SOD2

id: P00447
gene_symbol: SOD2
aliases:
  - YHR008C
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:559292
  label: Saccharomyces cerevisiae
description: Manganese-dependent superoxide dismutase localized to the mitochondrial matrix. SOD2 catalyzes the dismutation of superoxide radicals (O2•−) to hydrogen peroxide and molecular oxygen, serving as a critical antioxidant defense mechanism against reactive oxygen species generated during mitochondrial respiration. The enzyme contains one manganese ion per subunit and functions as a homotetramer.
existing_annotations:
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IBA annotation for mitochondrial localization based on phylogenetic inference across orthologous SOD2 proteins. Well-supported by multiple direct experimental observations confirming mitochondrial matrix localization.
    action: ACCEPT
    reason: SOD2 is a well-established mitochondrial protein. The mitochondrial localization is supported by extensive evidence including direct biochemical purification from mitochondria, subcellular fractionation studies, and the presence of a mitochondrial transit peptide (residues 1-26) that is cleaved upon import. IBA inference from orthologous sequences is appropriate for this annotation as SOD2 localization is conserved across eukaryotes.
    supported_by:
      - reference_id: PMID:238997
        supporting_text: "The cyanide-insensitive superoxide dismutase of yeast has been shown to be localized in the mitochondrial matrix."
      - reference_id: PMID:15851472
        supporting_text: "Manganese-dependent superoxide dismutase 2 (SOD2) in the mitochondria plays a key role in protection against oxidative stress."
- term:
    id: GO:0004784
    label: superoxide dismutase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IBA annotation for superoxide dismutase catalytic activity, inferred from orthologous SOD2 proteins. Core molecular function of SOD2 and highly conserved across eukaryotes. This annotation is more specific and appropriate than broader "oxidoreductase activity" annotations.
    action: ACCEPT
    reason: >
      SOD2's primary molecular function is superoxide dismutase activity. The enzyme
      catalyzes conversion of superoxide anion to hydrogen peroxide and oxygen
      (EC 1.15.1.1). This is a highly specific and informative functional annotation
      representing the core catalytic activity. IBA inference is appropriate given
      the high conservation of this enzyme family across eukaryotes and consistent
      functional characterization of SOD2 orthologs.
    supported_by:
      - reference_id: PMID:238997
        supporting_text: "This enzyme has been isolated in good yield from bakers' yeast...This enzyme has activity comparable to that of other previously reported superoxide dismutases"
      - reference_id: PMID:15851472
        supporting_text: "Manganese-dependent superoxide dismutase 2 (SOD2) in the mitochondria plays a key role in protection against oxidative stress"
- term:
    id: GO:0030145
    label: manganese ion binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >
      IBA annotation for manganese ion binding cofactor requirement. SOD2 requires
      manganese for catalytic activity with 1 Mn2+ per subunit. Critical for enzyme
      function and essential for distinguishing from cytoplasmic Fe-SOD1.
    action: ACCEPT
    reason: >
      SOD2 is a manganese-dependent superoxide dismutase, distinguishing it from the
      iron-dependent SOD1 isoform found in the cytoplasm. The UniProt entry explicitly
      states "Binds 1 Mn(2+) ion per subunit" with specific binding residues identified
      (positions 52, 107, 194, 198). Manganese insertion is essential during import
      into mitochondria and is mechanistically coupled to the mitochondrial import
      process. This annotation is more specific and informative than generic "metal ion
      binding" annotations and reflects the specialized cofactor requirement.
    supported_by:
      - reference_id: PMID:238997
        supporting_text: "This enzyme contains 1 atom of manganese per subunit and its absorption in the visible suggests Mn(III) in the resting enzyme."
      - reference_id: PMID:15851472
        supporting_text: "We found that a mitochondrial localization is essential...Manganese insertion is only possible with a newly synthesized polypeptide."
- term:
    id: GO:0004784
    label: superoxide dismutase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >
      IEA annotation via InterPro mapping (IPR001189: Mn/Fe superoxide dismutase).
      Redundant with IBA and IDA annotations for the same function but from automated
      computational mapping. Acceptable but less evidence-rich than experimental data.
    action: ACCEPT
    reason: >
      This IEA annotation derives from InterPro domain mapping, which appropriately
      identifies SOD2 as a superoxide dismutase based on conserved protein domains.
