GSTZ1

Summary

GSTZ1 (glutathione S-transferase zeta 1, HGNC:4643) is a protein-coding gene on chromosome 14q24.3, encoding Maleylacetoacetate isomerase (O43708). Bifunctional enzyme showing minimal glutathione-conjugating activity with ethacrynic acid and 7-chloro-4-nitrobenz-2-oxa-1,3-diazole and maleylacetoacetate isomerase activity.

This gene is a member of the glutathione S-transferase (GSTs) super-family which encodes multifunctional enzymes important in the detoxification of electrophilic molecules, including carcinogens, mutagens, and several therapeutic drugs, by conjugation with glutathione. This enzyme catalyzes the conversion of maleylacetoacetate to fumarylacetoacatate, which is one of the steps in the phenylalanine/tyrosine degradation pathway. Deficiency of a similar gene in mouse causes oxidative stress. Several transcript variants of this gene encode multiple protein isoforms.

Source: NCBI Gene 2954 — RefSeq curated summary.

At a glance

• Gene–disease (curated): maleylacetoacetate isomerase deficiency (Moderate, ClinGen)
• Clinical variants (ClinVar): 60 total — 2 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 2
• Druggable target: yes
• MANE Select transcript: NM_145870

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4643
Approved symbol	GSTZ1
Name	glutathione S-transferase zeta 1
Location	14q24.3
Locus type	gene with protein product
Status	Approved
Aliases	GSTZ1-1, MAAI, MAI
Ensembl gene	ENSG00000100577
Ensembl biotype	protein_coding
OMIM	603758
Entrez	2954

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 17 protein_coding, 7 retained_intron, 1 nonsense_mediated_decay

ENST00000216465, ENST00000349555, ENST00000361389, ENST00000393734, ENST00000553268, ENST00000553431, ENST00000553586, ENST00000553770, ENST00000553838, ENST00000554279, ENST00000554381, ENST00000554846, ENST00000555093, ENST00000555208, ENST00000555583, ENST00000556627, ENST00000556914, ENST00000557053, ENST00000557639, ENST00000860516, ENST00000860517, ENST00000937391, ENST00000937392, ENST00000937393, ENST00000937394

RefSeq mRNA: 4 — MANE Select: NM_145870 NM_001312660, NM_001363703, NM_145870, NM_145871

CCDS: CCDS86416, CCDS9858, CCDS9859, CCDS9860

Canonical transcript exons

ENST00000216465 — 9 exons

Exon	Start	End
ENSE00001094097	77321036	77321183
ENSE00002479832	77331069	77331597
ENSE00003487202	77327472	77327552
ENSE00003514472	77326838	77326905
ENSE00003530168	77329123	77329201
ENSE00003533768	77324870	77324921
ENSE00003584984	77329755	77329807
ENSE00003586529	77330310	77330359
ENSE00003784615	77327912	77328037

Expression profiles

Bgee: expression breadth ubiquitous, 269 present calls, max score 97.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.5190 / max 83.8423, expressed in 1790 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
140774	12.4602	1790
140776	0.0432	5
140775	0.0157	6

Top tissues by expression

290 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	97.46	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	95.79	gold quality
right testis	UBERON:0004534	95.46	gold quality
liver	UBERON:0002107	95.41	gold quality
left testis	UBERON:0004533	95.23	gold quality
endometrium epithelium	UBERON:0004811	94.44	gold quality
testis	UBERON:0000473	93.22	gold quality
right adrenal gland	UBERON:0001233	92.20	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.15	gold quality
mucosa of transverse colon	UBERON:0004991	92.11	gold quality
right adrenal gland cortex	UBERON:0035827	91.74	gold quality
gastrocnemius	UBERON:0001388	91.56	gold quality
left adrenal gland	UBERON:0001234	91.35	gold quality
muscle of leg	UBERON:0001383	91.00	gold quality
left adrenal gland cortex	UBERON:0035825	90.79	gold quality
adrenal tissue	UBERON:0018303	90.47	gold quality
adrenal cortex	UBERON:0001235	90.12	gold quality
adrenal gland	UBERON:0002369	89.97	gold quality
muscle organ	UBERON:0001630	89.48	gold quality
lower esophagus mucosa	UBERON:0035834	89.02	gold quality
rectum	UBERON:0001052	88.44	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	88.30	gold quality
esophagus mucosa	UBERON:0002469	88.27	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	88.09	gold quality
apex of heart	UBERON:0002098	87.92	gold quality
skin of leg	UBERON:0001511	87.84	gold quality
islet of Langerhans	UBERON:0000006	87.83	gold quality
minor salivary gland	UBERON:0001830	87.68	gold quality
saliva-secreting gland	UBERON:0001044	87.55	gold quality
gluteal muscle	UBERON:0002000	87.22	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.25

