CHAC2

Summary

CHAC2 (ChaC glutathione specific gamma-glutamylcyclotransferase 2, HGNC:32363) is a protein-coding gene on chromosome 2p16.2, encoding Glutathione-specific gamma-glutamylcyclotransferase 2 (Q8WUX2). Catalyzes the cleavage of glutathione into 5-oxo-L-proline and a Cys-Gly dipeptide.

The protein encoded by this gene is a gamma-glutamyl cyclotransferase that catalyzes the conversion of glutathione to 5-oxoproline and cysteinylglycine. It is thought that this gene is upregulated in response to endoplasmic reticulum stress and that the glutathione depletion enhances apoptosis.

Source: NCBI Gene 494143 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• MANE Select transcript: NM_001008708

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:32363
Approved symbol	CHAC2
Name	ChaC glutathione specific gamma-glutamylcyclotransferase 2
Location	2p16.2
Locus type	gene with protein product
Status	Approved
Aliases	GCG1
Ensembl gene	ENSG00000143942
Ensembl biotype	protein_coding
OMIM	617446
Entrez	494143

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000295304, ENST00000893858

RefSeq mRNA: 2 — MANE Select: NM_001008708 NM_001008708, NM_001346127

CCDS: CCDS33196

Canonical transcript exons

ENST00000295304 — 3 exons

Exon	Start	End
ENSE00001072047	53771907	53771942
ENSE00001137131	53774142	53775196
ENSE00001137139	53767804	53768021

Expression profiles

Bgee: expression breadth ubiquitous, 202 present calls, max score 86.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.6083 / max 109.4995, expressed in 1512 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
20226	6.1366	1480
20231	0.1846	72
20229	0.1451	56
20230	0.1420	66

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.82	gold quality
trabecular bone tissue	UBERON:0002483	83.41	gold quality
secondary oocyte	CL:0000655	83.10	gold quality
esophagus squamous epithelium	UBERON:0006920	80.18	gold quality
jejunal mucosa	UBERON:0000399	79.24	gold quality
mucosa of transverse colon	UBERON:0004991	78.43	gold quality
islet of Langerhans	UBERON:0000006	78.32	gold quality
gastrocnemius	UBERON:0001388	77.15	gold quality
mucosa of sigmoid colon	UBERON:0004993	77.15	gold quality
bone marrow	UBERON:0002371	77.08	gold quality
muscle of leg	UBERON:0001383	76.37	gold quality
colonic mucosa	UBERON:0000317	76.24	gold quality
duodenum	UBERON:0002114	76.20	gold quality
oral cavity	UBERON:0000167	75.86	gold quality
epithelial cell of pancreas	CL:0000083	75.18	silver quality
vermiform appendix	UBERON:0001154	74.83	gold quality
left adrenal gland	UBERON:0001234	74.82	gold quality
right adrenal gland cortex	UBERON:0035827	74.75	gold quality
right adrenal gland	UBERON:0001233	74.66	gold quality
left adrenal gland cortex	UBERON:0035825	74.15	gold quality
adrenal tissue	UBERON:0018303	73.98	gold quality
rectum	UBERON:0001052	73.89	gold quality
lower esophagus mucosa	UBERON:0035834	73.58	gold quality
ileal mucosa	UBERON:0000331	73.54	gold quality
adrenal gland	UBERON:0002369	73.49	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	73.37	gold quality
esophagus mucosa	UBERON:0002469	73.33	gold quality
heart right ventricle	UBERON:0002080	72.99	silver quality
jejunum	UBERON:0002115	72.87	gold quality
lymph node	UBERON:0000029	72.81	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.79

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

49 targeting CHAC2, 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-4282	99.99	75.36	6408
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-323A-3P	99.79	70.30	1739
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-6126	99.62	68.09	996
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-888-5P	99.30	70.15	1855
HSA-MIR-223-5P	99.24	68.82	1206
HSA-MIR-4263	99.18	69.25	2236
HSA-MIR-4528	99.18	69.77	1936
HSA-MIR-4478	99.07	65.16	2320
HSA-MIR-6830-5P	99.01	68.73	1884
HSA-MIR-4744	99.01	69.91	1581

Literature-anchored findings (GeneRIF, showing 5)