      While less informative than direct experimental evidence, automated annotations
      based on InterPro are generally reliable for well-characterized enzyme families.
      The annotation is not contradicted by experimental evidence and supports the
      core function identified by IBA and IDA annotations.
    supported_by:
      - reference_id: GO_REF:0000120
        supporting_text: Combined Automated Annotation using Multiple IEA Methods based on InterPro domain mapping
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >
      IEA annotation for mitochondrial localization via ARBA machine learning models.
      Represents automated inference from amino acid sequence patterns associated with
      mitochondrial proteins. Redundant with direct experimental evidence.
    action: ACCEPT
    reason: >
      ARBA machine learning models provide evidence for mitochondrial localization
      based on sequence patterns trained on experimentally validated mitochondrial
      proteins. While less directly informative than experimental evidence, this IEA
      annotation is consistent with and supported by extensive experimental data
      including direct biochemical purification and subcellular localization studies.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >
      IEA annotation based on UniProtKB subcellular location vocabulary mapping to
      "Mitochondrion matrix". More specific than broader "mitochondrion" annotation,
      reflecting SOD2's precise subcellular compartment.
    action: ACCEPT
    reason: >
      The annotation correctly identifies the mitochondrial matrix as SOD2's specific
      subcellular compartment. This IEA is derived from structured UniProtKB annotation
      and is supported by direct experimental evidence. The matrix localization is
      essential for SOD2 function in protecting mitochondrial proteins and DNA from
      superoxide generated by the electron transport chain. This is more specific and
      informative than the broader "mitochondrion" annotations.
    supported_by:
      - reference_id: PMID:238997
        supporting_text: "The cyanide-insensitive superoxide dismutase of yeast has been shown to be localized in the mitochondrial matrix."
- term:
    id: GO:0006801
    label: superoxide metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >
      IEA annotation for involvement in superoxide metabolic process based on InterPro
      domain mapping. Reasonable but somewhat redundant with more specific process
      annotations like "removal of superoxide radicals".
    action: ACCEPT
    reason: >
      This annotation appropriately captures SOD2's involvement in superoxide metabolism
      through the dismutation reaction. However, it is broader than the more specific
      functional process "removal of superoxide radicals" (GO:0019430) which more
      precisely describes the biological outcome. The annotation is not incorrect but
      represents a higher-level categorization of the more specific process.
- term:
    id: GO:0016209
    label: antioxidant activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >
      IEA annotation based on UniProtKB keyword mapping (KW-0049: Antioxidant).
      Accurate but relatively broad characterization of SOD2's functional role.
    action: ACCEPT
    reason: >
      SOD2 is correctly characterized as having antioxidant activity through its
      superoxide dismutase function. While this annotation is less specific than
      GO:0004784 (superoxide dismutase activity), it is accurate and captures the
      physiological consequence of the enzyme's catalytic activity. Antioxidant
      activity represents an appropriate functional categorization for SOD2.
- term:
    id: GO:0016491
    label: oxidoreductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >
      IEA annotation based on UniProtKB keyword mapping (KW-0560: Oxidoreductase).
      Correct but very broad categorization of enzymatic function.
    action: KEEP_AS_NON_CORE
    reason: >
      While technically correct that superoxide dismutase is an oxidoreductase enzyme
      (catalyzing electron transfer in the dismutation reaction), this annotation is
      overly broad and lacks specificity. The broader "oxidoreductase activity"
      encompasses thousands of diverse enzymatic activities and provides minimal
      functional information. More specific annotations like "superoxide dismutase
      activity" and "antioxidant activity" are far more informative. However, it is
      not incorrect, so retaining it as non-core is appropriate to avoid cluttering
      the functional annotation space.
- term:
    id: GO:0019430
    label: removal of superoxide radicals
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  review:
    summary: >
      IEA annotation inferred via logical inference from the primary superoxide
      dismutase activity annotation. Accurately captures the functional consequence
      of SOD2's enzymatic activity.
    action: ACCEPT
    reason: >
      This process annotation appropriately captures the biological function of SOD2.
      The enzyme removes/detoxifies superoxide radicals by catalyzing their conversion
      to hydrogen peroxide and oxygen. This is the functional outcome of the superoxide
      dismutase catalytic activity and is logically inferred from that core function.
