 68 citations.

  8. (montlloralbalate2022sod1integratesoxygen pages 1-2): Claudia Montllor-Albalate, Hyojung Kim, Anna E. Thompson, Alex P. Jonke, Matthew P. Torres, and Amit R. Reddi. Sod1 integrates oxygen availability to redox regulate nadph production and the thiol redoxome. Dec 2022. URL: https://doi.org/10.1073/pnas.2023328119, doi:10.1073/pnas.2023328119. This article has 92 citations and is from a highest quality peer-reviewed journal.

  9. (montlloralbalate2022sod1integratesoxygen pages 3-4): Claudia Montllor-Albalate, Hyojung Kim, Anna E. Thompson, Alex P. Jonke, Matthew P. Torres, and Amit R. Reddi. Sod1 integrates oxygen availability to redox regulate nadph production and the thiol redoxome. Dec 2022. URL: https://doi.org/10.1073/pnas.2023328119, doi:10.1073/pnas.2023328119. This article has 92 citations and is from a highest quality peer-reviewed journal.

  10. (chandel2021nadphtheforgottenreducing pages 1-3): Navdeep S. Chandel. Nadph-the forgotten reducing equivalent. Cold Spring Harbor perspectives in biology, 13 6:a040550, Jun 2021. URL: https://doi.org/10.1101/cshperspect.a040550, doi:10.1101/cshperspect.a040550. This article has 160 citations and is from a peer-reviewed journal.

  11. (anwar2025therapeuticapplicationsand pages 1-3): S. Anwar, Tarique Sarwar, Amjad Ali Khan, and A. Rahmani. Therapeutic applications and mechanisms of superoxide dismutase (sod) in different pathogenesis. Biomolecules, Aug 2025. URL: https://doi.org/10.3390/biom15081130, doi:10.3390/biom15081130. This article has 60 citations.

Artifacts

Citations

  1. boyd2020coppersourcesfor pages 1-3
  2. damiano2020metabolismregulationand pages 1-3
  3. chandel2021nadphtheforgottenreducing pages 1-3
  4. anwar2025therapeuticapplicationsand pages 1-3
  5. rosa2021superoxidedismutaseadministration pages 1-2
  6. zheng2023theapplicationsand pages 1-2
  7. Cu-Zn
  8. https://doi.org/10.1002/anie.202000451,
  9. https://doi.org/10.3390/molecules26071844,
  10. https://doi.org/10.3390/antiox11020427,
  11. https://doi.org/10.3390/antiox12091675,
  12. https://doi.org/10.3390/antiox9060500,
  13. https://doi.org/10.3390/ijms21186606,
  14. https://doi.org/10.1073/pnas.2023328119,
  15. https://doi.org/10.1101/cshperspect.a040550,
  16. https://doi.org/10.3390/biom15081130,

📚 Additional Documentation

Notes

(SOD1-notes.md)

SOD1 (human) — research notes

UniProt: P00441 (SODC_HUMAN). HGNC:11179. 154 aa. EC=1.15.1.1 (Cu-Zn superoxide dismutase).
Chromosome 21. Erythrocyte/cytosolic enzyme; one of the most abundant cytosolic proteins.

Core enzymatic function

  • Cu/Zn superoxide dismutase: catalyzes 2 superoxide + 2 H+ = H2O2 + O2 (RHEA:20696, EC 1.15.1.1)
    [UniProt P00441 CATALYTIC ACTIVITY; ECO:0000269|PubMed:24140062].
  • "Destroys radicals which are normally produced within the cells and which are toxic to biological
    systems" [UniProt FUNCTION, PubMed:24140062].
  • Binds 1 copper ion + 1 zinc ion per subunit; copper is catalytic, zinc structural
    [UniProt COFACTOR, PubMed:17888947 "Binds 1 copper ion per subunit"; "Binds 1 zinc ion per subunit"].
  • Homodimer, non-disulfide-linked; unusually stable quaternary structure controlled by metal occupancy
    and disulfide status [UniProt SUBUNIT; PubMed:15326189].
  • Newer (2023) activity: also oxidizes hydrogen sulfide (H2S) to sulfate, EC 1.8.-.-, a H2S/RSS
    detoxifying role [UniProt; PubMed:36630448 — abstract not cached but UniProt-curated].

Metal binding details

  • PMID:17381088 — zinc binding to apo-SOD1; structural/stability role; IDA zinc ion binding.
  • PMID:17008312 — copper supply; supports
    copper ion binding (IDA). Note: this paper localizes Sod1 metallation to IMS, NOT matrix; the
    GOA "mitochondrial matrix" NAS annotation from this PMID is a misread (the CuL complex is in matrix,
    but SOD1 itself is in IMS/cytosol).

Copper chaperone (CCS) / maturation

  • PMID:9726962 — SOD1 binds its copper chaperone CCS (chaperone binding).
  • PMID:30735496 hCCS catalyses SOD1 folding, copper insertion, disulfide formation; structures of
    reaction precursors/intermediates/products. Supports "superoxide dismutase copper chaperone complex"
    (GO:1902694, part_of).
  • PMID:31292775 —
    SOD1:CCS:Ctr1 heterotrimer; SOD1 activation terminates the interaction. Protein binding (CCS).
  • PMID:24026195 —
    CCS-dependent oxidation-coupled import of SOD1 into mitochondrial IMS. Supports IMS localization (IDA).
  • PMID:24567322 DJ-1 (PARK7) is a copper chaperone activating SOD1 — supports SOD activity (IDA) and
    removal of superoxide radicals (IDA), and copper delivery.

Subcellular localization

  • Primary: cytosol/cytoplasm. PMID:1332049 — strongly supports
    cytosol + nucleus; argues AGAINST mitochondrion/secretory; peroxisome labeling near background.
  • Also nucleus [PMID:22496122 palmitoylation Cys-7 helps nuclear targeting; UniProt SUBCELLULAR LOCATION
    "Nucleus {PubMed:22496122}"].
  • A minor pool in mitochondrial intermembrane space (IMS), delivered via CCS [PMID:24026195;
    PMID:17008312]. Reactome R-HSA-3777112 SOD1 dismutation in IMS.
  • Secreted/extracellular pool: SOD1 detected extracellularly/in exosomes [PMID:9453566 blood;
    PMID:23533145, PMID:19056867 urinary/prostatic exosomes — HDA proteomics]. Minor, non-core.
  • Plasma membrane colocalization on endocytosis into endothelial cells PMID:17077646.

Oxidative-stress defense / downstream processes

  • PMID:16790527 — supports removal of superoxide
    radicals (IDA), response to superoxide (IDA), regulation of mitochondrial membrane potential (IMP),
    redundancy of SOD1 in redox homeostasis.
  • PMID:12551919 CuZn-SOD overexpression modulates hydroperoxide-induced apoptosis in PC-12 — supports
    superoxide metabolic process (IDA); apoptosis effects are downstream/context-specific.
  • PMID:24140062 — SOD activity (IDA),
    reactive oxygen species metabolic process (IDA), hydrogen peroxide biosynthesis (product of SOD).

Moonlighting / interactions (mostly non-core)

  • PMID:18219391 — small GTPase binding (Rac1), regulation of
    GTPase activity, positive regulation of superoxide anion generation (via Nox). Real but specialized.
  • PMID:17324120 — protein phosphatase 2B (calcineurin) binding. Direct, specialized.
  • PMID:26643113 —
    protein binding (disease context).
  • PMID:12968035 Murr1/COMMD1–Wilson disease protein paper; SOD1 IPI listed in GOA but this paper is
    about copper toxicosis, peripheral. Generic protein binding.

ALS / disease (gain-of-function; downstream of core enzyme)

  • PMID:17504823 — ALS is a
    toxic gain-of-function (misfolding/aggregation), NOT loss of dismutase activity. Localization: wtSOD1
    cytoplasm + nuclei; mutant mainly cytoplasmic.
  • PMID:24023695 HSJ1/DNAJB2 chaperone reduces mutant SOD1 aggregation in SOD1(G93A) mice — chaperone
    interaction; nucleus/cytoplasm localization (IDA in mouse model).
  • Many interactome/aggregation papers (PMID:16369483, 16595634, 19171884, 21252941, 23831581, 19022905,
    19369197, 19828437, 21257910, 31999698, 32814053, 29128334, 33961781, 28514442, 20195357, 24981860,
    24234043) — generic "protein binding" IPI, largely high-throughput or aggregation-context; non-core.

