GCLC

Summary

GCLC (glutamate-cysteine ligase catalytic subunit, HGNC:4311) is a protein-coding gene on chromosome 6p12.1, encoding Glutamate–cysteine ligase catalytic subunit (P48506). Catalyzes the ATP-dependent ligation of L-glutamate and L-cysteine and participates in the first and rate-limiting step in glutathione biosynthesis.

Glutamate-cysteine ligase, also known as gamma-glutamylcysteine synthetase is the first rate-limiting enzyme of glutathione synthesis. The enzyme consists of two subunits, a heavy catalytic subunit and a light regulatory subunit. This locus encodes the catalytic subunit, while the regulatory subunit is derived from a different gene located on chromosome 1p22-p21. Mutations at this locus have been associated with hemolytic anemia due to deficiency of gamma-glutamylcysteine synthetase and susceptibility to myocardial infarction.

Source: NCBI Gene 2729 — RefSeq curated summary.

At a glance

• Gene–disease (curated): gamma-glutamylcysteine synthetase deficiency (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 8
• Clinical variants (ClinVar): 228 total — 2 pathogenic
• Phenotypes (HPO): 56
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001498

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4311
Approved symbol	GCLC
Name	glutamate-cysteine ligase catalytic subunit
Location	6p12.1
Locus type	gene with protein product
Status	Approved
Aliases	GCS
Ensembl gene	ENSG00000001084
Ensembl biotype	protein_coding
OMIM	606857
Entrez	2729

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 8 protein_coding, 5 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000504353, ENST00000504525, ENST00000505197, ENST00000505294, ENST00000509541, ENST00000510837, ENST00000513939, ENST00000514004, ENST00000514373, ENST00000514933, ENST00000515580, ENST00000616923, ENST00000643939, ENST00000650454, ENST00000856227

RefSeq mRNA: 2 — MANE Select: NM_001498 NM_001197115, NM_001498

CCDS: CCDS4952, CCDS75471

Canonical transcript exons

ENST00000650454 — 16 exons

Exon	Start	End
ENSE00000468131	53520778	53520960
ENSE00000756766	53516109	53516222
ENSE00003496575	53514204	53514337
ENSE00003509813	53522415	53522527
ENSE00003553813	53500432	53500513
ENSE00003561759	53508595	53508711
ENSE00003570027	53506913	53507025
ENSE00003570483	53500045	53500165
ENSE00003577529	53505392	53505496
ENSE00003593051	53507480	53507618
ENSE00003633470	53509176	53509250
ENSE00003655732	53514439	53514497
ENSE00003664094	53505803	53505895
ENSE00003668288	53497341	53498967
ENSE00003687614	53500247	53500350
ENSE00003833402	53544496	53545101

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 97.13.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.4355 / max 1381.8605, expressed in 1792 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74020	13.4514	1375
74018	7.3175	1728
74019	2.3386	1210
74017	0.2859	75
74016	0.0421	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bronchial epithelial cell	CL:0002328	97.13	gold quality
right uterine tube	UBERON:0001302	97.08	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.25	gold quality
gingival epithelium	UBERON:0001949	96.16	gold quality
epithelium of bronchus	UBERON:0002031	96.07	gold quality
bronchus	UBERON:0002185	96.01	gold quality
liver	UBERON:0002107	95.90	gold quality
nasal cavity epithelium	UBERON:0005384	95.86	gold quality
islet of Langerhans	UBERON:0000006	95.60	gold quality
nasal cavity mucosa	UBERON:0001826	95.56	gold quality
colonic epithelium	UBERON:0000397	95.32	gold quality
gingiva	UBERON:0001828	94.98	gold quality
jejunal mucosa	UBERON:0000399	94.97	gold quality
right lobe of liver	UBERON:0001114	94.74	gold quality
secondary oocyte	CL:0000655	94.69	gold quality
urinary bladder	UBERON:0001255	94.69	gold quality
corpus callosum	UBERON:0002336	94.37	gold quality
trabecular bone tissue	UBERON:0002483	94.09	gold quality
duodenum	UBERON:0002114	93.83	gold quality
adrenal tissue	UBERON:0018303	92.97	gold quality
esophagus squamous epithelium	UBERON:0006920	92.57	gold quality
mucosa of stomach	UBERON:0001199	92.54	gold quality
stromal cell of endometrium	CL:0002255	92.52	gold quality
bone marrow	UBERON:0002371	92.50	gold quality
trachea	UBERON:0003126	92.44	gold quality
bone marrow cell	CL:0002092	92.38	gold quality
esophagus mucosa	UBERON:0002469	92.37	gold quality
mucosa of paranasal sinus	UBERON:0005030	92.00	gold quality
rectum	UBERON:0001052	91.84	gold quality
squamous epithelium	UBERON:0006914	91.84	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	50.04
E-GEOD-125970	yes	7.29
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, ATF3, EGR1, ESR1, ESR2, FOSL1, GSX1, JUN, JUND, MAF, MAFF, MTF1, MYC, MYCN, NFE2, NFE2L1, NFE2L2, NFKB1, NFKB, NKRF, NRF1, PPARA, RELA, SMAD3, SP1, TCF3, USF1

