id: O43708
gene_symbol: GSTZ1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  GSTZ1 is a cytosolic, homodimeric enzyme of the glutathione transferase (GST)
  superfamily (Zeta class) that is bifunctional. Its principal physiological role
  is maleylacetoacetate isomerase (MAAI; EC 5.2.1.2), catalysing the
  glutathione-dependent cis-trans isomerisation of 4-maleylacetoacetate to
  4-fumarylacetoacetate. This is the penultimate step of the phenylalanine/tyrosine
  catabolic pathway that ultimately yields fumarate and acetoacetate, and it is the
  reaction that gives the gene its "maleylacetoacetate isomerase" name. Glutathione
  serves as an essential cofactor that is regenerated during the isomerisation. As a
  canonical member of the GST family the enzyme also possesses classical glutathione
  S-transferase activity (EC 2.5.1.18), although its conjugating activity toward
  standard GST substrates is weak, and it has low glutathione peroxidase activity
  toward organic hydroperoxides. GSTZ1 is the enzyme responsible for the glutathione-
  dependent biotransformation (dehalogenation/oxygenation) of the drug and
  environmental contaminant dichloroacetate (DCA) to glyoxylate; DCA inactivates
  GSTZ1 in a mechanism-based manner, so repeated DCA exposure reduces its own
  clearance. The enzyme is predominantly cytosolic but is also found in the
  mitochondrial matrix. It is most highly expressed in liver and kidney (where
  tyrosine catabolism is active) but is expressed broadly across tissues. Loss of
  GSTZ1/MAAI function causes maleylacetoacetate isomerase deficiency, a biochemically
  mild, generally benign inborn error characterised by elevated succinylacetone (and
  maleylacetone) in blood and urine, usually detected on newborn screening, rather
  than a severe tyrosinemia.
alternative_products:
- name: '1'
  id: O43708-1
- name: '2'
  id: O43708-2
  sequence_note: VSP_039862
- name: '3'
  id: O43708-3
  sequence_note: VSP_047392
existing_annotations:
- term:
    id: GO:0016034
    label: maleylacetoacetate isomerase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) inference of maleylacetoacetate isomerase (MAAI) activity, the
      defining and core molecular function of GSTZ1. This is well supported by direct
      biochemical characterisation of the human enzyme and by the Zeta-class panel.
    action: ACCEPT
    reason: >-
      MAAI activity is the primary physiological function of GSTZ1 and is directly
      demonstrated for the human recombinant enzyme (see the IDA annotation from
      PMID:10739172). The IBA correctly captures the ancestral, conserved function of
      the Zeta family.
    supported_by:
    - reference_id: PMID:9417084
      supporting_text: >-
        characterize at the cDNA level the human gene for maleylacetoacetate isomerase
        (MAAI, EC 5.2.1.2), the only as yet unidentified structural gene of the
        phenylalanine catabolic pathway
- term:
    id: GO:0004364
    label: glutathione transferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) inference of glutathione transferase activity, reflecting
      GSTZ1's membership in the GST superfamily. The activity is genuine but weak
      toward classical GST substrates and is secondary to the MAAI role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Recombinant human GSTZ1-1 has only minimal glutathione-conjugating activity with
      classical GST substrates, so while this activity is real (and mechanistically
      underlies DCA biotransformation), it is not the enzyme's core evolved function.
    supported_by:
    - reference_id: PMID:9396740
      supporting_text: >-
        The protein is a dimer composed of 24.2 kDa subunits and has minimal
        glutathione-conjugating activity with ethacrynic acid and
        7-chloro-4-nitrobenz-2-oxa-1, 3-diazole
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) inference of mitochondrial localisation. GSTZ1 is
      experimentally detected in the mitochondrial matrix as well as the cytosol, but
      its canonical/primary compartment is the cytosol.
    action: KEEP_AS_NON_CORE
    reason: >-
      Mitochondrial localisation is experimentally supported (submitochondrial
      fractionation places GSTZ1 in the matrix; PMID:20884751), but the enzyme is
      predominantly cytosolic and its core function is exerted in the cytosol.