Bioinformatic-only / orthology-transfer (ISS GO_REF:0000024, IEA GO_REF:0000107) processes

  • Large set of organismal/physiological process terms transferred from orthologs (mouse Sod1 KO
    phenotypes): ovarian follicle development, placenta development, retina homeostasis, myeloid cell
    homeostasis, spermatogenesis, embryo implantation, sensory perception of sound, locomotory behavior,
    regulation of blood pressure, response to heat/ethanol/H2O2/copper/cadmium/ATP/K+/CO/amphetamine/
    antipsychotic, thymus development, T-cell differentiation, neurofilament organization, PNS myelin
    maintenance, vascular smooth-muscle relaxation, stereocilium organization, heart contraction, etc.
    These reflect pleiotropic phenotypes of Sod1-null mice / overexpression and are downstream of the
    core antioxidant function. Keep as NON_CORE (or REMOVE if unsupported/over-specific).
  • Mouse Sod1-/- phenotypes (hepatocellular carcinoma, reduced fertility, hearing loss, accelerated
    aging) are well documented and underlie many of these transfers; they are genuine consequences of
    lost antioxidant protection but are not the molecular "core function."

Key conclusions for review

  • CORE: superoxide dismutase activity (GO:0004784); copper ion binding (GO:0005507); zinc ion binding
    (GO:0008270); removal of superoxide radicals (GO:0019430) / superoxide metabolic process (GO:0006801);
    cytosol (GO:0005829); homodimerization (GO:0042803). Nucleus is a genuine secondary localization.
  • IMS (GO:0005758) is a real minor catalytic location (IDA, Reactome).
  • Avoid endorsing bare GO:0005515 protein binding; KEEP_AS_NON_CORE at most, note more informative
    partners where direct (CCS chaperone binding, Rac1, calcineurin).
  • Mitochondrion (whole) and peroxisome are largely IBA/IEA over-annotations; PMID:1332049 explicitly
    found mitochondria/secretory compartments did NOT label and peroxisome ~background. Mark accordingly.