• Human and mouse ChaC2 proteins purified in vitro show 10-20-fold lower catalytic efficiency than ChaC1, although they showed comparable Km values (PMID:27913623)
• Results showed for the first time that CHAC2 was degraded by the ubiquitin-proteasome pathway and CHAC2 expression inhibited tumor cell growth, proliferation, migration in vitro and in vivo. Mechanistic study showed that CHAC2 induced mitochondrial apoptosis and autophagy through unfolded protein response. (PMID:28837156)
• The data revealed that CHAC2 prevented CHAC1-mediated GSH degradation, which suggests that CHAC2 competes with CHAC1 to maintain GSH homeostasis. (PMID:29054545)
• Structural and Functional Analyses of Human ChaC2 in Glutathione Metabolism. (PMID:31878259)
• E3 ubiquitin ligase RNF148 functions as an oncogene in colorectal cancer by ubiquitination-mediated degradation of CHAC2. (PMID:38190483)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	chac2	ENSDARG00000055078
mus_musculus	Chac2	ENSMUSG00000020309
rattus_norvegicus	Chac2	ENSRNOG00000070799
drosophila_melanogaster	CG2540	FBGN0030411

Paralogs (1): CHAC1 (ENSG00000128965)

Protein

Protein identifiers

Glutathione-specific gamma-glutamylcyclotransferase 2 — Q8WUX2 (reviewed: Q8WUX2)

Alternative names: Cation transport regulator-like protein 2

All UniProt accessions (1): Q8WUX2

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the cleavage of glutathione into 5-oxo-L-proline and a Cys-Gly dipeptide. Acts specifically on glutathione, but not on other gamma-glutamyl peptides.

Subunit / interactions. Monomer.

Subcellular location. Cytoplasm. Cytosol.

Similarity. Belongs to the gamma-glutamylcyclotransferase family. ChaC subfamily.

RefSeq proteins (2): NP_001008708, NP_001333056 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006840	ChaC	Family
IPR013024	GGCT-like	Domain
IPR036568	GGCT-like_sf	Homologous_superfamily

Pfam: PF04752

Enzyme classification (BRENDA):

• EC 4.3.2.7 — glutathione-specific gamma-glutamylcyclotransferase (BRENDA: 4 organisms, 6 substrates, 0 inhibitors, 4 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GLUTATHIONE	3–3.7	3

Catalyzed reactions (Rhea), 1 shown:

• glutathione = L-cysteinylglycine + 5-oxo-L-proline (RHEA:47724)

UniProt features (16 total): strand 6, helix 6, chain 1, active site 1, binding site 1, sequence variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6KY1	X-RAY DIFFRACTION	2.04
6KY0	X-RAY DIFFRACTION	2.06
6K95	X-RAY DIFFRACTION	2.29

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WUX2-F1	93.61	0.83

Functional residue map

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

Catalytic / active sites (1): 83 (proton acceptor)

Ligand- & substrate-binding residues (1): 3–8

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-174403	Glutathione synthesis and recycling

MSigDB gene sets: 121 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, REACTOME_BIOLOGICAL_OXIDATIONS, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_MODIFIED_AMINO_ACID_CATABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_SULFUR_COMPOUND_CATABOLIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS, REACTOME_GLUTATHIONE_CONJUGATION, GOBP_GLUTATHIONE_METABOLIC_PROCESS, CUI_TCF21_TARGETS_2_DN, GOBP_MODIFIED_AMINO_ACID_METABOLIC_PROCESS, NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_UP, ZHAN_MULTIPLE_MYELOMA_CD2_DN

GO Biological Process (3): glutathione metabolic process (GO:0006749), glutathione catabolic process (GO:0006751), glutathione biosynthetic process (GO:0006750)

GO Molecular Function (3): glutathione specific gamma-glutamylcyclotransferase activity (GO:0061928), gamma-glutamylcyclotransferase activity (GO:0003839), lyase activity (GO:0016829)

GO Cellular Component (2): cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Glutathione conjugation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
glutathione metabolic process	2
amidine-lyase activity	2
cellular anatomical structure	2
modified amino acid metabolic process	1
sulfur compound metabolic process	1
modified amino acid catabolic process	1
sulfur compound catabolic process	1
nonribosomal peptide biosynthetic process	1
modified amino acid biosynthetic process	1
sulfur compound biosynthetic process	1
catalytic activity	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