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, PPARG

miRNA regulators (miRDB)

16 targeting GSTZ1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-542-3P	99.34	67.58	1270
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-214-3P	98.71	68.12	2128
HSA-MIR-761	98.71	68.07	2051
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-3198	97.84	65.64	579
HSA-MIR-4309	97.84	65.45	588
HSA-MIR-6734-5P	95.70	65.56	950

Literature-anchored findings (GeneRIF, showing 33)

• A new allele of GSTZ1 (maleylacetoacetate isomerase), characterized by a Thr82Met substitution and termed GSTZ1d, has been identified by analysis of the expressed sequence tag (EST) database. (PMID:11692075)
• Single nucleotide polymorphisms may alter GSTZ1 expression, which may alter the pharmacokinetics of DCA, which is used therapeutically for the treatment of lactic acidosis. (PMID:16609361)
• Kinetic studies revealed that the catalytic mechanism of Se-hGSTZ1-1 belong in a ping-pong mechanism similar to that of the natural glutathione peroxidase. (PMID:18373941)
• The results are consistent with the hypothesis that reduced dopamine metabolism adversely affects cognition. (PMID:18628685)
• MDR analysis revealed a three-gene combination, consisting of NOS3 (p.Glu298Asp), GSTZ1 (p.Lys32Glu), and GSTP1 (p.Ile105Val), that provided the highest predictive model for gentamicin-induced vestibular dysfunction. (PMID:18776599)
• it is unlikely that glutathione S-transferases GSTA2, GSTM2, GSTO1, GSTO2, and GSTZ1 participate in breast cancer susceptibility. (PMID:19859803)
• our results did not reveal a consistent pattern between GSTM1 and GSTZ genotypes and increased occurrence of adverse sperm outcomes (PMID:20214911)
• subjects with polymorphisms in GSTZ1 have a higher trihalomethanes induced bladder cancer susceptibility (PMID:20675267)
• Results describe the genotypic frequencies of glutathione S-transferase Z1 polymorphisms among an Iranian population. (PMID:21107728)
• The results of this study did not support the association between genetic polymorphisms of glutathione S-transferase Z1 (GSTZ1) and susceptibility to schizophrenia. (PMID:21183226)
• polymorphisms of GSTZ1 showed strong linkage disequilibrium among cancer patients and control su (PMID:21823988)
• Our study did not support any association between susceptibility to exudative AMD (age-related macular degeneration) and polymorphisms of GSTZ1. (PMID:21948024)
• Data suggest neonatal onset and age-related increase in GSTZ1 protein expression during liver development/growth. GSTZ1 haplotype influences activity with dichloroacetate but not protein expression. (PMID:22028318)
• This study was performed on 228 BPD patients and 234 control subjects. Among early-onset patients, the variant alleles of Glu32Lys and G-1002A increased BPD susceptibility. (PMID:22374552)
• e report for the first time the conversion of human glutathione transferase Zeta (hGSTZ1-1) into seleno-hGSTZ1-1 by means of genetic engineering in eukaryotes. (PMID:22561244)
• Two SNPs, rs282070 located in intron 1 of the MAP3K7 gene, and rs2111699 located in intron 1 of the GSTZ1 gene, were significantly associated (after adjustment for multiple testing) with longevity in stage 2 (PMID:22576335)
• The present results indicate that the haplotype of “-1002A, 32Lys, 42Arg” (containing three variant alleles) of GSTZ1 have protective effect compared to the other haplotypes. (PMID:22729907)
• The ping-pong catalytic mechanism of Se-hGSTZ1-1 is similar to that of the natural GPX. (PMID:23280616)
• Elucidation of the role of individual residues in the N-terminal, SSC motif of human GSTZ1. (PMID:23299908)
• The data indicates no association between GSTZ1 genotypes and risk of gastric cancer. (PMID:24719983)
• Haplotype variations in glutathione transferase zeta 1 influence the kinetics and dynamics of chronic dichloroacetate in children (PMID:25079374)
• We conclude that the lower expression of GSTZ1 in Whites who possess the K carrier haplotype results in lower enzymatic activity and slower metabolism of DCA, compared with those who possess the non-K carrier haplotype (PMID:25738370)
• rs7975 GG carriers had an increased risk of below-reference sperm motility (PMID:26970898)
• mild hypersuccinylacetonaemia (MHSA)can be caused by sequence variants in GSTZ1. Such individuals have thus far remained asymptomatic despite receiving no specific treatment. (PMID:27876694)
• Some properties of cytosolic and mitochondrial GSTZ1 differed. (PMID:29853471)
• Results suggested that GSTZ1-1 is downregulated in hepatocellular carcinoma (HCC) and may serve as a prognostic marker. These data indicate an alternative oncogenic action of succinylacetone through activation of the NRF2/IGF1R axis by alkylation of KEAP1. (PMID:31267557)
• First clinical trial of dichloroacetate (DCA) in multiple myeloma patients revealed that GSTZ1 genotypes are correlated with drug concentrations, tolerability, and disease outcomes. Promoter GSTZ1 polymorphisms may be important determinants of DCA concentrations and neuropathy during chronic treatment. (PMID:31624634)
• Study shows that GSTZ1 is markedly downregulated in hepatocellular carcinoma (HCC) thus predicting a poor prognosis. GSTZ1 deficiency induces oxidative stress, thus activating the KEAP1/NRF2 signaling pathway, which promotes HCC progression. (PMID:31666108)
• GSTZ1-1 downregulates Wnt/beta-catenin signalling in hepatocellular carcinoma cells. (PMID:31782257)
• Age-Related Changes in miRNA Expression Influence GSTZ1 and Other Drug Metabolizing Enzymes. (PMID:32357971)
• GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis. (PMID:33931597)
• Glutathione S-transferase zeta 1 alters the HMGB1/GPX4 axis to drive ferroptosis in bladder cancer cells. (PMID:36905252)
• Clinical physiology and pharmacology of GSTZ1/MAAI. (PMID:37742772)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	gstz1	ENSDARG00000027984
mus_musculus	Gstz1	ENSMUSG00000021033
rattus_norvegicus	Gstz1	ENSRNOG00000047708
drosophila_melanogaster	GstZ1	FBGN0037696
drosophila_melanogaster	GstZ2	FBGN0037697
caenorhabditis_elegans		WBGENE00001790