    supported_by:
    - reference_id: PMID:20884751
      supporting_text: >-
        an enzyme colocalized in cytosol and mitochondrial matrix
- term:
    id: GO:0006559
    label: L-phenylalanine catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) inference that GSTZ1 participates in the phenylalanine
      catabolic pathway (the common Phe/Tyr degradation route). This is the core
      biological process in which the MAAI activity operates.
    action: ACCEPT
    reason: >-
      MAAI is the fifth enzyme of the L-phenylalanine (and tyrosine) degradation
      pathway that produces fumarate and acetoacetate; this pathway membership is a
      core aspect of GSTZ1 biology.
    supported_by:
    - reference_id: PMID:9417084
      supporting_text: >-
        maleylacetoacetate isomerase (MAAI, EC 5.2.1.2), the only as yet unidentified
        structural gene of the phenylalanine catabolic pathway
- term:
    id: GO:0006749
    label: glutathione metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) inference of participation in glutathione metabolic process,
      reflecting the enzyme's use of glutathione as a cofactor/co-substrate.
    action: KEEP_AS_NON_CORE
    reason: >-
      Glutathione is an obligatory cofactor for the MAAI reaction and a co-substrate
      for the GST activity, so this process annotation is correct, but it is ancillary
      to the enzyme's core role in tyrosine/phenylalanine catabolism rather than a
      primary function in glutathione homeostasis.
    supported_by:
    - reference_id: PMID:10739172
      supporting_text: >-
        Discovery of a functional polymorphism in human glutathione transferase zeta
- term:
    id: GO:0003824
    label: catalytic activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Root-level InterPro2GO mapping of generic catalytic activity from the GST_Zeta
      InterPro signature. Uninformative given the specific activities already
      annotated.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0003824 catalytic activity is a very high-level molecular function term that
      conveys no specific information. The enzyme's activities are captured precisely
      by GO:0016034 (MAAI) and GO:0004364 (glutathione transferase), so this generic
      term is redundant and over-general.
- term:
    id: GO:0004364
    label: glutathione transferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic (UniProt/RHEA/EC) mapping of glutathione transferase activity
      (EC 2.5.1.18, RHEA:16437). Duplicates the IBA/IDA glutathione transferase
      annotations; genuine but secondary.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct GST activity assignment (the enzyme is an EC 2.5.1.18 glutathione
      transferase) but conjugating activity toward standard substrates is weak and
      secondary to the MAAI isomerase role.
    supported_by:
    - reference_id: PMID:9396740
      supporting_text: >-
        has minimal glutathione-conjugating activity with ethacrynic acid and
        7-chloro-4-nitrobenz-2-oxa-1, 3-diazole
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Electronic (UniProt-SubCell) mapping of cytoplasmic localisation. Correct but
      more general than the specific cytosol annotation.
    action: ACCEPT
    reason: >-
      GSTZ1 is a cytoplasmic/cytosolic enzyme (UniProt subcellular location:
      Cytoplasm). The term is correct though less specific than GO:0005829 cytosol.
- term:
    id: GO:0009072
    label: aromatic amino acid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO mapping to aromatic amino acid metabolic process, the parent branch
      encompassing phenylalanine/tyrosine catabolism.
    action: ACCEPT
    reason: >-
      Correct, if general: MAAI acts in the degradation of the aromatic amino acids
      phenylalanine and tyrosine. Consistent with the more specific L-phenylalanine and
      L-tyrosine catabolic process annotations.
- term:
    id: GO:0016034
    label: maleylacetoacetate isomerase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic (UniProt/RHEA/EC 5.2.1.2, RHEA:14817) mapping of MAAI activity.