      The annotation is supported by extensive evidence of SOD2's role in cellular
      antioxidant defense.
    supported_by:
      - reference_id: PMID:3520557
        supporting_text: "MnSOD contributes to the natural protection of cells against oxygen toxicity"
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >
      IEA annotation for general metal ion binding based on InterPro domain mapping.
      Accurate but very broad and less specific than the manganese-specific annotation.
    action: KEEP_AS_NON_CORE
    reason: >
      SOD2 does bind a metal ion (specifically manganese), making this annotation
      technically correct. However, it is overly general and lacks the specificity
      that makes GO:0030145 (manganese ion binding) superior. While some genes may
      require annotation at this level of generality, SOD2's cofactor requirement is
      specifically and characteristically for manganese rather than other metal ions.
      The more specific "manganese ion binding" annotation is far more informative
      and should be prioritized. Retaining this as non-core avoids redundancy.
- term:
    id: GO:0098869
    label: cellular oxidant detoxification
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  review:
    summary: >
      IEA annotation for cellular oxidant detoxification, inferred from antioxidant
      activity via logical inference. Captures the cellular process consequence of
      SOD2's enzymatic function.
    action: ACCEPT
    reason: >
      This process annotation appropriately characterizes SOD2's role in protecting
      cells from reactive oxygen species. The enzyme detoxifies superoxide and
      contributes to overall cellular antioxidant defense. The annotation is logically
      inferred from the antioxidant activity function and is supported by experimental
      evidence of SOD2's essential role in protecting cells against oxidative stress,
      particularly in mitochondria where high ROS levels are generated.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HDA
  original_reference_id: PMID:24769239
  review:
    summary: >
      HDA annotation from quantitative proteomic study identifying SOD2 in isolated
      mitochondria during proteomic survey of mitochondrial proteins under different
      growth conditions. Supports mitochondrial localization.
    action: ACCEPT
    reason: >
      This HDA annotation is based on direct detection of SOD2 protein in isolated
      mitochondrial fractions using mass spectrometry. Quantitative proteomics provides
      strong evidence for protein localization. The study systematically identified
      mitochondrial proteins and their relative abundance across different metabolic
      conditions. This represents solid experimental evidence for mitochondrial
      presence, though less specific than subcellular fractionation at the matrix level.
    supported_by:
      - reference_id: PMID:24769239
        supporting_text: "Label free quantitative analysis of protein accumulation revealed significant variation of 176 mitochondrial proteins"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HDA
  original_reference_id: PMID:11914276
  review:
    summary: >
      HDA annotation from proteome-scale high-throughput subcellular localization study
      mapping yeast protein localization. Confirms mitochondrial localization through
      immunolocalization-based approach.
    action: ACCEPT
    reason: >
      This study represents the first large-scale proteome localization study in yeast,
      using high-throughput immunolocalization of epitope-tagged proteins to determine
      subcellular localization. SOD2 was identified among proteins localized to
      mitochondria. This represents direct experimental evidence for mitochondrial
      localization at genome scale. The methodology is robust though localization to
      the matrix specifically would require additional evidence.
    supported_by:
      - reference_id: PMID:11914276
        supporting_text: "We estimate the yeast proteome to encompass approximately 5100 soluble proteins and >1000 transmembrane proteins. Our results indicate that 47% of yeast proteins are cytoplasmic, 13% mitochondrial"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HDA
  original_reference_id: PMID:14576278
  review:
    summary: >
      HDA annotation from comprehensive mass spectrometry-based proteomics of purified
      yeast mitochondria. SOD2 identified in mitochondrial proteome catalog.
    action: ACCEPT
    reason: >
      This landmark study identified >750 different proteins from highly purified yeast
      mitochondria using tandem mass spectrometry. SOD2 was identified in this
      comprehensive mitochondrial proteome. The study analyzed only mitochondrial
      fractions, providing direct evidence for mitochondrial localization. This
      represents strong experimental support from a well-cited mitochondrial proteomics
      resource.
    supported_by:
      - reference_id: PMID:14576278
        supporting_text: "From >20 million MS spectra, 750 different proteins were identified, indicating an involvement of mitochondria in numerous cellular processes"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HDA
  original_reference_id: PMID:16823961
  review:
    summary: >
      HDA annotation from advanced proteomics study combining multidimensional
      separation techniques to characterize the complete yeast mitochondrial proteome.