miRNA regulators (miRDB)

143 targeting GCLC, 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-3163	100.00	77.23	8605
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-493-5P	99.96	72.47	2382
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AR-5P	99.94	71.28	3515

Literature-anchored findings (GeneRIF, showing 40)

• Expression of the gamma-glutamylcysteine synthetase heavy subunit gene is inducible by certain nonsteroidal anti-inflammatory drugs (e.g., indomethacin) in colon cancer cells. (PMID:11820781)
• Genetic determinants of lung cancer short-term survival: the role of glutathione-related genes (PMID:11844594)
• Oxidant stress induces gamma-glutamylcysteine synthetase and glutathione synthesis in human bronchial epithelial NCI-H292 cells. (PMID:11972604)
• identification of a variant antioxidant response element in the promoter region (PMID:12070177)
• redox-sensitive elements directing expression of the glutamate cysteine ligase in CYP2E1-expressing cells are present in the ARE4 distal portion of the 5’-flanking region, perhaps a reflection of metabolic adaptation to CYP2E1-generated oxidative stress. (PMID:12500194)
• A new gamma-GCSH mutation from gamma-GCS deficiency, a C>T missense mutation at nucleotide 379, encodes a predicted Arg127Cys amino acid change. The mutated amino acid lies within a cleft on the protein surface of gamma-GCSH, containing Cys249. (PMID:12663448)
• GCS is up-regulated by antiestrogens mediated by estrogen receptor beta. (PMID:14676828)
• Review. The most important element in both Gclc and Gclm expression is the electrophile response element in their promoters. (PMID:15451055)
• data provide the first report of glutamylcysteine ligase (GCLC) expression in the islet and demonstrate that adenoviral overexpression of GCLC increases intracellular glutathione levels and protects the beta cell from adverse effects of IL-1 beta (PMID:15485876)
• Adrenomedullin regulates cellular glutathione content via modulation of gamma-glutamate-cysteine ligase catalytic subunit expression (PMID:16322067)
• Results suggest that TNF-alpha elevates the expression of lens epithelium-derived growth factor (LEDGF) and that LEDGF is one of the transactivators of gamma-glutamylcysteine synthetase heavy subunit gene. (PMID:16403949)
• Drug-resistant cells have the inherent ability to maintain increased gamma-GCS activity. (PMID:16491484)
• This study found an association between variants in GCLC, a novel candidate gene, and cystic fibrosis lung function; this effect was observed only in patients with a mild CFTR (cystic fibrosis transmembrane conductance regulator) genotype (PMID:16690975)
• Activation of insulin signaling through PI3K/Akt/mTOR/Nrf2/ GCLc pathway affords significant cell protection by maintaining cellular redox balance. (PMID:17109620)
• The genetic polymorphism in GCLC -129C/T is not associated with susceptibility to COPD in a southern Chinese population of Han nationality. (PMID:17207022)
• upregulation of gamma-glutamate-cysteine ligase as part of the long-term adaptation process to iron accumulation in neurons (PMID:17344309)
• GCLC promoter polymorphisms may influence glutamate decarboxylase 65 autoantibody levels the age at which type 1 diabettes is diagnosed. (PMID:17479437)
• The -588TT/-23TT genotype was found to be associated with decreased risk of allergic asthma after adjustment for age, gender and smoking status using regression analysis (OR=0.33 95% CI 0.15-0.70, p=0.036) but with increased risk of non-allergic asthma. (PMID:17643973)
• GCLC T allele, together with hypertension and male sex, is associated with cardiovascular events in our study population. (PMID:18035085)