      Duplicates the IBA/IDA MAAI annotations for the core function.
    action: ACCEPT
    reason: >-
      Correct assignment of the defining EC 5.2.1.2 maleylacetoacetate isomerase
      activity, independently confirmed experimentally (PMID:10739172).
    supported_by:
    - reference_id: PMID:10739172
      supporting_text: >-
        Discovery of a functional polymorphism in human glutathione transferase zeta
- term:
    id: GO:0098869
    label: cellular oxidant detoxification
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: >-
      Inter-ontology (GOC) inference of cellular oxidant detoxification derived from the
      glutathione peroxidase activity annotation (GO:0004602).
    action: KEEP_AS_NON_CORE
    reason: >-
      GSTZ1 has low glutathione peroxidase activity toward organic hydroperoxides, so a
      minor role in oxidant detoxification is plausible, but this is peripheral to its
      core tyrosine-catabolism function and depends on a weak enzymatic activity.
    supported_by:
    - reference_id: PMID:9396740
      supporting_text: >-
        GSTZ1-1 has glutathione peroxidase activity with t-butyl and cumene
        hydroperoxides
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17474147
  qualifier: enables
  review:
    summary: >-
      Generic protein binding from a high-throughput SH3-domain peptide array screen.
      Uninformative and not tied to any established biological function of GSTZ1.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0005515 protein binding is an uninformative molecular function term. This
      annotation derives from a systematic peptide-array interactome screen (SH3
      domains) with no demonstrated functional consequence for GSTZ1.
    supported_by:
    - reference_id: PMID:17474147
      supporting_text: >-
        Systematic identification of SH3 domain-mediated human protein-protein
        interactions by peptide array target screening
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Generic protein binding from the HuRI binary interactome map. Uninformative
      high-throughput interactor set (e.g. NCK1, QARS1, TRAF2, GORASP2) with no
      established functional relevance to GSTZ1.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0005515 protein binding is uninformative and this is a systematic
      all-by-all binary interactome dataset; none of the interactors define a specific
      molecular function of GSTZ1.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: >-
        we present a human 'all-by-all' reference interactome map of human binary
        protein interactions, or 'HuRI'
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: >-
      Identical protein binding (self-interaction) from a proteome-scale interactome
      screen, consistent with the enzyme being a homodimer.
    action: KEEP_AS_NON_CORE
    reason: >-
      GSTZ1 is a homodimer (established by crystallography, PMID:11327815), so
      self-interaction is genuine. It is retained as a non-core structural property
      rather than a core molecular function.
    supported_by:
    - reference_id: PMID:16189514
      supporting_text: >-
        Towards a proteome-scale map of the human protein-protein interaction network
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: >-
      Identical protein binding (self-interaction) from a proteome-scale interactome
      map, consistent with the homodimeric quaternary structure.
    action: KEEP_AS_NON_CORE
    reason: >-
      Self-interaction reflects the known homodimeric assembly of GSTZ1; genuine but a
      structural property rather than a core molecular function.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: >-
        A proteome-scale map of the human interactome network
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Identical protein binding (self-interaction) from the HuRI binary interactome
      map, consistent with the homodimeric structure of GSTZ1.
    action: KEEP_AS_NON_CORE
    reason: >-
      Self-interaction reflects the homodimeric assembly established by
      crystallography (PMID:11327815); retained as a non-core structural property.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: >-
        a human 'all-by-all' reference interactome map of human binary protein
        interactions, or 'HuRI'
- term:
    id: GO:0006559
    label: L-phenylalanine catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      UniPathway-based electronic annotation to the L-phenylalanine degradation
      pathway (UPA00139), matching the UniProt PATHWAY statement (step 5/6).
    action: ACCEPT
    reason: >-
      Correct pathway membership: MAAI catalyses step 5 of L-phenylalanine degradation
      to acetoacetate and fumarate, per the UniProt UniPathway annotation.
    supported_by:
    - reference_id: PMID:9417084
      supporting_text: >-
        the only as yet unidentified structural gene of the phenylalanine catabolic
        pathway
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:20884751
  qualifier: is_active_in
  review:
    summary: >-
      Direct assay (immunodetection, LC-MS/MS, submitochondrial fractionation) placing
      active GSTZ1 in liver mitochondria, where it also biotransforms DCA. A genuine
      secondary localisation alongside the predominant cytosolic pool.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally supported mitochondrial localisation and activity, but GSTZ1 is
      predominantly cytosolic; the mitochondrial pool is secondary to the core cytosolic
      MAAI function. Defer to the experimental annotation (do not remove).