📄 View Raw YAML

 
id: P00441
gene_symbol: SOD1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: SOD1 encodes Cu/Zn superoxide dismutase, a highly abundant homodimeric metalloenzyme that catalyzes the dismutation of superoxide radical (O2.-) into molecular oxygen and hydrogen peroxide (EC 1.15.1.1), providing a first line of antioxidant defense. Each ~16 kDa subunit adopts an eight-stranded Greek-key beta-barrel and binds one catalytic copper ion and one structural zinc ion; an intrasubunit disulfide bond (Cys58-Cys147) and zinc binding stabilize the unusually robust dimer. Catalytic copper is delivered by the copper chaperone CCS, which also promotes intramolecular disulfide formation during maturation. SOD1 is predominantly cytosolic, with a functional minor pool in the mitochondrial intermembrane space (imported with CCS) that detoxifies mitochondria-derived superoxide, and additional pools detected in the nucleus and extracellularly. Beyond its dismutase activity, SOD1 has been reported to oxidize hydrogen sulfide to sulfate (a reactive-sulfur-species detoxifying activity) and to act as a redox sensor that binds Rac1 to modulate NADPH oxidase. Loss of SOD1 activity causes a recessive neurological syndrome (STAHP), whereas dominant missense variants cause familial amyotrophic lateral sclerosis through a toxic gain-of-function involving destabilization, misfolding, and aggregation of the protein.
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links
  findings: []
- id: PMID:12968035
  title: "The copper toxicosis gene product Murr1 directly interacts with the Wilson disease protein."
  findings: []
- id: PMID:16369483
  title: "Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis."
  findings: []
- id: PMID:16595634
  title: "Spinal cord endoplasmic reticulum stress associated with a microsomal accumulation of mutant superoxide dismutase-1 in an ALS model."
  findings: []
- id: PMID:19171884
  title: Progressive aggregation despite chaperone associations of a mutant SOD1-YFP in transgenic mice that develop ALS.
  findings: []
- id: PMID:20195357
  title: "A comprehensive resource of interacting protein regions for refining human transcription factor networks."
  findings: []
- id: PMID:21252941
  title: "BAG3 mediates chaperone-based aggresome-targeting and selective autophagy of misfolded proteins."
  findings: []
- id: PMID:22508683
  title: "Molecular and biochemical characterization of a unique mutation in CCS, the human copper chaperone to superoxide dismutase."
  findings: []
- id: PMID:24234043
  title: "Cystatin B and SOD1: protein–protein interaction and possible relation to neurodegeneration."
  findings: []
- id: PMID:24981860
  title: "Human-chromatin-related protein interactions identify a demethylase complex required for chromosome segregation."
  findings: []
- id: PMID:26643113
  title: alpha-synuclein interacts with SOD1 and promotes its oligomerization.
  findings: []
- id: PMID:28514442
  title: "Architecture of the human interactome defines protein communities and disease networks."
  findings: []
- id: PMID:29128334
  title: "A Map of Human Mitochondrial Protein Interactions Linked to Neurodegeneration Reveals New Mechanisms of Redox Homeostasis and NF-κB Signaling."
  findings: []
- id: PMID:32814053
  title: "Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains."
  findings: []
- id: PMID:33961781
  title: "Dual proteome-scale networks reveal cell-specific remodeling of the human interactome."
  findings: []
- id: PMID:17592131
  title: "Metal-free superoxide dismutase forms soluble oligomers under physiological conditions: a possible general mechanism for familial ALS."
  findings: []
- id: PMID:19022905
  title: "Initiation and elongation in fibrillation of ALS-linked superoxide dismutase."
  findings: []
- id: PMID:19369197
  title: "Structural and dynamic aspects related to oligomerization of apo SOD1 and its mutants."
  findings: []
- id: PMID:19828437
  title: "Transient structural distortion of metal-free Cu/Zn superoxide dismutase triggers aberrant oligomerization."
  findings: []
- id: PMID:21257910
  title: "Decreased stability and increased formation of soluble aggregates by immature superoxide dismutase do not account for disease severity in ALS."
  findings: []
- id: PMID:23831581
  title: "Intracellular seeded aggregation of mutant Cu,Zn-superoxide dismutase associated with amyotrophic lateral sclerosis."
  findings: []
- id: PMID:31999698
  title: "Tryptophan residue 32 in human Cu-Zn superoxide dismutase modulates prion-like propagation and strain selection."
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs by Ensembl Compara
  findings: []
- id: PMID:24026195
  title: Human copper chaperone for superoxide dismutase 1 mediates its own oxidation-dependent import into mitochondria.
  findings: []
- id: PMID:31292775
  title: Copper-zinc superoxide dismutase (Sod1) activation terminates interaction between its copper chaperone (Ccs) and the cytosolic metal-binding domain of the copper importer Ctr1.
  findings: []
- id: PMID:30735496
  title: Molecular recognition and maturation of SOD1 by its evolutionarily destabilised cognate chaperone hCCS.
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: PMID:34800366
  title: 'Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.'
  findings: []
- id: PMID:24567322
  title: DJ-1 is a copper chaperone acting on SOD1 activation.
  findings: []
- id: PMID:16254550
  title: Expression of superoxide dismutase in whole lens prevents cataract formation.
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: PMID:24784232
  title: "A new transcriptional role for matrix metalloproteinase-12 in antiviral immunity."
  findings: []
- id: PMID:24023695
  title: Molecular chaperone mediated late-stage neuroprotection in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis.
  findings: []
- id: PMID:22496122
  title: Endothelial cell palmitoylproteomic identifies novel lipid-modified targets and potential substrates for protein acyl transferases.
  findings: []
- id: PMID:19741096
  title: 'Mitochondrial ubiquitin ligase MITOL ubiquitinates mutant SOD1 and attenuates mutant SOD1-induced reactive oxygen species generation.'
  findings: []
- id: PMID:23533145
  title: 'In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.'
  findings: []
- id: PMID:21630459
  title: "Proteomic characterization of the human sperm nucleus."
  findings: []
- id: PMID:24140062
  title: SIRT5 desuccinylates and activates SOD1 to eliminate ROS.
  findings: []
- id: PMID:19056867
  title: 'Large-scale proteomics and phosphoproteomics of urinary exosomes.'
  findings: []
- id: Reactome:R-HSA-3777112
  title: Reactome pathway annotation
  findings: []
- id: Reactome:R-HSA-8950771
  title: Reactome pathway annotation
  findings: []
- id: Reactome:R-HSA-3299691
  title: Reactome pathway annotation
  findings: []
- id: Reactome:R-HSA-3299753
  title: Reactome pathway annotation
  findings: []
- id: PMID:12551919
  title: Differential effects of superoxide dismutase isoform expression on hydroperoxide-induced apoptosis in PC-12 cells.
  findings: []
- id: PMID:18219391
  title: SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model.
  findings: []
- id: PMID:1332049
  title: Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells.
  findings: []
- id: Reactome:R-HSA-482772
  title: Reactome pathway annotation
  findings: []
- id: Reactome:R-HSA-3697860
  title: Reactome pathway annotation
  findings: []
- id: Reactome:R-HSA-8951723
  title: Reactome pathway annotation
  findings: []
- id: PMID:20510358
  title: 'Effects of ALS-related SOD1 mutants on dynein- and KIF5-mediated retrograde and anterograde axonal transport.'
  findings: []
- id: PMID:18809582
  title: "Nucleophosmin serves as a rate-limiting nuclear export chaperone for the Mammalian ribosome."
  findings: []
- id: PMID:12485882
  title: 'Implication of copper zinc superoxide dismutase (SOD-1) in human placenta development.'
  findings: []
- id: PMID:11527942
  title: "Superoxide dismutase isoenzymes in the normal and diseased human cornea."
  findings: []
- id: PMID:10920331
  title: 'Differential localization of placental extracellular superoxide dismutase as pregnancy progresses.'
  findings: []
- id: PMID:17381088
  title: Binding of a single zinc ion to one subunit of copper-zinc superoxide dismutase apoprotein substantially influences the structure and stability of the entire homodimeric protein.
  findings: []
- id: PMID:16716898
  title: 'Early thymic T cell development in young transgenic mice overexpressing human Cu/Zn superoxide dismutase, a model of Down syndrome.'
  findings: []
- id: PMID:9539776
  title: "Overexpression of human copper, zinc-superoxide dismutase (SOD1) prevents postischemic injury."
  findings: []
- id: PMID:15544046
  title: Gene transfer of CuZn superoxide dismutase enhances the synthesis of vascular endothelial growth factor.
  findings: []
- id: PMID:17324120
  title: Activation of brain calcineurin (Cn) by Cu-Zn superoxide dismutase (SOD1) depends on direct SOD1-Cn protein interactions occurring in vitro and in vivo.
  findings: []
- id: PMID:17008312
  title: 'Mitochondrial matrix copper complex used in metallation of cytochrome oxidase and superoxide dismutase.'
  findings: []
- id: PMID:16790527
  title: 'Mitochondrial damage due to SOD1 deficiency in SH-SY5Y neuroblastoma cells: a rationale for the redundancy of SOD1.'
  findings: []
- id: PMID:9453566
  title: "CuZn-superoxide dismutase, extracellular superoxide dismutase, and glutathione peroxidase in blood from individuals homozygous for Asp90Ala CuZu-superoxide dismutase mutation."
  findings: []
- id: PMID:17504823
  title: 'Mutation of SOD1 in ALS: a gain of a loss of function.'
  findings: []
- id: PMID:9726962
  title: 'The copper chaperone CCS directly interacts with copper/zinc superoxide dismutase.'
  findings: []
- id: PMID:17077646
  title: "Rapid endocytosis of copper-zinc superoxide dismutase into human endothelial cells: role for its vascular activity."
  findings: []
- id: file:human/SOD1/SOD1-deep-research-falcon.md
  title: Falcon deep research report for SOD1
  reference_review:
    relevance: MEDIUM
    correctness: UNVERIFIED
    review_notes: "LLM-generated synthesis (Edison/Falcon). It accurately recapitulates the well-established core picture of SOD1 (Cu/Zn dismutation of superoxide to H2O2 and O2 at the diffusion limit; copper redox cycling; Cu coordination by His46/His48/His63/His120 and Zn by His63/His71/His80/Asp83; CCS-mediated maturation with the Cys-Cys disulfide; cytosolic/IMS/nuclear localization). It also foregrounds a non-canonical metabolic-regulatory role in which SOD1-derived H2O2 oxidizes GAPDH and reroutes flux to the oxidative pentose phosphate pathway/NADPH (Montllor-Albalate et al. 2022 PNAS) and an emerging H2S-oxidase activity. These secondary claims are cited only to review-level/summary sources here and are not in GOA; individual primary PMIDs were not independently verified against the cache, so correctness is UNVERIFIED and these are treated as supporting context only, not grounds to add new annotations."
  findings: []
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: "IBA across the Cu/Zn-SOD family annotates SOD1 active in the nucleus; SOD1 has a reproducible secondary nuclear pool that participates in the oxidative stress response and has been linked to roles in transcription and ribosome biogenesis."
    action: KEEP_AS_NON_CORE
    reason: "Nuclear localization is genuine but secondary to the predominant cytosolic site of catalysis; kept as non-core."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Cu,Zn-SOD was found widely distributed in the cell cytosol and in the cell nucleus"
    - reference_id: file:human/SOD1/SOD1-deep-research-falcon.md
      supporting_text: "substantial nuclear localization of SOD1 under both normal and pathological conditions, where it participates in oxidative stress response and may have regulatory roles in transcription and ribosome biogenesis"
- term:
    id: GO:0019430
    label: removal of superoxide radicals
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: "IBA: removal of superoxide radicals; the direct process consequence of dismutase activity."
    action: ACCEPT
    reason: "Strongly phylogenetically supported and equivalent to the core enzymatic role."
    supported_by:
    - reference_id: PMID:16790527
      supporting_text: "Superoxide dismutases (SODs) represent the first line of defense against oxidative stress"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: "IBA: SOD1 active in mitochondrion; reflects the intermembrane-space pool."
    action: KEEP_AS_NON_CORE
    reason: "The functional mitochondrial pool is specifically the intermembrane space (GO:0005758); the generic 'mitochondrion' is a broader, non-core localization."
    supported_by:
    - reference_id: PMID:24026195
      supporting_text: "both localize to the cytosol and the mitochondrial intermembrane space where they specifically counteract mitochondria-derived superoxide"