    action: ACCEPT
    reason: >
      This study used orthogonal proteomics approaches to achieve the most comprehensive
      characterization of the yeast mitochondrial proteome, identifying 851 different
      proteins. SOD2 was identified as a mitochondrial protein in this resource. The
      use of multiple complementary separation and detection methods increases
      confidence in protein identification. This represents high-quality experimental
      evidence for mitochondrial localization from a mature proteomics platform.
    supported_by:
      - reference_id: PMID:16823961
        supporting_text: "A total of 851 different proteins (PROMITO dataset) were identified by use of multidimensional LC-MS/MS"
- term:
    id: GO:0004784
    label: superoxide dismutase activity
  evidence_type: IDA
  original_reference_id: PMID:15851472
  review:
    summary: >
      IDA annotation from direct enzymatic assay study characterizing manganese
      activation of SOD2 in mitochondria. Demonstrates enzyme activity and essential
      cofactor requirement.
    action: ACCEPT
    reason: >
      This IDA annotation is from direct biochemical characterization of SOD2 enzyme
      activity in mitochondrial context. The study specifically examined manganese
      activation of SOD2, demonstrating the enzyme's superoxide dismutase activity
      and its dependence on mitochondrial import for proper cofactor insertion. This
      represents strong experimental evidence for the core molecular function.
    supported_by:
      - reference_id: PMID:15851472
        supporting_text: "Manganese-dependent superoxide dismutase 2 (SOD2) in the mitochondria plays a key role in protection against oxidative stress. Here we probed the pathway by which SOD2 acquires its manganese catalytic cofactor."
- term:
    id: GO:0004784
    label: superoxide dismutase activity
  evidence_type: IDA
  original_reference_id: PMID:238997
  review:
    summary: >
      IDA annotation from the landmark 1975 study that first isolated and characterized
      manganese-containing SOD from yeast. Original biochemical characterization of
      enzyme activity.
    action: ACCEPT
    reason: >
      This is from the seminal study that first isolated yeast mitochondrial SOD and
      demonstrated its superoxide dismutase activity in vitro. The study characterized
      the enzyme's molecular weight (96,000 Da tetramer), subunit structure, manganese
      content (1 Mn per subunit), and catalytic activity. This represents foundational
      experimental evidence for SOD2's molecular function and remains a critical
      reference for the enzyme's properties.
    supported_by:
      - reference_id: PMID:238997
        supporting_text: "This enzyme has been isolated in good yield from bakers' yeast...This enzyme contains 1 atom of manganese per subunit...This enzyme has activity comparable to that of other previously reported superoxide dismutases"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:15851472
  review:
    summary: >
      IDA annotation from manganese activation study that demonstrated SOD2's
      mitochondrial localization is essential for cofactor insertion and activation.
    action: ACCEPT
    reason: >
      The study directly showed that mitochondrial localization of SOD2 is essential
      for proper manganese insertion and enzyme activation. Cytosolic versions of SOD2
      remain largely apo (without manganese) unless cells are exposed to toxic manganese
      levels. This demonstrates mechanistically that SOD2's mitochondrial localization
      is not just coincidental but essential for function. The study provides strong
      experimental evidence for mitochondrial localization integrated with functional
      characterization.
    supported_by:
      - reference_id: PMID:15851472
        supporting_text: "We found that a mitochondrial localization is essential...By reversibly blocking mitochondrial import in vivo, we noted that newly synthesized Sod2p can enter mitochondria but not a Sod2p polypeptide that was allowed to accumulate in the cytosol."
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IDA
  original_reference_id: PMID:238997
  review:
    summary: >
      IDA annotation from original characterization study that specifically localized
      the enzyme to the mitochondrial matrix compartment. Foundational evidence for
      subcellular compartmentalization.
    action: ACCEPT
    reason: >
      The seminal 1975 study explicitly localized the cyanide-insensitive (manganese)
      superoxide dismutase to the mitochondrial matrix, the innermost mitochondrial
      compartment where the electron transport chain generates superoxide and where
      SOD2 provides essential antioxidant protection. This specific subcellular
      localization is more informative than broader mitochondrion annotations and
      accurately reflects the enzyme's functional compartment. This remains the gold
      standard evidence for matrix localization.
    supported_by:
      - reference_id: PMID:238997
        supporting_text: "The cyanide-insensitive superoxide dismutase of yeast has been shown to be localized in the mitochondrial matrix."