    supported_by:
    - reference_id: PMID:20884751
      supporting_text: >-
        Immunoreactive GSTZ1 was detected in liver mitochondria from humans and rats,
        and its identity was confirmed by liquid chromatography/tandem mass spectrometry
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:20884751
  qualifier: is_active_in
  review:
    summary: >-
      Direct assay demonstrating catalytically active GSTZ1 in the cytosol, the
      predominant and canonical compartment for the enzyme.
    action: ACCEPT
    reason: >-
      Cytosol is the primary subcellular location where GSTZ1 exerts its MAAI and GST
      activities; DCA dechlorination activity is 2.5-3-fold higher in cytosol than in
      whole mitochondria.
    supported_by:
    - reference_id: PMID:20884751
      supporting_text: >-
        The specific activity of GSTZ1-catalyzed dechlorination of DCA was 2.5- to
        3-fold higher in cytosol than in whole mitochondria
- term:
    id: GO:1990748
    label: cellular detoxification
  evidence_type: IDA
  original_reference_id: PMID:20884751
  qualifier: involved_in
  review:
    summary: >-
      Direct-assay annotation of cellular detoxification, reflecting GSTZ1-catalysed
      glutathione-dependent biotransformation of dichloroacetate (a drug/xenobiotic) to
      glyoxylate.
    action: KEEP_AS_NON_CORE
    reason: >-
      GSTZ1 genuinely detoxifies/biotransforms dichloroacetate, a pharmacologically and
      environmentally relevant halogenated compound. This xenobiotic-handling role is a
      real but non-core function relative to tyrosine catabolism.
    supported_by:
    - reference_id: PMID:20884751
      supporting_text: >-
        a cytosolic enzyme that converts DCA to glyoxylate
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput mitochondrial proteomics detection of GSTZ1, corroborating the
      secondary mitochondrial pool.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with the IDA mitochondrial localisation; a genuine but secondary
      compartment for the predominantly cytosolic enzyme.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: >-
        Quantitative high-confidence human mitochondrial proteome and its dynamics in
        cellular context
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9011595
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) placement of GSTZ1 in the mitochondrial matrix, associated with
      the DCA dehalogenation reaction. Matches submitochondrial fractionation data.
    action: KEEP_AS_NON_CORE
    reason: >-
      Matrix localisation is supported by rat submitochondrial fractionation
      (PMID:20884751), but is secondary to the predominant cytosolic pool.
    supported_by:
    - reference_id: PMID:20884751
      supporting_text: >-
        Study of rat submitochondrial fractions revealed GSTZ1 to be localized in the
        mitochondrial matrix
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-176054
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) annotation of cytosolic localisation associated with GST-mediated
      glutathione conjugation. Consistent with the canonical compartment of GSTZ1.
    action: ACCEPT
    reason: >-
      Cytosol is the primary compartment of GSTZ1; this Reactome TAS annotation agrees
      with direct experimental evidence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71173
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) annotation of cytosolic localisation associated with the 4-MAA
      isomerisation reaction (GSTZ1 isomerizes 4-MAA), consistent with the enzyme's
      canonical cytosolic MAAI activity.
    action: ACCEPT
    reason: >-
      Reflects the cytosolic MAAI reaction in tyrosine catabolism; cytosol is the
      primary compartment for this core function.
- term:
    id: GO:0004364
    label: glutathione transferase activity
  evidence_type: IDA
  original_reference_id: PMID:10739172
  qualifier: enables
  review:
    summary: >-
      Direct-assay characterisation of glutathione transferase activity of recombinant
      human GSTZ1 allelic variants, including 3.6-fold higher DCA activity for the
      GSTZ1a-1a form.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine, directly demonstrated GST activity (the enzyme is EC 2.5.1.18) that
      mechanistically underlies DCA biotransformation, but conjugating activity toward
      standard substrates is weak and secondary to the MAAI role.
    supported_by:
    - reference_id: PMID:10739172
      supporting_text: >-
        GSTZ1a-1a displayed differences in activity towards several substrates compared
        with GSTZ1b-1b and GSTZ1c-1c, including 3.6-fold higher activity towards
        dichloroacetate
- term:
    id: GO:0006749
    label: glutathione metabolic process
  evidence_type: IDA
  original_reference_id: PMID:10739172
  qualifier: involved_in
  review:
    summary: >-
      Direct-assay annotation of participation in glutathione metabolic process,
      reflecting glutathione use during GSTZ1 catalysis.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct given the obligatory role of glutathione as cofactor/co-substrate, but
      ancillary to the core tyrosine-catabolism function rather than a primary role in
      glutathione homeostasis.