- term:
    id: GO:0005507
    label: copper ion binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: "IBA: copper ion binding, the catalytic metal of SOD1."
    action: ACCEPT
    reason: "Phylogenetically well-supported; copper is the catalytic cofactor."
    supported_by:
    - reference_id: PMID:31292775
      supporting_text: "Copper-zinc superoxide dismutase (Sod1) is a critical antioxidant enzyme that rids the cell of reactive oxygen through the redox cycling of a catalytic copper ion provided by its copper chaperone (Ccs)."
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: "IBA: SOD1 active in peroxisome; weakly supported in human cells."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Peroxisomal localization is poorly supported; EM immunocytochemistry found SOD1 primarily cytosolic with peroxisome labeling near background. Likely over-annotation."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells."
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: "IBA: cytosol; SOD1 is principally cytosolic."
    action: ACCEPT
    reason: "Core compartment; matches direct human-cell localization."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells."
- term:
    id: GO:0004784
    label: superoxide dismutase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: "SOD1 catalyzes dismutation of superoxide to O2 + H2O2 (EC 1.15.1.1); the defining molecular function."
    action: ACCEPT
    reason: "IEA mapping from RHEA/EC is correct and matches direct experimental evidence."
    supported_by:
    - reference_id: PMID:24140062
      supporting_text: "Cu/Zn superoxide dismutase (SOD1) is a key antioxidant enzyme."
- term:
    id: GO:0005507
    label: copper ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: "Copper ion binding (IEA); the catalytic copper cofactor."
    action: ACCEPT
    reason: "Correct metal-binding mapping."
    supported_by:
    - reference_id: PMID:31292775
      supporting_text: "Copper-zinc superoxide dismutase (Sod1) is a critical antioxidant enzyme that rids the cell of reactive oxygen through the redox cycling of a catalytic copper ion provided by its copper chaperone (Ccs)."
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: "Nucleus (IEA, SubCell)."
    action: KEEP_AS_NON_CORE
    reason: "Secondary nuclear pool; non-core."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Cu,Zn-SOD was found widely distributed in the cell cytosol and in the cell nucleus"
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: "Cytoplasm (IEA, SubCell)."
    action: ACCEPT
    reason: "Consistent with predominant cytosolic localization."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells."
- term:
    id: GO:0006801
    label: superoxide metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: "Superoxide metabolic process (IEA); core process parent of dismutation."
    action: ACCEPT
    reason: "Correct broad parent of the reaction."
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: "Broad 'metal ion binding' (IEA, InterPro)."
    action: KEEP_AS_NON_CORE
    reason: "Correct but less informative than the specific copper (GO:0005507) and zinc (GO:0008270) ion binding annotations; retained as a broader parent."
- term:
    id: GO:1904115
    label: axon cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: located_in
  review:
    summary: "Axon cytoplasm (IEA), inferred from axonal-transport annotations of the rodent ortholog."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Derived computationally from ortholog axonal-transport annotations; not a core human SOD1 localization."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12968035
  qualifier: enables
  review:
    summary: "Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding)."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16369483
  qualifier: enables
  review:
    summary: "Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding)."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16595634
  qualifier: enables
  review:
    summary: "Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding)."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19171884
  qualifier: enables
  review:
    summary: "Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding)."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20195357
  qualifier: enables
  review:
    summary: "Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding)."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21252941
  qualifier: enables
  review:
    summary: "Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding)."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22508683
  qualifier: enables
  review:
    summary: "Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding)."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24234043
  qualifier: enables
  review:
    summary: "Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding)."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24981860
  qualifier: enables
  review:
    summary: "Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding)."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26643113
  qualifier: enables
  review:
    summary: "Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding)."
    supported_by:
    - reference_id: PMID:26643113
      supporting_text: "α-synuclein interacts with SOD1 and promotes its oligomerization."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: "Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding)."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29128334
  qualifier: enables
  review:
    summary: "Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding)."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: "Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding)."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: "Generic protein-binding interaction (IPI) from interaction proteomics/two-hybrid datasets."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding)."
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:17592131
  qualifier: enables
  review:
    summary: "SOD1 self-association (identical protein binding); SOD1 functions as a homodimer."
    action: ACCEPT
    reason: "SOD1 is an obligate homodimer; identical protein binding (homodimerization) is a genuine and informative molecular function supported by structural and interaction studies."
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:19022905
  qualifier: enables
  review:
    summary: "SOD1 self-association (identical protein binding); SOD1 functions as a homodimer."
    action: ACCEPT
    reason: "SOD1 is an obligate homodimer; identical protein binding (homodimerization) is a genuine and informative molecular function supported by structural and interaction studies."
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:19171884
  qualifier: enables
  review:
    summary: "SOD1 self-association (identical protein binding); SOD1 functions as a homodimer."
    action: ACCEPT
    reason: "SOD1 is an obligate homodimer; identical protein binding (homodimerization) is a genuine and informative molecular function supported by structural and interaction studies."
    supported_by:
    - reference_id: PMID:19171884
      supporting_text: "superoxide dismutase 1 (SOD1)-linked amyotrophic"
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:19369197
  qualifier: enables
  review:
    summary: "SOD1 self-association (identical protein binding); SOD1 functions as a homodimer."
    action: ACCEPT
    reason: "SOD1 is an obligate homodimer; identical protein binding (homodimerization) is a genuine and informative molecular function supported by structural and interaction studies."
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:19828437
  qualifier: enables
  review:
    summary: "SOD1 self-association (identical protein binding); SOD1 functions as a homodimer."
    action: ACCEPT
    reason: "SOD1 is an obligate homodimer; identical protein binding (homodimerization) is a genuine and informative molecular function supported by structural and interaction studies."
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:21257910
  qualifier: enables
  review:
    summary: "SOD1 self-association (identical protein binding); SOD1 functions as a homodimer."
    action: ACCEPT
    reason: "SOD1 is an obligate homodimer; identical protein binding (homodimerization) is a genuine and informative molecular function supported by structural and interaction studies."
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:23831581
  qualifier: enables
  review:
    summary: "SOD1 self-association (identical protein binding); SOD1 functions as a homodimer."
    action: ACCEPT
    reason: "SOD1 is an obligate homodimer; identical protein binding (homodimerization) is a genuine and informative molecular function supported by structural and interaction studies."
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:26643113
  qualifier: enables
  review:
    summary: "SOD1 self-association (identical protein binding); SOD1 functions as a homodimer."
    action: ACCEPT
    reason: "SOD1 is an obligate homodimer; identical protein binding (homodimerization) is a genuine and informative molecular function supported by structural and interaction studies."
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:31999698
  qualifier: enables
  review:
    summary: "SOD1 self-association (identical protein binding); SOD1 functions as a homodimer."
    action: ACCEPT
    reason: "SOD1 is an obligate homodimer; identical protein binding (homodimerization) is a genuine and informative molecular function supported by structural and interaction studies."
- term:
    id: GO:0001975
    label: response to amphetamine
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: "Response to amphetamine (IEA, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: "Extracellular region (IEA)."
    action: KEEP_AS_NON_CORE
    reason: "A minor secreted/extracellular pool of SOD1 (including exosomes) exists but is peripheral to the cytosolic antioxidant function."
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: "Lysosome (IEA, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Minor/ortholog-transferred localization; non-core."
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: "Peroxisome (IEA, ortholog)."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Weakly supported in human; same concern as the IBA peroxisome call."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells."
- term:
    id: GO:0006979
    label: response to oxidative stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: "Response to oxidative stress (IEA, ortholog); SOD1 is a first-line antioxidant defense."
    action: ACCEPT
    reason: "Core defensive role against oxidative stress."
    supported_by:
    - reference_id: PMID:16790527
      supporting_text: "Superoxide dismutases (SODs) represent the first line of defense against oxidative stress"
- term:
    id: GO:0008089
    label: anterograde axonal transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: "Anterograde axonal transport (IEA, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0008090
    label: retrograde axonal transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: "Retrograde axonal transport (IEA, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0019430
    label: removal of superoxide radicals
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: "Removal of superoxide radicals (IEA, ortholog); core process."
    action: ACCEPT
    reason: "Equivalent to the core enzymatic role."
    supported_by:
    - reference_id: PMID:16790527
      supporting_text: "Superoxide dismutases (SODs) represent the first line of defense against oxidative stress"
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: "Enzyme binding (IEA, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Generic and uninformative; more specific informative binding (e.g. calcineurin/PP2B, Rac1, CCS) is captured elsewhere. Non-core."
- term:
    id: GO:0030141
    label: secretory granule
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: "Secretory granule (IEA, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Minor ortholog-transferred localization; non-core."
- term:
    id: GO:0030346
    label: protein phosphatase 2B binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: "Protein phosphatase 2B (calcineurin) binding (IEA, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "SOD1 directly binds and activates calcineurin (protein phosphatase 2B); a specific, experimentally supported interaction, though peripheral to the core antioxidant function."
- term:
    id: GO:0031045
    label: dense core granule
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: "Dense core granule (IEA, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Minor ortholog-transferred localization; non-core."
- term:
    id: GO:0031667
    label: response to nutrient levels