720 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CHAC2	ASB3	Q9Y575	725
CHAC2	SP5	Q6BEB4	586
CHAC2	GPR75	O95800	574
CHAC2	PEX11B	O96011	511
CHAC2	VPS13A	Q96RL7	502
CHAC2	PSME4	Q14997	473
CHAC2	ERLEC1	Q96DZ1	461
CHAC2	PLAAT1	Q9HDD0	441
CHAC2	GGCT	O75223	434
CHAC2	RWDD1	Q9H446	427
CHAC2	ZNF428	Q96B54	413
CHAC2	MGST2	Q99735	397
CHAC2	FAM135A	Q9P2D6	397
CHAC2	ANKRD34C	P0C6C1	396
CHAC2	FAM81A	Q8TBF8	394

IntAct

12 interactions, top by confidence:

A	B	Type	Score
FSD1	UBFD1	psi-mi:“MI:0914”(association)	0.530
HAPLN3	HSPA5	psi-mi:“MI:0914”(association)	0.530
CDKN2AIP	IFT88	psi-mi:“MI:0914”(association)	0.350
CHAC2	TOM1	psi-mi:“MI:0914”(association)	0.350
BTN3A1	PIK3CA	psi-mi:“MI:0914”(association)	0.350
RBM42	TNFSF10	psi-mi:“MI:0914”(association)	0.350
ZNF577	DDI2	psi-mi:“MI:0914”(association)	0.350
STMN3	ZER1	psi-mi:“MI:0914”(association)	0.350
CHAC2	CST4	psi-mi:“MI:0914”(association)	0.350

BioGRID (75): CHAC2 (Affinity Capture-MS), CHAC2 (Affinity Capture-MS), CHAC2 (Affinity Capture-MS), CHAC2 (Affinity Capture-MS), CHAC2 (Affinity Capture-MS), CHAC2 (Affinity Capture-MS), HERC1 (Affinity Capture-MS), SCAF1 (Affinity Capture-MS), CHAC2 (Affinity Capture-MS), CHAC2 (Affinity Capture-MS), TOM1 (Affinity Capture-MS), CHAC2 (Affinity Capture-MS), CHAC2 (Affinity Capture-MS), CHAC2 (Affinity Capture-MS), CST1 (Affinity Capture-MS)

ESM2 similar proteins: A3KNL6, A8E534, B3STU3, E0CTF3, F6HH45, O75223, O95568, P61801, Q08J23, Q0IIH4, Q28C69, Q2KIJ2, Q32LE4, Q3BCR0, Q3BCR2, Q3BCR3, Q3BCR9, Q4KM84, Q4KM86, Q4KMJ1, Q5PPV4, Q5R699, Q5SPB6, Q5ZI66, Q5ZIW7, Q641Z5, Q66I06, Q66KX0, Q6EIC1, Q6PZ05, Q7T287, Q7ZU92, Q84MC1, Q84QC1, Q8C9S8, Q8GXF0, Q8GY54, Q8R3J5, Q8RX28, Q8VYW1

Diamond homologs: B3STU3, P32656, P39163, P87305, Q0IIH4, Q4KMJ1, Q5PPV4, Q5SPB6, Q5ZI66, Q641Z5, Q84MC1, Q84QC1, Q8GY54, Q8R3J5, Q8WUX2, Q9BUX1, Q9CQG1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
miR-223-5p	“down-regulates quantity by destabilization”	CHAC2	“post transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	0
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

609 predictions. Top by Δscore:

