GSTZ1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0016034 maleylacetoacetate isomerase activity	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:9417084 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 file:human/GSTZ1/GSTZ1-uniprot.txt Reaction=4-maleylacetoacetate = 4-fumarylacetoacetate; file:interpro/panther/PTHR42673/PTHR42673-paint.tsv PTN001344486 GO:0016034 F IBD
GO:0004364 glutathione transferase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) inference of glutathione transferase activity, reflecting GSTZ1's membership in the GST superfamily. The activity is weak toward classical GST substrates but substantial toward haloacids, where it underlies the glutathione-dependent dehalogenation of dichloroacetate. Reason: Directly demonstrated for the recombinant human enzyme (IDA, PMID:10739172) and recorded by UniProt as EC 2.5.1.18 alongside the isomerase reaction. Conjugating activity toward classical GST substrates (CDNB-type) is minimal, but the glutathione-dependent dehalogenation/oxygenation of dichloroacetate to glyoxylate is a well-characterized, pharmacologically important GSTZ1-catalysed reaction, so this is a genuine second activity rather than a family-level over-propagation. The IBD for the term sits at the family-root node PTN001344486 and is seeded in part by GSTZ1 itself, which is expected: the gene's own experimental annotation is one of the descendant evidences the PAINT curator used. Supporting Evidence: PMID:9396740 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
GO:0005739 mitochondrion	IBA GO_REF:0000033	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:20884751 an enzyme colocalized in cytosol and mitochondrial matrix
GO:0006559 L-phenylalanine catabolic process	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:9417084 maleylacetoacetate isomerase (MAAI, EC 5.2.1.2), the only as yet unidentified structural gene of the phenylalanine catabolic pathway
GO:0006749 glutathione metabolic process	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic (IBA) inference of participation in glutathione metabolic process, reflecting the enzyme's use of glutathione as a cofactor/co-substrate. 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. Supporting Evidence: file:human/GSTZ1/GSTZ1-uniprot.txt Note=Glutathione is required for the MAAI activity. file:interpro/panther/PTHR42673/PTHR42673-paint.tsv PTN001344486 GO:0006749 P IBD
GO:0003824 catalytic activity	IEA GO_REF:0000002	TOO GENERAL	Summary: Root-level InterPro2GO mapping of generic catalytic activity from the GST_Zeta InterPro signature. True but uninformative given the specific activities already annotated. Reason: GSTZ1 is certainly a catalytic protein, so the claim is not wrong; the term is simply entailed by the specific molecular functions accepted in this review, GO:0016034 maleylacetoacetate isomerase activity and GO:0004364 glutathione transferase activity, and adds nothing on its own.
GO:0004364 glutathione transferase activity	IEA GO_REF:0000120	ACCEPT	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. Reason: Correct GST activity assignment: UniProt records the EC 2.5.1.18 reaction (RHEA:16437) with experimental evidence tied to PubMed:10739172. Conjugating activity toward standard CDNB-type substrates is weak, but the glutathione-dependent dehalogenation of dichloroacetate is a genuine, directly assayed GSTZ1 reaction. Supporting Evidence: PMID:9396740 has minimal glutathione-conjugating activity with ethacrynic acid and 7-chloro-4-nitrobenz-2-oxa-1, 3-diazole
GO:0005737 cytoplasm	IEA GO_REF:0000120	MODIFY	Summary: Electronic (UniProt-SubCell) mapping of cytoplasmic localisation. Correct but more general than the specific cytosol annotation the gene already carries. Reason: The claim is right but less specific than the evidence supports: GSTZ1 is experimentally shown to be catalytically active in the cytosol (IDA, PMID:20884751), and GO:0005829 cytosol, a descendant of cytoplasm that the gene already carries by IDA and TAS, is the term the evidence warrants. Proposed replacements: cytosol
GO:0009072 aromatic amino acid metabolic process	IEA GO_REF:0000002	TOO GENERAL	Summary: InterPro2GO mapping to aromatic amino acid metabolic process, the parent branch encompassing phenylalanine/tyrosine catabolism. True but entailed by the specific pathway terms. Reason: MAAI does act in the degradation of the aromatic amino acids phenylalanine and tyrosine, so the term is true; it is entailed by the GO:0006559 L-phenylalanine catabolic process and GO:0006572 L-tyrosine catabolic process annotations asserted elsewhere in this review and carries no additional information.