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: "Response to nutrient levels (IEA, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: "Protein-containing complex (IEA, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Very generic; SOD1's specific complexes (homodimer, CCS chaperone complex) are captured by more precise terms. Non-core."
- term:
    id: GO:0034465
    label: response to carbon monoxide
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: "Response to carbon monoxide (IEA, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: "Cellular response to oxidative stress (IEA, ortholog)."
    action: ACCEPT
    reason: "Consistent with SOD1's antioxidant defense role."
    supported_by:
    - reference_id: PMID:16790527
      supporting_text: "Superoxide dismutases (SODs) represent the first line of defense against oxidative stress"
- term:
    id: GO:0035865
    label: cellular response to potassium ion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: "Cellular response to potassium ion (IEA, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0043025
    label: neuronal cell body
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: "Neuronal cell body (IEA, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Cell-type-specific localization; non-core."
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: "Negative regulation of apoptotic process (IEA, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "SOD1 is broadly cytoprotective/anti-apoptotic via ROS removal; this downstream process is non-core."
- term:
    id: GO:0046688
    label: response to copper ion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: "Response to copper ion (IEA, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0050665
    label: hydrogen peroxide biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: "Hydrogen peroxide biosynthetic process (IEA); H2O2 is the SOD reaction product."
    action: ACCEPT
    reason: "H2O2 is the direct product of dismutation; correct consequence of SOD1 activity."
- term:
    id: GO:0050728
    label: negative regulation of inflammatory response
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: "Negative regulation of inflammatory response (IEA, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0050766
    label: positive regulation of phagocytosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: "Positive regulation of phagocytosis (IEA, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0071276
    label: cellular response to cadmium ion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: "Cellular response to cadmium ion (IEA, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0071318
    label: cellular response to ATP
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: "Cellular response to ATP (IEA, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0097332
    label: response to antipsychotic drug
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: "Response to antipsychotic drug (IEA, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0005758
    label: mitochondrial intermembrane space
  evidence_type: IDA
  original_reference_id: PMID:24026195
  qualifier: is_active_in
  review:
    summary: "Mitochondrial intermembrane space as active location (IDA)."
    action: ACCEPT
    reason: "Direct evidence for a functional IMS pool dismutating mitochondria-derived superoxide."
    supported_by:
    - reference_id: PMID:24026195
      supporting_text: "both localize to the cytosol and the mitochondrial intermembrane space where they specifically counteract mitochondria-derived superoxide"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: PMID:24026195
  qualifier: is_active_in
  review:
    summary: "Cytosol as active location (TAS)."
    action: ACCEPT
    reason: "Core compartment."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells."
- term:
    id: GO:0019430
    label: removal of superoxide radicals
  evidence_type: NAS
  original_reference_id: PMID:31292775
  qualifier: involved_in
  review:
    summary: "Removal of superoxide radicals asserted for the SOD1/CCS complex (NAS)."
    action: ACCEPT
    reason: "Equivalent to the core process."
    supported_by:
    - reference_id: PMID:31292775
      supporting_text: "Copper-zinc superoxide dismutase (Sod1) is a critical antioxidant enzyme that rids the cell of reactive oxygen through the redox cycling of a catalytic copper ion provided by its copper chaperone (Ccs)."
- term:
    id: GO:1902694
    label: superoxide dismutase copper chaperone complex
  evidence_type: IPI
  original_reference_id: PMID:30735496
  qualifier: part_of
  review:
    summary: "SOD1 is part of the superoxide dismutase copper chaperone complex (with CCS)."
    action: ACCEPT
    reason: "Directly supported: hCCS recognizes and matures SOD1 (copper insertion, disulfide formation) via a defined heterocomplex."
    supported_by:
    - reference_id: PMID:30735496
      supporting_text: "Molecular recognition and maturation of SOD1 by its evolutionarily destabilised cognate chaperone hCCS."
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: "Nucleoplasm (IDA, HPA)."
    action: KEEP_AS_NON_CORE
    reason: "Secondary nuclear pool; non-core."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Cu,Zn-SOD was found widely distributed in the cell cytosol and in the cell nucleus"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: "Cytosol (IDA, HPA immunofluorescence)."
    action: ACCEPT
    reason: "Core compartment."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells."
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: "Mitochondrion (HTP proteomics)."
    action: KEEP_AS_NON_CORE
    reason: "High-throughput; consistent with IMS pool but non-specific."
- term:
    id: GO:0019430
    label: removal of superoxide radicals
  evidence_type: IDA
  original_reference_id: PMID:24567322
  qualifier: involved_in
  review:
    summary: "DJ-1/PARK7 copper chaperone activates SOD1, restoring superoxide removal."
    action: ACCEPT
    reason: "Direct demonstration of SOD1 activation and superoxide removal."
    supported_by:
    - reference_id: PMID:24567322
      supporting_text: "DJ-1 is a copper chaperone acting on SOD1 activation."
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:24567322
  qualifier: enables
  review:
    summary: "Protein homodimerization activity (IPI); SOD1 is an obligate homodimer."
    action: ACCEPT
    reason: "Homodimerization is a core structural property required for activity."
    supported_by:
    - reference_id: PMID:24567322
      supporting_text: "DJ-1 is a copper chaperone acting on SOD1 activation."
- term:
    id: GO:0019430
    label: removal of superoxide radicals
  evidence_type: IDA
  original_reference_id: PMID:16254550
  qualifier: involved_in
  review:
    summary: "SOD1 expression in lens prevents oxidative cataract via superoxide removal."
    action: ACCEPT
    reason: "Functional demonstration of antioxidant protection."
    supported_by:
    - reference_id: PMID:16254550
      supporting_text: "overexpression of superoxide dismutase (SOD) in intact lenses could prevent cataract formation induced by oxidative stress"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31292775
  qualifier: enables
  review:
    summary: "Protein-binding interaction with CCS (IPI)."
    action: KEEP_AS_NON_CORE
    reason: "Bare 'protein binding', but the partner (copper chaperone CCS) is functionally central; the informative aspect is captured by the copper chaperone complex and chaperone-binding annotations. Kept non-core."
    supported_by:
    - reference_id: PMID:31292775
      supporting_text: "provided by its copper chaperone (Ccs)"
- term:
    id: GO:0043410
    label: positive regulation of MAPK cascade
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: acts_upstream_of_or_within
  review:
    summary: "Positive regulation of MAPK cascade (ISS, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:24784232
  qualifier: located_in
  review:
    summary: "Cytoplasm (IDA)."
    action: ACCEPT
    reason: "Core compartment."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24023695
  qualifier: enables
  review:
    summary: "Protein-binding interaction with the chaperone HSJ1/DNAJB2 (IPI)."
    action: KEEP_AS_NON_CORE
    reason: "Disease-context chaperone interaction (mutant SOD1 aggregation); bare protein binding, non-core."
    supported_by:
    - reference_id: PMID:24023695
      supporting_text: "HSJ1a preferentially bound to mutant SOD1"
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:24023695
  qualifier: located_in
  review:
    summary: "Nucleus (IDA)."
    action: KEEP_AS_NON_CORE
    reason: "Secondary nuclear pool; non-core."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Cu,Zn-SOD was found widely distributed in the cell cytosol and in the cell nucleus"
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:24023695
  qualifier: located_in
  review:
    summary: "Cytoplasm (IDA)."
    action: ACCEPT
    reason: "Core compartment."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells."
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:22496122
  qualifier: located_in
  review:
    summary: "Nucleus (IDA); Cys7 palmitoylation promotes nuclear targeting."
    action: KEEP_AS_NON_CORE
    reason: "Genuine secondary nuclear pool regulated by palmitoylation; non-core."
    supported_by:
    - reference_id: PMID:22496122
      supporting_text: "palmitoylproteins identified is superoxide dismutase-1, an intensively studied enzyme that protects all cells from oxidative damage"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:19741096
  qualifier: located_in
  review:
    summary: "Mitochondrion (IDA); ALS-mutant SOD1 accumulates in mitochondria."
    action: KEEP_AS_NON_CORE
    reason: "Derives from mutant SOD1 aggregation/accumulation in mitochondria, a disease context rather than the core wild-type location."
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: "Extracellular exosome (HDA proteomics)."
    action: KEEP_AS_NON_CORE
    reason: "A minor secreted/extracellular pool of SOD1 (including exosomes) exists but is peripheral to the cytosolic antioxidant function."
- term:
    id: GO:0004784
    label: superoxide dismutase activity
  evidence_type: IDA
  original_reference_id: PMID:24567322
  qualifier: enables
  review:
    summary: "Direct SOD activity assay (DJ-1/SOD1 study)."
    action: ACCEPT
    reason: "Confirms the core molecular function."
    supported_by:
    - reference_id: PMID:24567322
      supporting_text: "DJ-1 is a copper chaperone acting on SOD1 activation."
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:21630459
  qualifier: located_in
  review:
    summary: "Nucleus (HDA proteomics)."
    action: KEEP_AS_NON_CORE
    reason: "Secondary nuclear pool; non-core."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Cu,Zn-SOD was found widely distributed in the cell cytosol and in the cell nucleus"
- term:
    id: GO:0004784
    label: superoxide dismutase activity
  evidence_type: IDA
  original_reference_id: PMID:24140062
  qualifier: enables
  review:
    summary: "Direct SOD activity assay; succinylation/SIRT5 regulation study."
    action: ACCEPT
    reason: "Confirms core function."
    supported_by:
    - reference_id: PMID:24140062
      supporting_text: "Cu/Zn superoxide dismutase (SOD1) is a key antioxidant enzyme."
- term:
    id: GO:0072593
    label: reactive oxygen species metabolic process
  evidence_type: IDA
  original_reference_id: PMID:24140062
  qualifier: involved_in
  review:
    summary: "Reactive oxygen species metabolic process (IDA). Beyond consuming superoxide, SOD1-derived H2O2 itself acts as a diffusible redox-signaling species, reinforcing SOD1's central role in cellular ROS metabolism."
    action: ACCEPT
    reason: "SOD1 directly governs cellular ROS levels; it both removes superoxide and generates H2O2, which functions in redox signaling, so the broad ROS metabolic process term is well supported."
    supported_by:
    - reference_id: PMID:24140062
      supporting_text: "SOD1-mediated ROS reduction is increased when SIRT5 is co-expressed."
    - reference_id: file:human/SOD1/SOD1-deep-research-falcon.md
      supporting_text: "H2O2 generated by SOD1 can diffuse across cellular membranes and oxidize specific protein thiols, thereby regulating enzyme activities, transcription factors, and signaling pathways"
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: "Extracellular exosome (HDA proteomics)."
    action: KEEP_AS_NON_CORE
    reason: "A minor secreted/extracellular pool of SOD1 (including exosomes) exists but is peripheral to the cytosolic antioxidant function."
- term:
    id: GO:0005758
    label: mitochondrial intermembrane space
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3777112
  qualifier: located_in
  review:
    summary: "Mitochondrial IMS (TAS, Reactome) dismutation."
    action: ACCEPT
    reason: "Functional IMS pool."
    supported_by:
    - reference_id: PMID:24026195