- term:
    id: GO:0072593
    label: reactive oxygen species metabolic process
  evidence_type: IMP
  original_reference_id: PMID:3520557
  review:
    summary: >
      IMP annotation from genetic knockout study demonstrating that SOD2 is essential
      for cellular protection against oxygen-induced ROS toxicity. Establishes
      biological role in ROS metabolism.
    action: ACCEPT
    reason: >
      This IMP annotation is from a landmark genetic study that created a SOD2-null
      mutant and demonstrated its hypersensitivity to oxygen. The mutant lacked
      cyanide-insensitive SOD activity and exhibited growth inhibition in
      oxygen-containing atmospheres, providing direct genetic evidence that SOD2
      contributes to cellular defense against oxygen toxicity through ROS metabolism.
      This represents the strongest type of biological process evidence showing that
      loss of protein function impairs the process.
    supported_by:
      - reference_id: PMID:3520557
        supporting_text: "In the absence of oxygen, the mutant grew as rapidly as the wild-type parent. However, increasing concentrations of oxygen led to a progressive inhibition of growth. The properties of this mutant provide direct evidence that MnSOD contributes to the natural protection of cells against oxygen toxicity."
core_functions:
  - molecular_function:
      id: GO:0004784
      label: superoxide dismutase activity
    description: >
      Superoxide dismutase activity is the core molecular function of SOD2. The enzyme
      catalyzes the highly specific reaction: 2 O2•− + 2 H+ → H2O2 + O2 (EC 1.15.1.1).
      Direct biochemical characterization (PMID:238997, PMID:15851472) demonstrates
      this catalytic activity. The enzyme requires manganese cofactor (1 Mn2+ per
      subunit) which is specifically inserted during mitochondrial import.
    directly_involved_in:
      - id: GO:0072593
        label: reactive oxygen species metabolic process
    locations:
      - id: GO:0005759
        label: mitochondrial matrix
    supported_by:
      - reference_id: PMID:238997
        supporting_text: "This enzyme has been isolated in good yield from bakers' yeast. This enzyme contains 1 atom of manganese per subunit and its absorption in the visible suggests Mn(III) in the resting enzyme."
      - reference_id: PMID:15851472
        supporting_text: "Manganese-dependent superoxide dismutase 2 (SOD2) in the mitochondria plays a key role in protection against oxidative stress."
proposed_new_terms: []
suggested_questions:
  - question: >
      What role does SOD2 phosphorylation play in regulating its activity or
      localization?
  - question: >
      Are there condition-specific changes in SOD2 expression or activity in response
      to metabolic state?
  - question: >
      Does SOD2 interact with other mitochondrial proteins to form a larger
      antioxidant defense complex?
suggested_experiments:
  - description: >
      Detailed kinetic analysis of SOD2 with various superoxide concentrations and pH
      conditions to establish optimal activity parameters in vivo
  - description: >
      Investigation of SOD2 regulation by reactive oxygen species or other cellular
      signals that might modulate its expression
  - description: >
      Analysis of the relationship between SOD2 activity and cellular aging or
      replicative lifespan in yeast
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11914276
  title: Subcellular localization of the yeast proteome.
  findings: []
- id: PMID:14576278
  title: The proteome of Saccharomyces cerevisiae mitochondria.
  findings: []
- id: PMID:15851472
  title: Manganese activation of superoxide dismutase 2 in the mitochondria of Saccharomyces
    cerevisiae.
  findings: []
- id: PMID:16823961
  title: 'Toward the complete yeast mitochondrial proteome: multidimensional separation
    techniques for mitochondrial proteomics.'
  findings: []
- id: PMID:238997
  title: Isolation and characterization of a manganese-containing superoxide dismutase
    from yeast.
  findings: []
- id: PMID:24769239
  title: Quantitative variations of the mitochondrial proteome and phosphoproteome
    during fermentative and respiratory growth in Saccharomyces cerevisiae.
  findings: []
- id: PMID:3520557
  title: A yeast mutant lacking mitochondrial manganese-superoxide dismutase is hypersensitive
    to oxygen.
  findings: []