• Glutamate cysteine ligase iz induced by hydroxynonenal through the c-Jun N-terminal kinase (JNK) pathway in respiratory epithelium. (PMID:18276794)
• GCLC is a novel susceptibility gene for low level of lung function in copd (PMID:18420959)
• decreasing trend of GCL activity was observed in the order of 7/7>7/9>9/9 (P=0.04) (PMID:18549827)
• results support the functional importance of insulin in Nrf2-dependent transcriptional upregulation of GCLc in GSH recovery during oxidative challenge and suggest a possible role for hypoglycemia in promoting insulin-mediated GCLc upregulation (PMID:18926903)
• study of consequences of impaired glutathione synthesis, due to GAG trinucleotide repeat polymorphism in catalytic subunit of glutamate cysteine ligase, on regulation of the proteome; findings show altered proteome reaction in response to oxidative stress (PMID:19041695)
• PD98059 and erythromycin could block AP-1 transduction pathway, but increase the synthesis of gamma-GCS induced by 4-hydroxynonenal in bronchial epithelial cells. (PMID:19567187)
• Polymorphisms of glutamate-cystein ligase and microsomal triglyceride transfer protein genes may be associated with non-alcoholic liver disease progression. (PMID:19817962)
• Regulation of GCL(cat) by MYCN accounts for the survival of neuroblastoma cells against oxidative damage; GCL should be considered a potential therapeutic target for the treatment of MYCN-amplified neuroblastoma. (PMID:20180881)
• An ethnic-specific polymorphism in the catalytic subunit of glutamate-cysteine ligase impairs the production of glutathione intermediates in vitro. (PMID:20655259)
• high-risk glutamate-cysteine ligase catalytic subunit GAG trinucleotide repeat genotypes lead to alterations of plasma thiols levels that reflect a dysregulation of redox control (PMID:20673128)
• Data show that activation of the PPARgamma/PGC-1alpha pathway may protect against COPD progression by upregulating gamma-GCS and relieving oxidative stress. (PMID:20732852)
• Posttranslational modification and regulation of glutamate-cysteine ligase by the alpha,beta-unsaturated aldehyde 4-hydroxy-2-nonenal. (PMID:20970495)
• SNPs not associted with schizophrenia in Japanese individuals (PMID:21105962)
• These results provide evidence that interaction of the two variations can efficiently impair GCLC expression and thus suggest its involvement in the pathogenesis of diseases related to GSH metabolism. (PMID:21156206)
• SNPs not associated with self-reported depression (PMID:21277635)
• the single nucleotide polymorphism (SNP) -129C/T (rs17883901) in glutamate-cysteine ligase catalytic subunit (GCLC) and SNPs I128T (rs3816873) and Q95H (rs61733139) in microsomal triglyceride transfer protein (MTTP) in nonalcoholic fatty liver disease (PMID:21438662)
• Results suggest that GAG polymorphism affects GCLC expression via translation, and thus may be associated with altered risk for GSH-related diseases and toxicities. (PMID:21444626)
• GCLC is a target gene of the BACH1 transcription factor according to ChIP-seq analysis in HEK 293 cells. (PMID:21555518)
• The impacts of four clinical missense mutations on GCLC enzymatic function in vivo and in vitro, was evaluated. (PMID:21657237)
• insulin increased GCLc promoter activity, which required a prerequisite increase or decrease in medium glucose (PMID:21871559)
• The functional SNPs CYBA -675 T –> A and GCLC rs17883901, probably associated with cellular redox imbalances, modulate the risk for renal disease in the studied population of type 1 diabetes patients (PMID:21962117)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gclc	ENSDARG00000013095
mus_musculus	Gclc	ENSMUSG00000032350
rattus_norvegicus	Gclc	ENSRNOG00000006302
drosophila_melanogaster	Gclc	FBGN0040319
caenorhabditis_elegans		WBGENE00001527