    supported_by:
    - reference_id: PMID:10739172
      supporting_text: >-
        human glutathione transferase zeta
- term:
    id: GO:0016034
    label: maleylacetoacetate isomerase activity
  evidence_type: IDA
  original_reference_id: PMID:10739172
  qualifier: enables
  review:
    summary: >-
      Direct-assay demonstration of maleylacetoacetate isomerase activity for
      recombinant human GSTZ1. This is the experimental anchor for the enzyme's core
      molecular function.
    action: ACCEPT
    reason: >-
      MAAI activity is directly demonstrated for the human enzyme and is the defining,
      core evolved function of GSTZ1 in tyrosine/phenylalanine catabolism. The variant
      proteins were purified and assayed for catalytic activity toward multiple
      substrates.
    supported_by:
    - reference_id: PMID:10739172
      supporting_text: >-
        The variant proteins were expressed in Escherichia coli as 6X His-tagged
        proteins and purified by Ni-agarose column chromatography
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:10739172
  qualifier: enables
  review:
    summary: >-
      Protein homodimerization activity: GSTZ1 functions as a homodimer, the active
      quaternary form of the enzyme.
    action: KEEP_AS_NON_CORE
    reason: >-
      Homodimerisation is genuine and structurally confirmed (crystal structure of the
      homodimer, PMID:11327815), forming the functional enzyme, but it is a structural
      property rather than the core catalytic molecular function.
    supported_by:
    - reference_id: PMID:10739172
      supporting_text: >-
        human glutathione transferase zeta
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Sequence-similarity (ISS) transfer of mitochondrial localisation from the mouse
      orthologue (Q9WVL0). Consistent with experimentally observed mitochondrial pool.
    action: KEEP_AS_NON_CORE
    reason: >-
      Corroborates the secondary mitochondrial localisation seen experimentally; the
      predominant compartment remains the cytosol.
- term:
    id: GO:0004364
    label: glutathione transferase activity
  evidence_type: TAS
  original_reference_id: PMID:9396740
  qualifier: enables
  review:
    summary: >-
      Author-stated (TAS) glutathione transferase activity from the original
      characterisation of the Zeta class of GSTs.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct classification as a GST, but the conjugating activity is explicitly
      minimal with standard substrates; secondary to the MAAI role.
    supported_by:
    - reference_id: PMID:9396740
      supporting_text: >-
        has minimal glutathione-conjugating activity with ethacrynic acid and
        7-chloro-4-nitrobenz-2-oxa-1, 3-diazole
- term:
    id: GO:0004602
    label: glutathione peroxidase activity
  evidence_type: TAS
  original_reference_id: PMID:9396740
  qualifier: enables
  review:
    summary: >-
      Author-stated (TAS) glutathione peroxidase activity toward organic
      hydroperoxides, reported to be low relative to other GSTs.
    action: KEEP_AS_NON_CORE
    reason: >-
      A genuine but low-level activity (with t-butyl and cumene hydroperoxides) that is
      peripheral to the enzyme's core MAAI function; underlies the derived oxidant
      detoxification annotation.
    supported_by:
    - reference_id: PMID:9396740
      supporting_text: >-
        Although low in comparison with other GSTs, GSTZ1-1 has glutathione peroxidase
        activity with t-butyl and cumene hydroperoxides
- term:
    id: GO:0006559
    label: L-phenylalanine catabolic process
  evidence_type: TAS
  original_reference_id: PMID:9417084
  qualifier: involved_in
  review:
    summary: >-
      Author-stated (TAS) participation in the phenylalanine catabolic pathway, from
      the paper that identified the human MAAI gene as the last structural gene of that
      pathway.
    action: ACCEPT
    reason: >-
      MAAI is a bona fide enzyme of the phenylalanine/tyrosine degradation pathway; this
      is a core biological process for GSTZ1.