GO:0016034 maleylacetoacetate isomerase activity	IEA GO_REF:0000120	ACCEPT	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. Reason: Correct assignment of the defining EC 5.2.1.2 maleylacetoacetate isomerase activity, independently confirmed experimentally (PMID:10739172). Supporting Evidence: file:human/GSTZ1/GSTZ1-uniprot.txt Reaction=4-maleylacetoacetate = 4-fumarylacetoacetate;
GO:0098869 cellular oxidant detoxification	IEA GO_REF:0000108	KEEP AS NON CORE	Summary: Inter-ontology (GOC) inference of cellular oxidant detoxification derived from the glutathione peroxidase activity annotation (GO:0004602). 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. Supporting Evidence: PMID:9396740 GSTZ1-1 has glutathione peroxidase activity with t-butyl and cumene hydroperoxides
GO:0005515 protein binding	IPI PMID:17474147 Systematic identification of SH3 domain-mediated human prote...	REMOVE	Summary: Generic protein binding from a high-throughput SH3-domain peptide array screen (interactor NCK1, UniProtKB:P16333). Uninformative and not tied to any established biological function of GSTZ1. Reason: GO:0005515 protein binding carries no functional information, and the cited peptide-array screen supports no more informative molecular function for GSTZ1: the reported partner (NCK1) has no mechanistic connection to the isomerase or transferase chemistry, and no complex or adapter role has been demonstrated. Removal does not mean the reported interaction is false; the interaction remains recorded in IntAct. Supporting Evidence: PMID:17474147 Systematic identification of SH3 domain-mediated human protein-protein interactions by peptide array target screening
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: Generic protein binding from the HuRI binary interactome map. Uninformative high-throughput interactor set (QARS1, TRAF2, GORASP2, CLVS2, PLEKHG4, TCP11, ZMYND12) with no established functional relevance to GSTZ1. Reason: GO:0005515 protein binding carries no functional information, and this systematic all-by-all binary interactome dataset supports no more informative replacement term: the interactors span unrelated processes and none has been shown to form a functional complex with GSTZ1 or to require it. The separate GO:0042802 identical protein binding rows capture the one interaction that is functionally meaningful (the homodimer). Removal does not mean the reported interactions are false. Supporting Evidence: PMID:32296183 we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'
GO:0042802 identical protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	KEEP AS NON CORE	Summary: Identical protein binding (self-interaction) from a proteome-scale interactome screen, consistent with the enzyme being a homodimer. 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. Supporting Evidence: PMID:16189514 Towards a proteome-scale map of the human protein-protein interaction network
GO:0042802 identical protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	KEEP AS NON CORE	Summary: Identical protein binding (self-interaction) from a proteome-scale interactome map, consistent with the homodimeric quaternary structure. Reason: Self-interaction reflects the known homodimeric assembly of GSTZ1; genuine but a structural property rather than a core molecular function. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network
GO:0042802 identical protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: Identical protein binding (self-interaction) from the HuRI binary interactome map, consistent with the homodimeric structure of GSTZ1. Reason: Self-interaction reflects the homodimeric assembly established by crystallography (PMID:11327815); retained as a non-core structural property. Supporting Evidence: PMID:32296183 a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'
GO:0006559 L-phenylalanine catabolic process	IEA GO_REF:0000041	ACCEPT	Summary: UniPathway-based electronic annotation to the L-phenylalanine degradation pathway (UPA00139), matching the UniProt PATHWAY statement (step 5/6). Reason: Correct pathway membership: MAAI catalyses step 5 of L-phenylalanine degradation to acetoacetate and fumarate, per the UniProt UniPathway annotation. Supporting Evidence: PMID:9417084 the only as yet unidentified structural gene of the phenylalanine catabolic pathway