Protein

Protein identifiers

Glutamate–cysteine ligase catalytic subunit — P48506 (reviewed: P48506)

Alternative names: GCS heavy chain, Gamma-ECS, Gamma-glutamylcysteine synthetase

All UniProt accessions (9): A0A0C4DGB2, A0A2R8Y648, A0A2R8YEL6, B4E2I4, D6RGF8, D6RIT4, E1CEI4, P48506, Q14TF0

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the ATP-dependent ligation of L-glutamate and L-cysteine and participates in the first and rate-limiting step in glutathione biosynthesis.

Subunit / interactions. Heterodimer of a catalytic heavy chain and a regulatory light chain.

Disease relevance. Anemia, congenital, non-spherocytic hemolytic, 7 (CNSHA7) [MIM:230450] An autosomal recessive disease characterized by hemolytic anemia, glutathione deficiency, myopathy, late-onset spinocerebellar degeneration, and peripheral neuropathy. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Feedback inhibition by glutathione.

Pathway. Sulfur metabolism; glutathione biosynthesis; glutathione from L-cysteine and L-glutamate: step 1/2.

Similarity. Belongs to the glutamate–cysteine ligase type 3 family.

RefSeq proteins (2): NP_001184044, NP_001489* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004308	GCS	Family
IPR014746	Gln_synth/guanido_kin_cat_dom	Homologous_superfamily

Pfam: PF03074

Enzyme classification (BRENDA):

• EC 6.3.2.2 — glutamate-cysteine ligase (BRENDA: 68 organisms, 284 substrates, 218 inhibitors, 346 Km, 118 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ATP	0.0001–45	80
L-GLUTAMATE	0.0032–1755.4	68
L-CYSTEINE	0.0001–2.7	48
L-GLU	0.03–229	42
L-CYS	0.05–57.3	32
L-ALPHA-AMINOBUTYRATE	0.25–380	18
L-2-AMINOBUTANOATE	0.14–10.4	14
L-2-AMINOBUTYRATE	0.8–5	6
2-AMINOBUTYRATE	0.32–10.4	4
4-AMINOBUTYRATE	1.3–150	3
GLUTAMATE	0.75–9.1	3
CYSTEINE	0.3–2.7	2
GAMMA-L-GLU-L-CYS	0.86–1.3	2
L-2-AMINOBUTYRIC ACID	5.4–6.1	2
(R)-BETA-AMINO-ISO-BUTYRATE	7.3	1

Catalyzed reactions (Rhea), 2 shown:

• L-cysteine + L-glutamate + ATP = gamma-L-glutamyl-L-cysteine + ADP + phosphate + H(+) (RHEA:13285)
• (2S)-2-aminobutanoate + L-glutamate + ATP = gamma-L-glutamyl-(2S)-2-aminobutanoate + ADP + phosphate + H(+) (RHEA:72067)

UniProt features (9 total): sequence variant 5, modified residue 3, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48506-F1	93.68	0.92

Functional residue map

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

Post-translational modifications (3): 1, 5, 8

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-174403	Glutathione synthesis and recycling
R-HSA-5578999	Defective GCLC causes HAGGSD
R-HSA-9818027	NFE2L2 regulating anti-oxidant/detoxification enzymes

MSigDB gene sets: 568 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, GCACCTT_MIR18A_MIR18B, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_MEMBRANE_DEPOLARIZATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, REACTOME_BIOLOGICAL_OXIDATIONS, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_RESPONSE_TO_PEPTIDE, FISCHER_G1_S_CELL_CYCLE, GOBP_CELLULAR_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_GLUTAMATE_METABOLIC_PROCESS