Paralogs (14): GSTO2 (ENSG00000065621), GSTT2 (ENSG00000099984), GDAP1 (ENSG00000104381), CLIC5 (ENSG00000112782), GDAP1L1 (ENSG00000124194), GSTT2B (ENSG00000133433), GSTO1 (ENSG00000148834), CLIC2 (ENSG00000155962), CLIC6 (ENSG00000159212), CLIC4 (ENSG00000169504), CLIC3 (ENSG00000169583), CLIC1 (ENSG00000213719), EEF1G (ENSG00000254772), GSTT4 (ENSG00000276950)

Protein

Protein identifiers

Maleylacetoacetate isomerase — O43708 (reviewed: O43708)

Alternative names: GSTZ1-1, Glutathione S-transferase zeta 1

All UniProt accessions (10): O43708, A0A0A0MR33, A0A0C4DFM0, G3V267, G3V3B9, G3V4T6, G3V5G8, G3V5T0, G3V5U6, H0YJN8

UniProt curated annotations — full annotation on UniProt →

Function. Bifunctional enzyme showing minimal glutathione-conjugating activity with ethacrynic acid and 7-chloro-4-nitrobenz-2-oxa-1,3-diazole and maleylacetoacetate isomerase activity. Also has low glutathione peroxidase activity with T-butyl and cumene hydroperoxides. Is able to catalyze the glutathione dependent oxygenation of dichloroacetic acid to glyoxylic acid.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm.

Tissue specificity. Mostly expressed in liver followed by kidney, skeletal muscle and brain. Also expressed in melanocytes, synovium, placenta, breast and fetal liver and heart.