      supporting_text: "both localize to the cytosol and the mitochondrial intermembrane space where they specifically counteract mitochondria-derived superoxide"
- term:
    id: GO:0005758
    label: mitochondrial intermembrane space
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8950771
  qualifier: located_in
  review:
    summary: "Mitochondrial IMS (TAS, Reactome) detoxification of ROS."
    action: ACCEPT
    reason: "Functional IMS pool."
    supported_by:
    - reference_id: PMID:24026195
      supporting_text: "both localize to the cytosol and the mitochondrial intermembrane space where they specifically counteract mitochondria-derived superoxide"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3299691
  qualifier: located_in
  review:
    summary: "Cytosol (TAS, Reactome)."
    action: ACCEPT
    reason: "Core compartment."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells."
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3299753
  qualifier: located_in
  review:
    summary: "Cytosol (TAS, Reactome)."
    action: ACCEPT
    reason: "Core compartment."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells."
- term:
    id: GO:0004784
    label: superoxide dismutase activity
  evidence_type: IDA
  original_reference_id: PMID:12551919
  qualifier: enables
  review:
    summary: "Direct SOD activity (CuZn-SOD overexpression in PC-12)."
    action: ACCEPT
    reason: "Confirms core function."
    supported_by:
    - reference_id: PMID:12551919
      supporting_text: "stably overexpress the human mitochondrial or cytoplasmic forms of superoxide"
- term:
    id: GO:0006801
    label: superoxide metabolic process
  evidence_type: IDA
  original_reference_id: PMID:12551919
  qualifier: involved_in
  review:
    summary: "Superoxide metabolic process (IDA)."
    action: ACCEPT
    reason: "SOD1 governs superoxide handling."
    supported_by:
    - reference_id: PMID:12551919
      supporting_text: "Stable overexpression of SOD isoforms"
- term:
    id: GO:1902177
    label: positive regulation of oxidative stress-induced intrinsic apoptotic signaling
      pathway
  evidence_type: IMP
  original_reference_id: PMID:12551919
  qualifier: involved_in
  review:
    summary: "Positive regulation of oxidative-stress-induced intrinsic apoptotic signaling (IMP)."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Derived from SOD isoform overexpression effects on hydroperoxide-induced apoptosis; SOD1 is canonically cytoprotective/antioxidant, so a 'positive regulation of apoptosis' process annotation is a context-specific over-annotation."
    supported_by:
    - reference_id: PMID:12551919
      supporting_text: "hydroperoxide-induced apoptosis"
- term:
    id: GO:0031267
    label: small GTPase binding
  evidence_type: IDA
  original_reference_id: PMID:18219391
  qualifier: enables
  review:
    summary: "Small GTPase (Rac1) binding (IDA)."
    action: KEEP_AS_NON_CORE
    reason: "SOD1 directly binds Rac1 as a redox sensor regulating NADPH oxidase; specific and experimentally supported but a specialized moonlighting role, non-core."
    supported_by:
    - reference_id: PMID:18219391
      supporting_text: "SOD1 is not just a catabolic enzyme, but can also directly regulate NADPH oxidase-dependent (Nox-dependent) O(2)(*-) production by binding Rac1 and inhibiting its GTPase activity."
- term:
    id: GO:0032930
    label: positive regulation of superoxide anion generation
  evidence_type: IDA
  original_reference_id: PMID:18219391
  qualifier: involved_in
  review:
    summary: "Positive regulation of superoxide anion generation (IDA), via Rac1/Nox regulation."
    action: KEEP_AS_NON_CORE
    reason: "Paradoxical relative to SOD1's superoxide-consuming activity; reflects the specialized Rac1/Nox redox-sensor role rather than the core function. Non-core."
    supported_by:
    - reference_id: PMID:18219391
      supporting_text: "SOD1 is not just a catabolic enzyme, but can also directly regulate NADPH oxidase-dependent (Nox-dependent) O(2)(*-) production by binding Rac1 and inhibiting its GTPase activity."
- term:
    id: GO:0043087
    label: regulation of GTPase activity
  evidence_type: IDA
  original_reference_id: PMID:18219391
  qualifier: involved_in
  review:
    summary: "Regulation of GTPase activity (IDA); SOD1 inhibits Rac1 GTPase."
    action: KEEP_AS_NON_CORE
    reason: "Specialized Rac1/Nox redox-sensor moonlighting role; non-core."
    supported_by:
    - reference_id: PMID:18219391
      supporting_text: "SOD1 is not just a catabolic enzyme, but can also directly regulate NADPH oxidase-dependent (Nox-dependent) O(2)(*-) production by binding Rac1 and inhibiting its GTPase activity."
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:1332049
  qualifier: located_in
  review:
    summary: "Nucleus (IDA, EM immunocytochemistry)."
    action: KEEP_AS_NON_CORE
    reason: "Secondary nuclear pool; non-core."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Cu,Zn-SOD was found widely distributed in the cell cytosol and in the cell nucleus"
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:1332049
  qualifier: located_in
  review:
    summary: "Peroxisome (IDA, EM immunocytochemistry)."
    action: MARK_AS_OVER_ANNOTATED
    reason: "The original EM immunocytochemistry study found SOD1 primarily cytosolic with peroxisome labeling only slightly above background; peroxisomal localization is weakly supported and treated as an over-annotation, consistent with the IBA/IEA/ISS peroxisome calls."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells."
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-482772
  qualifier: located_in
  review:
    summary: "Extracellular region (TAS, Reactome)."
    action: KEEP_AS_NON_CORE
    reason: "A minor secreted/extracellular pool of SOD1 (including exosomes) exists but is peripheral to the cytosolic antioxidant function."
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3697860
  qualifier: located_in
  review:
    summary: "Cytosol (TAS, Reactome)."
    action: ACCEPT
    reason: "Core compartment."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells."
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-482772
  qualifier: located_in
  review:
    summary: "Cytosol (TAS, Reactome)."
    action: ACCEPT
    reason: "Core compartment."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells."
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8951723
  qualifier: located_in
  review:
    summary: "Cytosol (TAS, Reactome)."
    action: ACCEPT
    reason: "Core compartment."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells."
- term:
    id: GO:0008089
    label: anterograde axonal transport
  evidence_type: ISS
  original_reference_id: PMID:20510358
  qualifier: involved_in
  review:
    summary: "Anterograde axonal transport (ISS, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0008090
    label: retrograde axonal transport
  evidence_type: ISS
  original_reference_id: PMID:20510358
  qualifier: involved_in
  review:
    summary: "Retrograde axonal transport (ISS, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:19741096
  qualifier: located_in
  review:
    summary: "Cytoplasm (IDA)."
    action: ACCEPT
    reason: "Core compartment."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells."
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: "Peroxisome (ISS, ortholog)."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Weakly supported in human; over-annotation."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells."
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:18809582
  qualifier: located_in
  review:
    summary: "Cytoplasm (IDA)."
    action: ACCEPT
    reason: "Core compartment."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells."
- term:
    id: GO:0001541
    label: ovarian follicle development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: "Ovarian follicle development (ISS, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0001890
    label: placenta development
  evidence_type: NAS
  original_reference_id: PMID:12485882
  qualifier: involved_in
  review:
    summary: "Placenta development (NAS)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0001895
    label: retina homeostasis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: "Retina homeostasis (ISS, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0002262
    label: myeloid cell homeostasis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: "Myeloid cell homeostasis (ISS, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:11527942
  qualifier: located_in
  review:
    summary: "Cytoplasm (IDA)."
    action: ACCEPT
    reason: "Core compartment."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells."
- term:
    id: GO:0006749
    label: glutathione metabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: "Glutathione metabolic process (ISS, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0006801
    label: superoxide metabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: "Superoxide metabolic process (ISS, ortholog); core process."
    action: ACCEPT
    reason: "Equivalent to the core role."
- term:
    id: GO:0006879
    label: intracellular iron ion homeostasis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: "Intracellular iron ion homeostasis (ISS, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0007283
    label: spermatogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: "Spermatogenesis (ISS, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0007566
    label: embryo implantation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: "Embryo implantation (ISS, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0007566
    label: embryo implantation
  evidence_type: NAS
  original_reference_id: PMID:10920331
  qualifier: involved_in
  review:
    summary: "Embryo implantation (NAS)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0007605
    label: sensory perception of sound
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: "Sensory perception of sound (ISS, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0007626
    label: locomotory behavior
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: "Locomotory behavior (ISS, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0008217
    label: regulation of blood pressure
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: "Regulation of blood pressure (ISS, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IDA
  original_reference_id: PMID:17381088
  qualifier: enables
  review:
    summary: "SOD1 binds one structural zinc ion per subunit (IDA)."
    action: ACCEPT
    reason: "Direct biochemical evidence; zinc is the structural cofactor stabilizing the dimer/active site."
    supported_by:
    - reference_id: PMID:17381088
      supporting_text: "Binding of a single zinc ion to one subunit of copper-zinc superoxide dismutase apoprotein substantially influences the structure and stability of the entire homodimeric protein."
- term:
    id: GO:0009408
    label: response to heat
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: "Response to heat (ISS, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0019226
    label: transmission of nerve impulse
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: "Transmission of nerve impulse (ISS, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0019430
    label: removal of superoxide radicals
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: "Removal of superoxide radicals (ISS, ortholog); core process."
    action: ACCEPT
    reason: "Equivalent to the core role."
- term:
    id: GO:0032287
    label: peripheral nervous system myelin maintenance
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: "Peripheral nervous system myelin maintenance (ISS, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0033081
    label: regulation of T cell differentiation in thymus
  evidence_type: NAS
  original_reference_id: PMID:16716898
  qualifier: involved_in
  review:
    summary: "Regulation of T cell differentiation in thymus (NAS)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0040014
    label: regulation of multicellular organism growth
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: "Regulation of multicellular organism growth (ISS, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0042542
    label: response to hydrogen peroxide
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: "Response to hydrogen peroxide (ISS, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0043524
    label: negative regulation of neuron apoptotic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: "Negative regulation of neuron apoptotic process (ISS, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "SOD1 is broadly neuroprotective via ROS removal; downstream process, non-core."
- term:
    id: GO:0045471
    label: response to ethanol
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: "Response to ethanol (ISS, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0046620