GO Biological Process (34): obsolete cysteine metabolic process (GO:0006534), glutamate metabolic process (GO:0006536), glutathione biosynthetic process (GO:0006750), response to oxidative stress (GO:0006979), response to nutrient (GO:0007584), response to heat (GO:0009408), response to xenobiotic stimulus (GO:0009410), response to hormone (GO:0009725), response to activity (GO:0014823), L-ascorbic acid metabolic process (GO:0019852), negative regulation of protein ubiquitination (GO:0031397), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), cellular response to insulin stimulus (GO:0032869), cellular response to hepatocyte growth factor stimulus (GO:0035729), negative regulation of apoptotic process (GO:0043066), negative regulation of neuron apoptotic process (GO:0043524), cellular response to fibroblast growth factor stimulus (GO:0044344), response to human chorionic gonadotropin (GO:0044752), cell redox homeostasis (GO:0045454), negative regulation of DNA-templated transcription (GO:0045892), response to arsenic-containing substance (GO:0046685), response to cadmium ion (GO:0046686), response to nitrosative stress (GO:0051409), regulation of mitochondrial depolarization (GO:0051900), response to interleukin-1 (GO:0070555), cellular response to mechanical stimulus (GO:0071260), cellular response to glucose stimulus (GO:0071333), cellular response to follicle-stimulating hormone stimulus (GO:0071372), cellular response to thyroxine stimulus (GO:0097069), blood vessel diameter maintenance (GO:0097746), negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway (GO:1901029), negative regulation of hepatic stellate cell activation (GO:2000490), negative regulation of extrinsic apoptotic signaling pathway (GO:2001237), glutathione metabolic process (GO:0006749)

GO Molecular Function (10): magnesium ion binding (GO:0000287), glutamate-cysteine ligase activity (GO:0004357), ATP binding (GO:0005524), glutamate binding (GO:0016595), ADP binding (GO:0043531), protein-containing complex binding (GO:0044877), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), ligase activity (GO:0016874)

GO Cellular Component (3): mitochondrion (GO:0005739), cytosol (GO:0005829), glutamate-cysteine ligase complex (GO:0017109)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Glutathione conjugation	1
Metabolic disorders of biological oxidation enzymes	1
Nuclear events mediated by NFE2L2	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to chemical	3
cytoplasm	3
response to stress	2
cellular response to growth factor stimulus	2
adenyl ribonucleotide binding	2
binding	2
amino acid metabolic process	1
dicarboxylic acid metabolic process	1
glutathione metabolic process	1
nonribosomal peptide biosynthetic process	1
modified amino acid biosynthetic process	1
sulfur compound biosynthetic process	1
response to nutrient levels	1
response to temperature stimulus	1
response to endogenous stimulus	1
response to stimulus	1
monosaccharide metabolic process	1
carboxylic acid metabolic process	1
lactone metabolic process	1
protein ubiquitination	1
regulation of protein ubiquitination	1
negative regulation of protein modification by small protein conjugation or removal	1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
positive regulation of proteasomal protein catabolic process	1
positive regulation of ubiquitin-dependent protein catabolic process	1
response to insulin	1
cellular response to peptide hormone stimulus	1
response to hepatocyte growth factor	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
response to fibroblast growth factor	1
response to gonadotropin	1
cellular homeostasis	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1

Protein interactions and networks

STRING

1868 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GCLC	GCLM	P48507	999
GCLC	NFE2L2	Q16236	930
GCLC	KEAP1	Q14145	904
GCLC	NQO1	P15559	903
GCLC	HMOX1	P09601	897
GCLC	GSR	P00390	811
GCLC	GPX4	P36969	803
GCLC	TXNRD1	Q16881	781
GCLC	GSS	P48637	762
GCLC	CRYZ	Q08257	742
GCLC	GPX2	P18283	740
GCLC	TXN	P10599	734
GCLC	SRXN1	Q9BYN0	725
GCLC	SOD1	P00441	711
GCLC	NFE2	Q16621	710

IntAct

16 interactions, top by confidence:

A	B	Type	Score
GCLC	GCLM	psi-mi:“MI:0914”(association)	0.790
GCLM	GCLC	psi-mi:“MI:0407”(direct interaction)	0.790
GCLC	GCLM	psi-mi:“MI:0915”(physical association)	0.790
GCLM	PRKCA	psi-mi:“MI:0914”(association)	0.530
PRR16	GCLC	psi-mi:“MI:0915”(physical association)	0.400
CCL22	GCLC	psi-mi:“MI:0915”(physical association)	0.370
TYW3	KIF2A	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
TYW3	ROCK2	psi-mi:“MI:0914”(association)	0.350
DDX28	UBA6	psi-mi:“MI:0914”(association)	0.350
DND1	UBA6	psi-mi:“MI:0914”(association)	0.350
GCLM	RFPL4A	psi-mi:“MI:0914”(association)	0.350
VENTX	UBA6	psi-mi:“MI:0914”(association)	0.350
GCLC		psi-mi:“MI:0915”(physical association)	0.000

BioGRID (44): DHRS11 (Co-fractionation), GCLC (Co-fractionation), GCLC (Co-fractionation), GCLC (Co-fractionation), GCLM (Affinity Capture-MS), GCLC (Affinity Capture-MS), NMD3 (Affinity Capture-MS), GCLC (Affinity Capture-RNA), GCLC (Affinity Capture-MS), GCLC (Affinity Capture-MS), GCLC (Negative Genetic), GCLC (Affinity Capture-RNA), GCLC (Negative Genetic), GCLC (Affinity Capture-MS), GCLC (Phenotypic Suppression)

ESM2 similar proteins: A8NS89, A8X3V8, F4JLK2, O17446, O61608, O82162, P17653, P19468, P21623, P25987, P32477, P42066, P48506, P86924, P86925, P90986, P97494, Q03460, Q03508, Q04564, Q04952, Q08760, Q09768, Q0DG35, Q20117, Q4WED9, Q54PC2, Q5RCS9, Q5ZIF3, Q6BIV1, Q6CVT0, Q6FLD4, Q7XZU0, Q7Z9H9, Q8T8C0, Q8X0X0, Q91WF7, Q92562, Q99312, Q99K23

Diamond homologs: P19468, P32477, P48506, P97494, Q09768, Q20117, Q54PC2, Q8X0X0, Q9HF78, Q9NFN6, Q9W3K5

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
MTF1	“up-regulates quantity by expression”	GCLC	“transcriptional regulation”
NFE2L2	“down-regulates quantity by repression”	GCLC	“transcriptional regulation”
NFE2L2	“up-regulates quantity by expression”	GCLC	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	93
Likely benign	68
Benign	28

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
3363108	NM_001498.4(GCLC):c.473C>T (p.Pro158Leu)	Pathogenic
3958	NM_001498.4(GCLC):c.1109A>T (p.His370Leu)	Pathogenic

SpliceAI

2390 predictions. Top by Δscore:

Variant	Effect	Δscore
6:53498965:CTC:C	acceptor_gain	1.0000
6:53498968:C:CC	acceptor_gain	1.0000
6:53500043:A:AC	donor_gain	1.0000
6:53500044:C:CC	donor_gain	1.0000
6:53500163:TTCC:T	acceptor_loss	1.0000
6:53500166:CTA:C	acceptor_loss	1.0000
6:53500167:T:C	acceptor_loss	1.0000
6:53500241:TCCTA:T	donor_loss	1.0000
6:53500242:CCTAC:C	donor_loss	1.0000
6:53500243:CTA:C	donor_loss	1.0000
6:53500244:TACC:T	donor_loss	1.0000
6:53500245:ACCTT:A	donor_gain	1.0000
6:53500246:C:CG	donor_loss	1.0000
6:53500246:CCTT:C	donor_gain	1.0000
6:53500246:CCTTC:C	donor_gain	1.0000
6:53500249:T:TA	donor_gain	1.0000
6:53500250:C:A	donor_gain	1.0000
6:53500347:CCAC:C	acceptor_gain	1.0000
6:53500348:CAC:C	acceptor_gain	1.0000
6:53500348:CACC:C	acceptor_gain	1.0000
6:53500349:ACC:A	acceptor_loss	1.0000
6:53500350:CCT:C	acceptor_loss	1.0000
6:53500351:C:CC	acceptor_gain	1.0000
6:53500351:CTG:C	acceptor_loss	1.0000
6:53500352:T:G	acceptor_loss	1.0000
6:53500355:C:CT	acceptor_gain	1.0000
6:53500355:C:T	acceptor_gain	1.0000
6:53500356:G:T	acceptor_gain	1.0000
6:53500447:T:A	donor_gain	1.0000
6:53505386:CCTTA:C	donor_loss	1.0000