Disease relevance. Maleylacetoacetate isomerase deficiency (MAAID) [MIM:617596] An autosomal recessive inborn error of metabolism characterized by mild elevations in succinylacetone in blood and urine, usually identified by newborn screening. Liver function and coagulation are normal. MAAID is a benign disorder. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Glutathione is required for the MAAI activity.

Pathway. Amino-acid degradation; L-phenylalanine degradation; acetoacetate and fumarate from L-phenylalanine: step 5/6.

Similarity. Belongs to the GST superfamily. Zeta family.

Isoforms (3)

UniProt ID	Names	Canonical?
O43708-1	1	yes
O43708-2	2
O43708-3	3

RefSeq proteins (4): NP_001299589, NP_001350632, NP_665877, NP_665878 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004045	Glutathione_S-Trfase_N	Domain
IPR004046	GST_C	Domain
IPR005955	GST_Zeta	Family
IPR010987	Glutathione-S-Trfase_C-like	Domain
IPR034330	GST_Zeta_C	Domain
IPR034333	GST_Zeta_N	Domain
IPR036249	Thioredoxin-like_sf	Homologous_superfamily
IPR036282	Glutathione-S-Trfase_C_sf	Homologous_superfamily
IPR040079	Glutathione_S-Trfase	Family

Pfam: PF13409, PF14497

Enzyme classification (BRENDA):

• EC 2.5.1.18 — glutathione transferase (BRENDA: 178 organisms, 548 substrates, 680 inhibitors, 878 Km, 525 kcat entries)
• EC 5.2.1.2 — maleylacetoacetate isomerase (BRENDA: 14 organisms, 26 substrates, 13 inhibitors, 19 Km, 18 kcat entries)

Substrate kinetics (BRENDA)

87 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
1-CHLORO-2,4-DINITROBENZENE	0.0003–223.6	289
GLUTATHIONE	0.0002–532.43	253
GSH	0.0003–37.4	62
REDUCED GLUTATHIONE	0.017–11.4	24
ETHACRYNIC ACID	0.0001–2.43	19
CUMENE HYDROPEROXIDE	0.038–14.3	10
(+)-2-BROMO-3-(4-NITROPHENYL)PROPANOIC ACID	0.023–0.417	8
MONOCHLOROBIMANE	0.004–0.25	8
(+/-)-2-BROMO-3-(4-NITROPHENYL)PROPIONIC ACID	0.023–0.417	8
4-CHLORO-7-NITROBENZO-2-OXA-1,3-DIAZOLE	0.324–3.866	7
1-IODOHEXANE	0.009–0.059	6
ALACHLOR	0.042–7.23	6
PHENETHYL ISOTHIOCYANATE	0.0065–0.14	6
STYRENE 7,8-OXIDE	0.064–0.365	6
1,2-DICHLORO-4-NITROBENZENE	0.27–1.4	5

Catalyzed reactions (Rhea), 2 shown:

• 4-maleylacetoacetate = 4-fumarylacetoacetate (RHEA:14817)
• RX + glutathione = an S-substituted glutathione + a halide anion + H(+) (RHEA:16437)

UniProt features (42 total): helix 13, sequence variant 7, binding site 6, modified residue 5, strand 5, domain 2, splice variant 2, chain 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1FW1	X-RAY DIFFRACTION	1.9
8E8P	X-RAY DIFFRACTION	2.28

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43708-F1	97.30	0.96

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (6): 14–19; 45; 59; 71–72; 111; 115–117

Post-translational modifications (5): 32, 57, 136, 177, 1

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-156590	Glutathione conjugation
R-HSA-204174	Regulation of pyruvate dehydrogenase (PDH) complex
R-HSA-8963684	Tyrosine catabolism
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism
R-HSA-156580	Phase II - Conjugation of compounds
R-HSA-211859	Biological oxidations
R-HSA-70268	Pyruvate metabolism
R-HSA-71291	Metabolism of amino acids and derivatives
R-HSA-8963691	Phenylalanine and tyrosine metabolism
R-HSA-9861718	Regulation of pyruvate metabolism

MSigDB gene sets: 194 (showing top): MODULE_93, REACTOME_BIOLOGICAL_OXIDATIONS, GRUETZMANN_PANCREATIC_CANCER_DN, YANG_BREAST_CANCER_ESR1_LASER_UP, PAL_PRMT5_TARGETS_UP, GNF2_GSTM1, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GNF2_HPN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_DN, DARWICHE_PAPILLOMA_RISK_HIGH_DN, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, GOMF_GLUTATHIONE_TRANSFERASE_ACTIVITY