GO:0005739 mitochondrion	IDA PMID:20884751 Mitochondrion as a novel site of dichloroacetate biotransfor...	KEEP AS NON CORE	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. 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). Supporting Evidence: PMID:20884751 Immunoreactive GSTZ1 was detected in liver mitochondria from humans and rats, and its identity was confirmed by liquid chromatography/tandem mass spectrometry
GO:0005829 cytosol	IDA PMID:20884751 Mitochondrion as a novel site of dichloroacetate biotransfor...	ACCEPT	Summary: Direct assay demonstrating catalytically active GSTZ1 in the cytosol, the predominant and canonical compartment for the enzyme. 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. Supporting Evidence: PMID:20884751 The specific activity of GSTZ1-catalyzed dechlorination of DCA was 2.5- to 3-fold higher in cytosol than in whole mitochondria
GO:1990748 cellular detoxification	IDA PMID:20884751 Mitochondrion as a novel site of dichloroacetate biotransfor...	ACCEPT	Summary: Direct-assay annotation of cellular detoxification, reflecting GSTZ1-catalysed glutathione-dependent biotransformation of dichloroacetate (a drug/xenobiotic) to glyoxylate. Reason: GSTZ1 is the enzyme that biotransforms dichloroacetate, a pharmacologically and environmentally relevant halogenated compound, in both the cytosol and the mitochondrial matrix; loss of GSTZ1 activity directly reduces DCA clearance. This is the process in which the enzyme's glutathione-dependent dehalogenation activity acts, and it is retained as the second core function alongside tyrosine/phenylalanine catabolism. Supporting Evidence: PMID:20884751 a cytosolic enzyme that converts DCA to glyoxylate
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	KEEP AS NON CORE	Summary: High-throughput mitochondrial proteomics detection of GSTZ1, corroborating the secondary mitochondrial pool. Reason: Consistent with the IDA mitochondrial localisation; a genuine but secondary compartment for the predominantly cytosolic enzyme. Supporting Evidence: PMID:34800366 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9011595	KEEP AS NON CORE	Summary: Reactome (TAS) placement of GSTZ1 in the mitochondrial matrix, associated with the DCA dehalogenation reaction. Matches submitochondrial fractionation data. Reason: Matrix localisation is supported by rat submitochondrial fractionation (PMID:20884751), but is secondary to the predominant cytosolic pool. Supporting Evidence: PMID:20884751 Study of rat submitochondrial fractions revealed GSTZ1 to be localized in the mitochondrial matrix
GO:0005829 cytosol	TAS Reactome:R-HSA-176054	ACCEPT	Summary: Reactome (TAS) annotation of cytosolic localisation associated with GST-mediated glutathione conjugation. Consistent with the canonical compartment of GSTZ1. Reason: Cytosol is the primary compartment of GSTZ1; this Reactome TAS annotation agrees with direct experimental evidence.
GO:0005829 cytosol	TAS Reactome:R-HSA-71173	ACCEPT	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. Reason: Reflects the cytosolic MAAI reaction in tyrosine catabolism; cytosol is the primary compartment for this core function.
GO:0004364 glutathione transferase activity	IDA PMID:10739172 Discovery of a functional polymorphism in human glutathione ...	ACCEPT	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. Reason: Directly demonstrated glutathione transferase activity of the purified recombinant human enzyme (EC 2.5.1.18), including allele-dependent activity toward dichloroacetate. This is the experimental anchor for the second core activity of GSTZ1, glutathione-dependent haloacid dehalogenation. Activity toward classical conjugation substrates is weak, which constrains how the term should be read but does not make it non-core. Supporting Evidence: PMID:10739172 GSTZ1a-1a displayed differences in activity towards several substrates compared with GSTZ1b-1b and GSTZ1c-1c, including 3.6-fold higher activity towards dichloroacetate
GO:0006749 glutathione metabolic process	IDA PMID:10739172 Discovery of a functional polymorphism in human glutathione ...	KEEP AS NON CORE	Summary: Direct-assay annotation of participation in glutathione metabolic process, reflecting glutathione use during GSTZ1 catalysis. 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. Supporting Evidence: file:human/GSTZ1/GSTZ1-uniprot.txt Note=Glutathione is required for the MAAI activity.