    label: regulation of organ growth
  evidence_type: NAS
  original_reference_id: PMID:16716898
  qualifier: involved_in
  review:
    summary: "Regulation of organ growth (NAS)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0046716
    label: muscle cell cellular homeostasis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: "Muscle cell cellular homeostasis (ISS, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0048538
    label: thymus development
  evidence_type: NAS
  original_reference_id: PMID:16716898
  qualifier: involved_in
  review:
    summary: "Thymus development (NAS)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0048678
    label: response to axon injury
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: "Response to axon injury (ISS, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0050665
    label: hydrogen peroxide biosynthetic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: "Hydrogen peroxide biosynthetic process (ISS); H2O2 is the SOD reaction product."
    action: ACCEPT
    reason: "H2O2 is the direct product of dismutation."
- term:
    id: GO:0060047
    label: heart contraction
  evidence_type: IDA
  original_reference_id: PMID:9539776
  qualifier: involved_in
  review:
    summary: "Heart contraction (IDA, ortholog/physiology)."
    action: KEEP_AS_NON_CORE
    reason: "Organ-physiology phenotype downstream of antioxidant protection; non-core."
- term:
    id: GO:0060052
    label: neurofilament cytoskeleton organization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: "Neurofilament cytoskeleton organization (ISS, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0060087
    label: relaxation of vascular associated smooth muscle
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: "Relaxation of vascular associated smooth muscle (ISS, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0060088
    label: auditory receptor cell stereocilium organization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: "Auditory receptor cell stereocilium organization (ISS, ortholog)."
    action: KEEP_AS_NON_CORE
    reason: "Transferred from the rodent ortholog (electronic/ortholog evidence); reflects a pleiotropic organismal response to the loss of antioxidant protection rather than a core molecular function. Kept as non-core."
- term:
    id: GO:0001819
    label: positive regulation of cytokine production
  evidence_type: IDA
  original_reference_id: PMID:15544046
  qualifier: involved_in
  review:
    summary: "Positive regulation of cytokine production (IDA)."
    action: KEEP_AS_NON_CORE
    reason: "Single-study immunomodulatory effect; downstream/peripheral, non-core."
    supported_by:
    - reference_id: PMID:15544046
      supporting_text: "Gene transfer of CuZn superoxide dismutase enhances the synthesis of vascular endothelial growth factor."
- term:
    id: GO:0004784
    label: superoxide dismutase activity
  evidence_type: IDA
  original_reference_id: PMID:15544046
  qualifier: enables
  review:
    summary: "Direct SOD activity assay."
    action: ACCEPT
    reason: "Confirms core function."
    supported_by:
    - reference_id: PMID:15544046
      supporting_text: "dismutase (CuZnSOD, SOD1). Overexpression of human SOD1"
- term:
    id: GO:0004784
    label: superoxide dismutase activity
  evidence_type: IDA
  original_reference_id: PMID:17324120
  qualifier: enables
  review:
    summary: "Direct SOD activity assay (calcineurin study)."
    action: ACCEPT
    reason: "Confirms core function."
    supported_by:
    - reference_id: PMID:17324120
      supporting_text: "Cu-Zn superoxide dismutase (SOD1)"
- term:
    id: GO:0005507
    label: copper ion binding
  evidence_type: IDA
  original_reference_id: PMID:17008312
  qualifier: enables
  review:
    summary: "Copper ion binding (IDA); SOD1 metallation in mitochondrial IMS."
    action: ACCEPT
    reason: "Direct evidence SOD1 acquires its catalytic copper."
    supported_by:
    - reference_id: PMID:31292775
      supporting_text: "Copper-zinc superoxide dismutase (Sod1) is a critical antioxidant enzyme that rids the cell of reactive oxygen through the redox cycling of a catalytic copper ion provided by its copper chaperone (Ccs)."
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: NAS
  original_reference_id: PMID:17008312
  qualifier: located_in
  review:
    summary: "Mitochondrial matrix (NAS)."
    action: REMOVE
    reason: "The functional and metallation pools of SOD1 are in the cytosol and mitochondrial intermembrane space, not the matrix; the matrix call appears to be a misassignment."
    supported_by:
    - reference_id: PMID:24026195
      supporting_text: "both localize to the cytosol and the mitochondrial intermembrane space where they specifically counteract mitochondria-derived superoxide"
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:17324120
  qualifier: colocalizes_with
  review:
    summary: "Plasma membrane colocalization (IDA)."
    action: KEEP_AS_NON_CORE
    reason: "Colocalization observed on endocytosis/specialized contexts; peripheral, non-core."
- term:
    id: GO:0030346
    label: protein phosphatase 2B binding
  evidence_type: IDA
  original_reference_id: PMID:17324120
  qualifier: enables
  review:
    summary: "Protein phosphatase 2B (calcineurin) binding (IDA)."
    action: KEEP_AS_NON_CORE
    reason: "SOD1 directly binds and activates calcineurin (protein phosphatase 2B); a specific, experimentally supported interaction, though peripheral to the core antioxidant function."
    supported_by:
    - reference_id: PMID:17324120
      supporting_text: "Activation of brain calcineurin (Cn) by Cu-Zn superoxide dismutase (SOD1) depends on direct SOD1-Cn protein interactions occurring in vitro and in vivo."
- term:
    id: GO:0032839
    label: dendrite cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:17324120
  qualifier: located_in
  review:
    summary: "Dendrite cytoplasm (IDA)."
    action: KEEP_AS_NON_CORE
    reason: "Cell-type-specific cytoplasmic localization; non-core."
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:17324120
  qualifier: part_of
  review:
    summary: "Protein-containing complex (IDA)."
    action: KEEP_AS_NON_CORE
    reason: "Generic; SOD1's specific complexes are captured by precise terms. Non-core."
- term:
    id: GO:0043025
    label: neuronal cell body
  evidence_type: IDA
  original_reference_id: PMID:17324120
  qualifier: located_in
  review:
    summary: "Neuronal cell body (IDA)."
    action: KEEP_AS_NON_CORE
    reason: "Cell-type-specific localization; non-core."
- term:
    id: GO:0050665
    label: hydrogen peroxide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:15544046
  qualifier: involved_in
  review:
    summary: "Hydrogen peroxide biosynthetic process (IDA); H2O2 produced by SOD1."
    action: ACCEPT
    reason: "H2O2 is the direct product of dismutation."
    supported_by:
    - reference_id: PMID:15544046
      supporting_text: "Overexpression of human SOD1"
- term:
    id: GO:0000303
    label: response to superoxide
  evidence_type: IDA
  original_reference_id: PMID:16790527
  qualifier: involved_in
  review:
    summary: "Response to superoxide (IDA); SOD1 deficiency raises steady-state superoxide."
    action: KEEP_AS_NON_CORE
    reason: "Real, but a downstream cellular-response framing; the core process is removal of superoxide."
    supported_by:
    - reference_id: PMID:16790527
      supporting_text: "The steady-state concentration of superoxide was significantly increased"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16790527
  qualifier: enables
  review:
    summary: "Generic protein-binding interaction (IPI)."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Bare 'protein binding' (GO:0005515) is uninformative per curation guidelines; these IPI entries are largely high-throughput or disease/aggregation-context interactions. Marked as over-annotated in favor of specific informative terms (copper ion binding, identical protein binding, protein-folding chaperone binding, small GTPase binding)."
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:9453566
  qualifier: located_in
  review:
    summary: "Extracellular region (IDA); SOD1 detected extracellularly."
    action: KEEP_AS_NON_CORE
    reason: "A minor secreted/extracellular pool of SOD1 (including exosomes) exists but is peripheral to the cytosolic antioxidant function."
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:17504823
  qualifier: located_in
  review:
    summary: "Nucleus (IDA)."
    action: KEEP_AS_NON_CORE
    reason: "Secondary nuclear pool; non-core."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Cu,Zn-SOD was found widely distributed in the cell cytosol and in the cell nucleus"
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:9726962
  qualifier: located_in
  review:
    summary: "Nucleus (IDA); SOD1/CCS study."
    action: KEEP_AS_NON_CORE
    reason: "Secondary nuclear pool; non-core."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Cu,Zn-SOD was found widely distributed in the cell cytosol and in the cell nucleus"
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:17077646
  qualifier: located_in
  review:
    summary: "Cytoplasm (IDA)."
    action: ACCEPT
    reason: "Core compartment."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells."
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:17504823
  qualifier: located_in
  review:
    summary: "Cytoplasm (IDA)."
    action: ACCEPT
    reason: "Core compartment."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells."
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:9726962
  qualifier: located_in
  review:
    summary: "Cytoplasm (IDA)."
    action: ACCEPT
    reason: "Core compartment."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells."
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:16790527
  qualifier: located_in
  review:
    summary: "Mitochondrion (IDA); SOD1 deficiency causes mitochondrial damage."
    action: KEEP_AS_NON_CORE
    reason: "Reflects functional impact on mitochondria; the specific functional pool is the IMS."
    supported_by:
    - reference_id: PMID:16790527
      supporting_text: "Mitochondrial damage due to SOD1 deficiency in SH-SY5Y neuroblastoma cells"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:16790527
  qualifier: located_in
  review:
    summary: "Cytosol (IDA)."
    action: ACCEPT
    reason: "Core compartment."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells."
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:17077646
  qualifier: colocalizes_with
  review:
    summary: "Plasma membrane colocalization (IDA); endocytic uptake context."
    action: KEEP_AS_NON_CORE
    reason: "Colocalization on endocytosis into endothelial cells; peripheral, non-core."
- term:
    id: GO:0031410
    label: cytoplasmic vesicle
  evidence_type: IDA
  original_reference_id: PMID:17077646
  qualifier: located_in
  review:
    summary: "Cytoplasmic vesicle (IDA); endocytic uptake context."
    action: KEEP_AS_NON_CORE
    reason: "Vesicular localization in an uptake/endocytosis context; non-core."
- term:
    id: GO:0043065
    label: positive regulation of apoptotic process
  evidence_type: IC
  original_reference_id: PMID:16790527
  qualifier: involved_in
  review:
    summary: "Positive regulation of apoptotic process (IC, chained off protein binding)."
    action: MARK_AS_OVER_ANNOTATED
    reason: "Inferred (IC) from a protein-binding annotation; SOD1 is canonically anti-apoptotic/cytoprotective, so a positive-apoptosis process annotation is a context-specific over-annotation."
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IPI
  original_reference_id: PMID:9726962
  qualifier: enables
  review:
    summary: "Protein-folding chaperone binding (IPI); SOD1 binds its CCS chaperone."
    action: ACCEPT
    reason: "Direct, informative interaction with the copper chaperone CCS that matures SOD1."
    supported_by:
    - reference_id: PMID:30735496
      supporting_text: "maturation of SOD1 by its evolutionarily destabilised cognate chaperone hCCS"
- term:
    id: GO:0051881
    label: regulation of mitochondrial membrane potential
  evidence_type: IMP
  original_reference_id: PMID:16790527
  qualifier: involved_in
  review:
    summary: "Regulation of mitochondrial membrane potential (IMP)."
    action: KEEP_AS_NON_CORE
    reason: "SOD1 knockdown impairs mitochondrial membrane potential; a downstream consequence of lost antioxidant protection, non-core."
    supported_by:
    - reference_id: PMID:16790527
      supporting_text: "impairment of the mitochondrial transmembrane potential"
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:1332049
  qualifier: located_in
  review:
    summary: "Cytoplasm (IDA, EM immunocytochemistry)."
    action: ACCEPT
    reason: "Core compartment."
    supported_by:
    - reference_id: PMID:1332049
      supporting_text: "Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells."