GO Biological Process (6): L-phenylalanine catabolic process (GO:0006559), L-tyrosine catabolic process (GO:0006572), glutathione metabolic process (GO:0006749), cellular detoxification (GO:1990748), aromatic amino acid metabolic process (GO:0009072), cellular oxidant detoxification (GO:0098869)

GO Molecular Function (9): glutathione transferase activity (GO:0004364), glutathione peroxidase activity (GO:0004602), maleylacetoacetate isomerase activity (GO:0016034), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), catalytic activity (GO:0003824), protein binding (GO:0005515), transferase activity (GO:0016740), isomerase activity (GO:0016853)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Metabolism	3
Phase II - Conjugation of compounds	1
Regulation of pyruvate metabolism	1
Phenylalanine and tyrosine metabolism	1
Biological oxidations	1
Aerobic respiration and respiratory electron transport	1
Metabolism of amino acids and derivatives	1
Pyruvate metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
aromatic amino acid catabolic process	2
L-amino acid catabolic process	2
proteinogenic amino acid catabolic process	2
catalytic activity	2
cytoplasm	2
cellular anatomical structure	2
modified amino acid metabolic process	1
sulfur compound metabolic process	1
cellular process	1
cellular response to toxic substance	1
detoxification	1
amino acid metabolic process	1
carboxylic acid metabolic process	1
cellular detoxification	1
transferase activity, transferring alkyl or aryl (other than methyl) groups	1
peroxidase activity	1
cis-trans isomerase activity	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
molecular_function	1
binding	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2484 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GSTZ1	HPGDS	O60760	929
GSTZ1	GSTP1	P09211	890
GSTZ1	GSTM5	P46439	863
GSTZ1	GSTM3	P21266	853
GSTZ1	GSTM1	P09488	841
GSTZ1	GSTM4	Q03013	840
GSTZ1	GSTM2	P28161	838
GSTZ1	GSTA2	P09210	812
GSTZ1	FAH	P16930	744
GSTZ1	HGD	Q93099	725
GSTZ1	SLCO6A1	Q86UG4	714
GSTZ1	GSTK1	Q9Y2Q3	645
GSTZ1	HPD	P32754	641
GSTZ1	GSTT2B	P0CG30	630
GSTZ1	GSTA1	P08263	610

IntAct

54 interactions, top by confidence:

A	B	Type	Score
GSTZ1	GSTZ1	psi-mi:“MI:0915”(physical association)	0.740
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
GSTZ1	TCP11	psi-mi:“MI:0915”(physical association)	0.560
GSTZ1	PLEKHG4	psi-mi:“MI:0915”(physical association)	0.560
GSTZ1	QARS1	psi-mi:“MI:0915”(physical association)	0.560
GSTZ1	TRAF2	psi-mi:“MI:0915”(physical association)	0.560
GSTZ1	ZMYND12	psi-mi:“MI:0915”(physical association)	0.560
GSTZ1	GORASP2	psi-mi:“MI:0915”(physical association)	0.560
GSTZ1	CLVS2	psi-mi:“MI:0915”(physical association)	0.560
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
GSTZ1	ABL1	psi-mi:“MI:0915”(physical association)	0.400
GSTZ1	FYN	psi-mi:“MI:0915”(physical association)	0.400
GRB2	GSTZ1	psi-mi:“MI:0915”(physical association)	0.400
NCK1	GSTZ1	psi-mi:“MI:0915”(physical association)	0.400
GSTZ1	KLHL24	psi-mi:“MI:0915”(physical association)	0.400
GSTZ1	PPP1CC	psi-mi:“MI:0915”(physical association)	0.370
ANG	DDX39A	psi-mi:“MI:0914”(association)	0.350
ICOS	GAK	psi-mi:“MI:0914”(association)	0.350
RBPMS	GSTZ1	psi-mi:“MI:0914”(association)	0.350
PLA2G4D	GSTZ1	psi-mi:“MI:0914”(association)	0.350