GO:0016034 maleylacetoacetate isomerase activity	IDA PMID:10739172 Discovery of a functional polymorphism in human glutathione ...	ACCEPT	Summary: Direct-assay demonstration of maleylacetoacetate isomerase activity for recombinant human GSTZ1. This is the experimental anchor for the enzyme's core molecular function. 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. Supporting Evidence: PMID:10739172 The variant proteins were expressed in Escherichia coli as 6X His-tagged proteins and purified by Ni-agarose column chromatography file:human/GSTZ1/GSTZ1-uniprot.txt Reaction=4-maleylacetoacetate = 4-fumarylacetoacetate;
GO:0042803 protein homodimerization activity	IPI PMID:10739172 Discovery of a functional polymorphism in human glutathione ...	KEEP AS NON CORE	Summary: Protein homodimerization activity: GSTZ1 functions as a homodimer, the active quaternary form of the enzyme. 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. Supporting Evidence: file:human/GSTZ1/GSTZ1-uniprot.txt Homodimer. {ECO:0000269\|PubMed:11327815}.
GO:0005739 mitochondrion	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Sequence-similarity (ISS) transfer of mitochondrial localisation from the mouse orthologue (Q9WVL0). Consistent with experimentally observed mitochondrial pool. Reason: Corroborates the secondary mitochondrial localisation seen experimentally; the predominant compartment remains the cytosol.
GO:0004364 glutathione transferase activity	TAS PMID:9396740 Zeta, a novel class of glutathione transferases in a range o...	ACCEPT	Summary: Author-stated (TAS) glutathione transferase activity from the original characterisation of the Zeta class of GSTs. Reason: Correct classification as a GST, from the paper that defined the Zeta class. The conjugating activity measured there with standard substrates (ethacrynic acid, NBD-Cl) is explicitly minimal; the physiologically important transferase-type reaction is the glutathione-dependent dehalogenation of dichloroacetate shown later (PMID:10739172, PMID:20884751). Supporting Evidence: PMID:9396740 has minimal glutathione-conjugating activity with ethacrynic acid and 7-chloro-4-nitrobenz-2-oxa-1, 3-diazole
GO:0004602 glutathione peroxidase activity	TAS PMID:9396740 Zeta, a novel class of glutathione transferases in a range o...	KEEP AS NON CORE	Summary: Author-stated (TAS) glutathione peroxidase activity toward organic hydroperoxides, reported to be low relative to other GSTs. 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. Supporting Evidence: PMID:9396740 Although low in comparison with other GSTs, GSTZ1-1 has glutathione peroxidase activity with t-butyl and cumene hydroperoxides
GO:0006559 L-phenylalanine catabolic process	TAS PMID:9417084 Characterization of a fungal maleylacetoacetate isomerase ge...	ACCEPT	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. Reason: MAAI is a bona fide enzyme of the phenylalanine/tyrosine degradation pathway; this is a core biological process for GSTZ1. Supporting Evidence: PMID:9417084 the only as yet unidentified structural gene of the phenylalanine catabolic pathway
GO:0016034 maleylacetoacetate isomerase activity	TAS PMID:10373324 Gene structure, chromosomal location, and expression pattern...	ACCEPT	Summary: Author-stated (TAS) maleylacetoacetate isomerase activity, from the paper reporting the human MAAI gene structure and expression. Reinforces the core molecular function. Reason: Reaffirms the defining EC 5.2.1.2 MAAI activity of GSTZ1, the core molecular function. Supporting Evidence: PMID:10373324 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
GO:0006572 L-tyrosine catabolic process	TAS PMID:10373324 Gene structure, chromosomal location, and expression pattern...	NEW	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. 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. Supporting Evidence: PMID:10373324 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
GO:1902000 homogentisate catabolic process	IC PMID:9417084 Characterization of a fungal maleylacetoacetate isomerase ge...	NEW	Summary: GSTZ1/MAAI catalyses the isomerization step between the homogentisate ring-cleavage and hydrolysis steps. Reason: GSTZ1 isomerizes maleylacetoacetate, the product of homogentisate ring cleavage, to fumarylacetoacetate, so it performs one of the three catalytic steps of homogentisate catabolism (participation, not mere requirement). GO:1902000 is not a subclass of the L-tyrosine or L-phenylalanine catabolic processes already accepted. Added for consistency with FAH, which carries the term, and with the other homogentisate-pathway exemplars. Supporting Evidence: PMID:9417084 They encode a protein with 45% sequence identity to MaiA, which showed MAAI activity when expressed in E. coli.

Gene Description

Existing Annotations Review

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