    supported_by:
    - reference_id: PMID:9417084
      supporting_text: >-
        the only as yet unidentified structural gene of the phenylalanine catabolic
        pathway
- term:
    id: GO:0016034
    label: maleylacetoacetate isomerase activity
  evidence_type: TAS
  original_reference_id: PMID:10373324
  qualifier: enables
  review:
    summary: >-
      Author-stated (TAS) maleylacetoacetate isomerase activity, from the paper
      reporting the human MAAI gene structure and expression. Reinforces the core
      molecular function.
    action: ACCEPT
    reason: >-
      Reaffirms the defining EC 5.2.1.2 MAAI activity of GSTZ1, the core molecular
      function.
    supported_by:
    - reference_id: PMID:10373324
      supporting_text: >-
        The gene for maleylacetoacetate isomerase (MAAI) (EC 5.2.1.2) was the last gene
        in the mammalian phenylalanine/tyrosine catabolic pathway to be cloned
- term:
    id: GO:0006572
    label: L-tyrosine catabolic process
  evidence_type: TAS
  original_reference_id: PMID:10373324
  qualifier: involved_in
  review:
    summary: >-
      L-tyrosine catabolic process is NOT present in the current GOA snapshot for GSTZ1
      but is the biological process most directly served by it: MAAI catalyses the
      penultimate step of tyrosine degradation. This is a reviewer-proposed (NEW)
      annotation, not an existing GOA row; it is supported by the MAAI-defining paper
      (PMID:10373324) and consistent with the UniProt "Tyrosine catabolism" keyword.
    action: NEW
    reason: >-
      Tyrosine catabolism is the specific pathway in which the maleylacetoacetate
      isomerase reaction operates (maleylacetoacetate and fumarylacetoacetate are
      tyrosine-degradation intermediates). This process should be annotated for GSTZ1
      and is used in the core function; the phenylalanine catabolic process annotations
      capture the shared upstream route but not the tyrosine-specific one.
    supported_by:
    - reference_id: PMID:10373324
      supporting_text: >-
        The gene for maleylacetoacetate isomerase (MAAI) (EC 5.2.1.2) was the last gene
        in the mammalian phenylalanine/tyrosine catabolic pathway to be cloned
core_functions:
- description: >-
    GSTZ1 is maleylacetoacetate isomerase (MAAI), the enzyme catalysing the
    glutathione-dependent cis-trans isomerisation of 4-maleylacetoacetate to
    4-fumarylacetoacetate (EC 5.2.1.2). This is the penultimate (fifth) step of the
    phenylalanine/tyrosine catabolic pathway and is the principal physiological role
    of the protein.
  molecular_function:
    id: GO:0016034
    label: maleylacetoacetate isomerase activity
  directly_involved_in:
  - id: GO:0006572
    label: L-tyrosine catabolic process
  - id: GO:0006559
    label: L-phenylalanine catabolic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:10739172
    supporting_text: >-
      GSTZ1a-1a displayed differences in activity towards several substrates compared
      with GSTZ1b-1b and GSTZ1c-1c, including 3.6-fold higher activity towards
      dichloroacetate
  - reference_id: PMID:9417084
    supporting_text: >-
      maleylacetoacetate isomerase (MAAI, EC 5.2.1.2), the only as yet unidentified
      structural gene of the phenylalanine catabolic pathway
- description: >-
    As a member of the glutathione transferase superfamily (Zeta class), GSTZ1 has
    glutathione transferase activity (EC 2.5.1.18) and is the enzyme responsible for
    the glutathione-dependent biotransformation of the drug/xenobiotic dichloroacetate
    to glyoxylate. Conjugating activity toward classical GST substrates is weak, so
    this is a secondary function relative to the MAAI role.
  molecular_function:
    id: GO:0004364
    label: glutathione transferase activity
  directly_involved_in:
  - id: GO:1990748
    label: cellular detoxification
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:20884751
    supporting_text: >-
      a cytosolic enzyme that converts DCA to glyoxylate
  - reference_id: PMID:9396740
    supporting_text: >-
      has minimal glutathione-conjugating activity with ethacrynic acid and
      7-chloro-4-nitrobenz-2-oxa-1, 3-diazole
proposed_new_terms: []
suggested_questions:
- question: >-
    Given that MAAI is expressed ubiquitously whereas the full phenylalanine/tyrosine
    catabolic pathway is restricted to liver and kidney, does GSTZ1 have a distinct
    physiological role in non-hepatic tissues?