core_functions:
- description: Cu/Zn superoxide dismutase that catalyzes dismutation of superoxide radical to molecular oxygen and hydrogen peroxide, the central antioxidant defense activity of the cytosol and mitochondrial intermembrane space.
  molecular_function:
    id: GO:0004784
    label: superoxide dismutase activity
  directly_involved_in:
  - id: GO:0019430
    label: removal of superoxide radicals
  - id: GO:0006801
    label: superoxide metabolic process
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0005758
    label: mitochondrial intermembrane space
  supported_by:
  - reference_id: PMID:24140062
    supporting_text: Cu/Zn superoxide dismutase (SOD1) is a key antioxidant enzyme.
  - reference_id: PMID:16790527
    supporting_text: Superoxide dismutases (SODs) represent the first line of defense against oxidative stress
  - reference_id: PMID:24026195
    supporting_text: both localize to the cytosol and the mitochondrial intermembrane space where they specifically counteract mitochondria-derived superoxide
- description: Binds one catalytic copper ion and one structural zinc ion per subunit; metal binding is required for catalysis and for stability of the homodimer. Catalytic copper is delivered by the CCS copper chaperone.
  molecular_function:
    id: GO:0005507
    label: copper ion binding
  in_complex:
    id: GO:1902694
    label: superoxide dismutase copper chaperone complex
  supported_by:
  - reference_id: PMID:31292775
    supporting_text: Copper-zinc superoxide dismutase (Sod1) is a critical antioxidant enzyme that rids the cell of reactive oxygen through the redox cycling of a catalytic copper ion provided by its copper chaperone (Ccs).
  - reference_id: PMID:17381088
    supporting_text: Binding of a single zinc ion to one subunit of copper-zinc superoxide dismutase apoprotein substantially influences the structure and stability of the entire homodimeric protein.
  - reference_id: PMID:30735496
    supporting_text: Molecular recognition and maturation of SOD1 by its evolutionarily destabilised cognate chaperone hCCS.
- description: Functions as an obligate homodimer; subunit self-association (identical protein binding) is intrinsic to the active enzyme and its unusual stability.
  molecular_function:
    id: GO:0042802
    label: identical protein binding
  supported_by:
  - reference_id: PMID:24567322
    supporting_text: DJ-1 is a copper chaperone acting on SOD1 activation.
proposed_new_terms: []
suggested_questions:
- question: Is the hydrogen sulfide oxidase activity (EC 1.8.-.-) of SOD1 a physiologically significant function in human tissues, and should it be captured by a distinct molecular-function annotation alongside superoxide dismutase activity?
  experts:
  - Switzer CH
  - Eaton P
- question: To what extent does the mitochondrial intermembrane-space pool of SOD1 contribute to total cellular superoxide detoxification versus the cytosolic pool in human neurons?
  experts:
  - Riemer J
suggested_experiments:
- hypothesis: SOD1's Rac1-binding redox-sensor function modulates NADPH oxidase output independently of its bulk dismutase activity.
  description: Use SOD1 separation-of-function variants (catalytically inactive but Rac1-binding competent, and vice versa) in human cells to dissociate dismutase activity from Rac1/Nox regulation, measuring superoxide flux and Rac1 GTPase activity.
  experiment_type: structure-function mutagenesis with redox/GTPase readouts
- hypothesis: The mitochondrial intermembrane-space SOD1 pool is required to protect against mitochondria-derived superoxide in human motor neurons.
  description: Compare superoxide levels, mitochondrial membrane potential, and viability in human iPSC-derived motor neurons with IMS-targeting-deficient versus wild-type SOD1, using CCS-dependent import mutants.
  experiment_type: organelle-targeted rescue in iPSC-derived neurons