BioGRID (27): GSTZ1 (Two-hybrid), GSTZ1 (Affinity Capture-MS), GSTZ1 (Two-hybrid), GSTZ1 (Co-fractionation), PRDX6 (Co-fractionation), GSTZ1 (Affinity Capture-MS), GSTZ1 (Two-hybrid), GSTZ1 (Proximity Label-MS), GSTZ1 (Affinity Capture-MS), GSTZ1 (Proximity Label-MS), GSTZ1 (Two-hybrid), GSTZ1 (Two-hybrid), GORASP2 (Two-hybrid), TCP11 (Two-hybrid), TRAF2 (Two-hybrid)

ESM2 similar proteins: A0A2P1DP90, A0A6J4B5J2, A2R3H4, A4GYZ0, A8DRH7, B3FWR8, B8NM79, D2YW48, G3Y417, J4UHQ8, M1W426, O04437, O43123, O43708, O59827, O80852, P30110, P40582, P42761, P49332, P57113, P9WEZ8, Q00717, Q04522, Q0CCY0, Q18938, Q2UPB2, Q4WHT7, Q4WQZ2, Q4WV19, Q54UR0, Q54YN2, Q6Q882, Q8DTN7, Q96324, Q9C8M3, Q9FUS6, Q9FUS8, Q9FUS9, Q9FWR4

Diamond homologs: D2YW48, O04437, O43123, O43708, O86043, P28342, P57108, P57109, P57113, Q03425, Q18938, Q4WHT7, Q54YN2, Q9KSB2, Q9VHD2, Q9VHD3, Q9WVL0, Q9X4F7, Q9ZVQ3, Q9ZVQ4, A2XMN2, O80662, P04907, P0ACA3, P0ACA4, P0ACA5, P0ACA6, P20135, P25317, P30711, P31784, P32111, P43387, P44521, P45207, P46430, P46433, P49332, P50471, Q03520

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 30 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
response to endoplasmic reticulum stress	5	28.8×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

60 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	3
Uncertain significance	30
Likely benign	5
Benign	4

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
2444067	NM_145870.3(GSTZ1):c.216+1G>A	Pathogenic
807427	NM_145870.3(GSTZ1):c.136-2A>G	Pathogenic
2506395	NM_145870.3(GSTZ1):c.128del (p.Gly43fs)	Likely pathogenic
431044	NM_145870.3(GSTZ1):c.295G>A (p.Val99Met)	Likely pathogenic
4820115	NM_145870.3(GSTZ1):c.328_334del (p.Ile110fs)	Likely pathogenic

SpliceAI

1909 predictions. Top by Δscore:

Variant	Effect	Δscore
14:77326836:A:AG	acceptor_gain	1.0000
14:77326837:G:GG	acceptor_gain	1.0000
14:77327549:G:GG	donor_gain	1.0000
14:77327553:G:GG	donor_gain	1.0000
14:77329119:ACAG:A	acceptor_loss	1.0000
14:77329120:C:G	acceptor_gain	1.0000
14:77329120:CAGA:C	acceptor_loss	1.0000
14:77329121:A:AG	acceptor_gain	1.0000
14:77329121:AGA:A	acceptor_loss	1.0000
14:77329122:G:GG	acceptor_gain	1.0000
14:77329122:GAAC:G	acceptor_gain	1.0000
14:77321127:G:GT	donor_gain	0.9900
14:77321210:G:T	donor_gain	0.9900
14:77324868:A:AG	acceptor_gain	0.9900
14:77324869:G:GG	acceptor_gain	0.9900
14:77324869:GCCC:G	acceptor_gain	0.9900
14:77326837:GCTCT:G	acceptor_gain	0.9900
14:77326901:AACAG:A	donor_loss	0.9900
14:77326902:ACAGG:A	donor_loss	0.9900
14:77326905:GGTA:G	donor_loss	0.9900
14:77326906:G:GA	donor_loss	0.9900
14:77326907:T:G	donor_loss	0.9900
14:77327470:A:AG	acceptor_gain	0.9900
14:77327471:G:GA	acceptor_gain	0.9900
14:77327550:TCA:T	donor_gain	0.9900
14:77327910:A:AG	acceptor_gain	0.9900
14:77327911:G:GG	acceptor_gain	0.9900
14:77329116:T:TA	acceptor_gain	0.9900
14:77329119:A:AG	acceptor_gain	0.9900
14:77329122:GA:G	acceptor_gain	0.9900