- question: >-
    What is the relative contribution of the cytosolic versus mitochondrial matrix
    pools of GSTZ1 to dichloroacetate biotransformation and to tyrosine catabolism
    in vivo?
suggested_experiments:
- description: >-
    Metabolic flux and metabolomic profiling of GSTZ1-knockout cells and MAAID patient
    samples to quantify accumulation of maleylacetoacetate/maleylacetone and downstream
    succinylacetone.
  hypothesis: >-
    Loss of GSTZ1 MAAI activity diverts tyrosine catabolism to produce
    maleylacetone and succinylacetone without causing severe fumarylacetoacetate-driven
    toxicity, consistent with the benign MAAID phenotype.
- description: >-
    Compartment-specific (cytosol vs mitochondrial matrix) activity assays and targeting
    experiments to determine how GSTZ1 reaches the mitochondrial matrix and whether the
    matrix pool contributes meaningfully to DCA clearance.
  hypothesis: >-
    The mitochondrial matrix pool of GSTZ1 arises from dual localisation of the same
    cytosolic protein and contributes a minor fraction of total DCA biotransformation.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  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: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10373324
  title: Gene structure, chromosomal location, and expression pattern of maleylacetoacetate
    isomerase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reports human MAAI gene structure and ubiquitous expression, and confirms MAAI as
      the last cloned gene of the mammalian Phe/Tyr catabolic pathway. Directly supports
      the core function and process annotations.
- id: PMID:10739172
  title: Discovery of a functional polymorphism in human glutathione transferase zeta
    by expressed sequence tag database analysis.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Primary experimental characterisation of recombinant human GSTZ1 allelic variants,
      including catalytic activity toward dichloroacetate. UniProt cites it for both
      catalytic activities and DCA oxygenation. Anchors the IDA MAAI/GST annotations.
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Proteome-scale binary interactome screen; supports only the self-interaction
      (homodimer) annotation, not any specific molecular function.
- id: PMID:17474147
  title: Systematic identification of SH3 domain-mediated human protein-protein interactions
    by peptide array target screening.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput SH3 peptide-array interactome screen; basis for an uninformative
      generic protein binding annotation with no established functional consequence.
- id: PMID:20884751
  title: Mitochondrion as a novel site of dichloroacetate biotransformation by glutathione
    transferase zeta 1.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Directly demonstrates cytosolic and mitochondrial-matrix localisation of active
      GSTZ1 and its role in DCA biotransformation. Anchors the cytosol/mitochondrion and
      cellular detoxification annotations.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Proteome-scale interactome map; supports only the homodimeric self-interaction
      annotation.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      HuRI all-by-all binary interactome; source of generic protein binding and
      identical protein binding annotations, none functionally characterised for GSTZ1.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      High-throughput mitochondrial proteome; corroborates the secondary mitochondrial
      localisation of GSTZ1.
- id: PMID:9396740
  title: Zeta, a novel class of glutathione transferases in a range of species from
    plants to humans.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Defines the Zeta class of GSTs and characterises recombinant human GSTZ1-1,
      documenting its minimal GST conjugating activity and low glutathione peroxidase
      activity. Supports the GST and GPx activity annotations.
- id: PMID:9417084
  title: Characterization of a fungal maleylacetoacetate isomerase gene and identification
    of its human homologue.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Identifies the human MAAI gene as the homologue of A. nidulans maiA and the last
      structural gene of the phenylalanine catabolic pathway. Supports the core MAAI and
      phenylalanine catabolism annotations.
- id: Reactome:R-HSA-176054
  title: GST dimers conjugate GSH with cytosolic substrates
  findings: []
- id: Reactome:R-HSA-71173
  title: GSTZ1 isomerizes 4-MAA
  findings: []
- id: Reactome:R-HSA-9011595
  title: GSTZ1 dimer dehalogenates DCA
  findings: []