Variant	Effect	Δscore
2:53768018:CAAG:C	donor_loss	1.0000
2:53768019:AAG:A	donor_loss	1.0000
2:53768020:AG:A	donor_loss	1.0000
2:53768021:GGTGA:G	donor_loss	1.0000
2:53768023:T:A	donor_loss	1.0000
2:53768212:T:TA	donor_gain	1.0000
2:53774141:GGGAT:G	acceptor_gain	1.0000
2:53768018:C:T	donor_gain	0.9900
2:53768171:TGCC:T	donor_gain	0.9900
2:53768173:C:CT	donor_gain	0.9900
2:53768209:C:CA	donor_gain	0.9900
2:53771900:A:AG	acceptor_gain	0.9900
2:53771901:A:G	acceptor_gain	0.9900
2:53774137:AACAG:A	acceptor_gain	0.9900
2:53774139:CA:C	acceptor_loss	0.9900
2:53774140:A:AG	acceptor_gain	0.9900
2:53774140:AG:A	acceptor_gain	0.9900
2:53774140:AGG:A	acceptor_gain	0.9900
2:53774141:G:GC	acceptor_loss	0.9900
2:53774141:G:GG	acceptor_gain	0.9900
2:53774141:GG:G	acceptor_gain	0.9900
2:53774141:GGG:G	acceptor_gain	0.9900
2:53768022:G:GG	donor_gain	0.9800
2:53771893:C:G	acceptor_gain	0.9800
2:53771905:A:AG	acceptor_gain	0.9800
2:53771906:G:GG	acceptor_gain	0.9800
2:53771906:GC:G	acceptor_gain	0.9800
2:53774138:A:G	acceptor_gain	0.9800
2:53768017:GCAAG:G	donor_gain	0.9700
2:53768208:T:TA	donor_gain	0.9700

AlphaMissense

1198 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:53767975:G:C	R30T	0.997
2:53767975:G:T	R30M	0.997
2:53767976:G:C	R30S	0.997
2:53767976:G:T	R30S	0.997
2:53768004:C:A	R40S	0.997
2:53774216:A:C	R82S	0.997
2:53774216:A:T	R82S	0.997
2:53774400:T:C	Y144H	0.997
2:53767905:G:T	G7W	0.996
2:53767906:G:A	G7E	0.996
2:53767954:G:A	G23E	0.996
2:53768001:C:G	H39D	0.996
2:53771915:A:C	R48S	0.996
2:53771915:A:T	R48S	0.996
2:53774215:G:C	R82T	0.996
2:53767896:T:C	F4L	0.995
2:53767898:T:A	F4L	0.995
2:53767898:T:G	F4L	0.995
2:53767980:T:C	F32L	0.995
2:53767982:C:A	F32L	0.995
2:53767982:C:G	F32L	0.995
2:53768003:C:A	H39Q	0.995
2:53768003:C:G	H39Q	0.995
2:53771926:T:A	L52H	0.995
2:53774161:C:A	A64D	0.995
2:53774219:A:C	E83D	0.995
2:53774219:A:T	E83D	0.995
2:53774393:T:A	N141K	0.995
2:53774393:T:G	N141K	0.995
2:53767978:G:C	R31P	0.994

dbSNP variants (sampled 300 via entrez): RS1000131331 (2:53772668 T>C), RS1000468676 (2:53770002 C>A), RS1000797367 (2:53770272 A>G), RS1001547970 (2:53775382 T>A), RS1002333226 (2:53768882 T>C), RS1002642515 (2:53773656 C>T), RS1003006005 (2:53771342 G>A), RS1003023686 (2:53766390 G>A), RS1003246973 (2:53771797 C>T), RS1003339685 (2:53770165 G>C), RS1003404315 (2:53766853 T>C), RS1004528400 (2:53769928 A>G), RS1004820766 (2:53774607 G>A), RS1005273456 (2:53772025 T>A,C), RS1005294403 (2:53767630 T>C)

Disease associations

OMIM: gene MIM:617446 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST010002_365	Refractive error	3.000000e-34
GCST010105_111	Nicotine dependence symptom count	7.000000e-06
GCST010105_151	Nicotine dependence symptom count	7.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009262	nicotine dependence symptom count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	9
bisphenol A	decreases expression, increases expression	3
Cyclosporine	affects expression, decreases expression	3
sodium arsenite	decreases expression, affects expression	2
entinostat	increases expression, affects cotreatment	2
Estradiol	increases expression	2
Nickel	increases expression	2
Cadmium Chloride	increases expression	2
afuresertib	decreases expression	1
bismuth tripotassium dicitrate	increases expression	1
methylparaben	decreases expression	1
o,p’-DDT	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
avobenzone	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
cylindrospermopsin	increases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
pyrimidifen	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
jinfukang	decreases expression, affects cotreatment	1
picoxystrobin	increases expression	1
Resveratrol	increases expression, affects cotreatment	1
Sunitinib	decreases expression	1

Clinical trials (associated diseases)

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