AlphaMissense

4228 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:53505468:G:T	A440D	1.000
6:53505820:C:T	E425K	1.000
6:53505824:T:A	R423S	1.000
6:53505824:T:G	R423S	1.000
6:53505829:A:G	W422R	1.000
6:53505829:A:T	W422R	1.000
6:53505831:C:T	G421E	1.000
6:53505857:C:A	K412N	1.000
6:53505857:C:G	K412N	1.000
6:53505859:T:C	K412E	1.000
6:53505863:T:A	R410S	1.000
6:53505863:T:G	R410S	1.000
6:53505864:C:G	R410T	1.000
6:53505875:C:A	W406C	1.000
6:53505875:C:G	W406C	1.000
6:53505877:A:G	W406R	1.000
6:53505877:A:T	W406R	1.000
6:53508651:A:G	W297R	1.000
6:53508651:A:T	W297R	1.000
6:53508700:A:C	S280R	1.000
6:53508700:A:T	S280R	1.000
6:53508702:T:G	S280R	1.000
6:53514210:A:C	C249W	1.000
6:53514226:C:T	G244E	1.000
6:53514470:C:A	R196S	1.000
6:53514470:C:G	R196S	1.000
6:53514471:C:A	R196M	1.000
6:53514471:C:G	R196T	1.000
6:53516111:G:C	F186L	1.000
6:53516111:G:T	F186L	1.000

dbSNP variants (sampled 300 via entrez): RS1000005683 (6:53504152 C>T), RS1000032438 (6:53535605 C>T), RS1000074206 (6:53541615 G>A), RS1000161902 (6:53518273 C>T), RS1000174717 (6:53533796 T>C), RS1000294399 (6:53511244 A>G), RS1000348551 (6:53517344 G>C), RS1000388788 (6:53524319 TA>T), RS1000435753 (6:53530830 C>T), RS1000478917 (6:53543090 T>C,G), RS1000509525 (6:53530517 G>A), RS1000557724 (6:53497224 T>C), RS1000701065 (6:53542399 G>A,C,T), RS1000725156 (6:53499214 G>A), RS1000740256 (6:53524045 G>A)

Disease associations

OMIM: gene MIM:606857 | disease phenotypes: MIM:230450, MIM:608446

GenCC curated gene-disease

Disease	Classification	Inheritance
gamma-glutamylcysteine synthetase deficiency	Strong	Autosomal recessive
cystic fibrosis	Supportive	Autosomal recessive

Mondo (3): gamma-glutamylcysteine synthetase deficiency (MONDO:0009259), myocardial infarction, susceptibility to (MONDO:0012039), cystic fibrosis (MONDO:0009061)

Orphanet (1): Glutamate-cysteine ligase deficiency (Orphanet:33574)

HPO phenotypes

56 total (30 of 56 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000246	Sinusitis
HP:0000365	Hearing impairment
HP:0000709	Psychosis
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000787	Nephrolithiasis
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0000952	Jaundice
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001271	Polyneuropathy
HP:0001347	Hyperreflexia
HP:0001392	Abnormality of the liver
HP:0001394	Cirrhosis
HP:0001433	Hepatosplenomegaly
HP:0001508	Failure to thrive
HP:0001738	Exocrine pancreatic insufficiency
HP:0001878	Hemolytic anemia
HP:0001923	Reticulocytosis
HP:0002020	Gastroesophageal reflux
HP:0002024	Malabsorption
HP:0002035	Rectal prolapse
HP:0002099	Asthma
HP:0002105	Hemoptysis
HP:0002107	Pneumothorax
HP:0002110	Bronchiectasis