AlphaMissense

1400 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:77327994:G:C	R100P	0.979
14:77324888:T:C	F12L	0.975
14:77324890:C:A	F12L	0.975
14:77324890:C:G	F12L	0.975
14:77324902:C:G	C16W	0.967
14:77331139:T:C	F199L	0.964
14:77331141:C:A	F199L	0.964
14:77331141:C:G	F199L	0.964
14:77324911:A:C	R19S	0.963
14:77324911:A:T	R19S	0.963
14:77324894:A:C	S14R	0.962
14:77324896:C:A	S14R	0.962
14:77324896:C:G	S14R	0.962
14:77330352:G:C	A173P	0.962
14:77329795:T:G	C154W	0.960
14:77326851:A:C	K27N	0.955
14:77326851:A:T	K27N	0.955
14:77326850:A:T	K27I	0.953
14:77329793:T:C	C154R	0.953
14:77330353:C:A	A173D	0.953
14:77330320:C:A	A162D	0.950
14:77327521:T:C	L62P	0.949
14:77330322:G:C	D163H	0.949
14:77330323:A:T	D163V	0.948
14:77324910:G:C	R19T	0.947
14:77327993:C:A	R100S	0.945
14:77324916:G:C	R21P	0.943
14:77330328:T:C	C165R	0.942
14:77331070:T:C	F176L	0.942
14:77331072:C:A	F176L	0.942

dbSNP variants (sampled 300 via entrez): RS1000138531 (14:77327045 C>T), RS1000386374 (14:77328893 G>A,C), RS1000573549 (14:77329333 A>G), RS1000790982 (14:77322011 G>A,T), RS1001276911 (14:77325803 G>A), RS1001449334 (14:77320908 C>A,T), RS1001554617 (14:77328309 G>C), RS1001749434 (14:77326138 G>A), RS1001935849 (14:77331071 T>A,G), RS1001968994 (14:77331314 C>A,T), RS1002177697 (14:77330172 C>T), RS1002218766 (14:77325793 A>C), RS1002651255 (14:77328857 T>C), RS1003121145 (14:77321532 C>A,G,T), RS1003355761 (14:77327101 G>C)

Disease associations

OMIM: gene MIM:603758 | disease phenotypes: MIM:617596

GenCC curated gene-disease

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
maleylacetoacetate isomerase deficiency	Moderate	AR

Mondo (1): maleylacetoacetate isomerase deficiency (MONDO:0060527)

Orphanet (0):

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001410	Decreased liver function

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4949 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs7972	GSTZ1, POMT2		0.00	0
rs7975	GSTZ1, POMT2		0.00	0
rs1046428	GSTZ1, POMT2		0.00	0

CTD chemical–gene interactions

71 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Glutathione	affects binding, affects metabolic processing	5
Dichloroacetic Acid	decreases activity, decreases reaction, affects binding, affects metabolic processing, increases metabolic processing	4
Valproic Acid	affects expression, decreases expression	4
maleylacetone	affects metabolic processing, decreases activity, increases alkylation	3
methylmercuric chloride	decreases expression, increases expression	2
Arsenic Trioxide	affects binding, decreases reaction, increases expression	2
Carbamazepine	affects expression, increases expression	2
Paraquat	increases expression, decreases reaction, affects cotreatment	2
Phenobarbital	affects expression, decreases expression	2
Aflatoxin B1	affects expression, decreases expression	2
afuresertib	increases expression	1
bisphenol F	increases expression	1
apocarotenal	decreases expression	1
naringenin	increases expression, decreases reaction	1
cumene hydroperoxide	affects metabolic processing	1
decabromobiphenyl ether	affects expression	1
beta-lapachone	decreases expression, increases expression	1
arsenite	increases reaction, affects binding	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
ochratoxin A	decreases expression	1
stilbene oxide	affects metabolic processing	1
cerous chloride	affects cotreatment, increases expression	1
butylbenzyl phthalate	increases expression	1
lanthanum chloride	affects cotreatment, increases expression	1
4-aminophenylarsenoxide	decreases reaction, affects binding	1
cadmium sulfide	increases expression	1
leukotriene A methyl ester	affects metabolic processing	1
dinophysistoxin 1	decreases expression	1
cyfluthrin	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1743237	ADMET	Substrates for human cytosolic glutathione transferase GSTZ1	Casarett and Doull’s Toxicology The Basic Science of Poisons, 7th edition

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.