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST003518_85	Daytime sleep phenotypes	4.000000e-06
GCST008151_61	Waist circumference	9.000000e-06
GCST008160_20	Waist circumference	9.000000e-06
GCST008169_13	Benign prostatic hyperplasia	5.000000e-06
GCST008169_6	Benign prostatic hyperplasia	5.000000e-07
GCST008362_157	Birth weight	2.000000e-11
GCST90002393_84	Monocyte count	2.000000e-12
GCST90002394_161	Monocyte percentage of white cells	8.000000e-14

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007828	daytime rest measurement
EFO:0004344	birth weight
EFO:0005091	monocyte count
EFO:0007989	monocyte percentage of leukocytes

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D003550	Cystic Fibrosis	C06.689.202; C08.381.187; C16.320.190; C16.614.213
C565557	Gamma-Glutamylcysteine Synthetase Deficiency, Hemolytic Anemia due to (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4055 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 11,158 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1256575	BUTHIONINE SULFOXIMINE	1	11,158

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs761142	Toxicity	3	sulfamethoxazole	HIV infectious disease

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs761142	GCLC	3	6.25	1	sulfamethoxazole

ChEMBL bioactivities

3 potent at pChembl≥5 of 4 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.41	Ki	390	nM	CHEMBL1627263
5.30	Ki	4950	nM	CHEMBL1159981
5.04	Ki	9230	nM	CHEMBL1159982

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases reaction, affects reaction, increases activity, decreases reaction, increases expression (+4 more)	26
sulforaphane	decreases methylation, increases expression, increases reaction, decreases reaction, decreases expression	9
Benzo(a)pyrene	decreases methylation, increases expression, increases methylation, affects cotreatment	9
Arsenic Trioxide	decreases expression, increases abundance, increases expression, decreases response to substance	8
Acetylcysteine	decreases reaction, increases expression, decreases expression	8
Arsenic	affects response to substance, affects abundance, decreases expression, decreases reaction, increases expression (+1 more)	8
Cadmium Chloride	affects cotreatment, increases expression, increases abundance, increases activity, increases reaction (+4 more)	8
Glutathione	increases reaction, increases chemical synthesis, increases activity, decreases reaction, decreases response to substance (+4 more)	7
Resveratrol	decreases expression, increases reaction, increases activity, decreases reaction, increases expression (+2 more)	6
Acetaminophen	decreases expression, increases expression, increases reaction, decreases reaction	6
Cisplatin	increases reaction, increases expression, decreases response to substance, decreases expression, decreases reaction (+1 more)	6
Hydrogen Peroxide	decreases expression, decreases reaction, affects expression, increases expression, affects reaction	6
Tobacco Smoke Pollution	affects expression, increases expression	6
bisphenol A	affects expression, affects cotreatment, increases expression	5
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	increases activity, increases expression, decreases reaction	5
Quercetin	decreases reaction, increases reaction, affects cotreatment, increases expression	5
lead acetate	affects cotreatment, increases abundance, increases expression, decreases reaction	4
cinnamaldehyde	decreases reaction, increases expression, increases activity, affects reaction	4
arsenite	affects binding, decreases reaction, affects reaction, increases abundance, affects cotreatment (+1 more)	4
2-tert-butylhydroquinone	affects expression, decreases expression, increases expression	4
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases reaction, increases expression, decreases expression	4
Air Pollutants	increases abundance, increases expression, decreases expression	4
Cadmium	decreases expression, increases abundance, increases expression, decreases uptake	4
Curcumin	increases expression, decreases expression, decreases reaction, increases activity	4
Doxorubicin	increases expression, affects cotreatment, decreases response to substance, increases reaction, decreases reaction	4
Mercury	increases abundance, increases expression, affects abundance, increases reaction, affects response to substance (+1 more)	4
Plant Extracts	decreases reaction, increases expression, increases activity	4
Cyclosporine	increases expression	4
Particulate Matter	increases abundance, increases expression, decreases expression	4
deoxynivalenol	decreases expression, increases reaction, decreases reaction	3

ChEMBL screening assays

14 unique, capped per target: 14 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118762	Binding	Binding affinity to GCLC in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C7D6	Abcam A-549 GCLC KO	Cancer cell line	Male
CVCL_C7DW	Abcam HCT 116 GCLC KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00157690	PHASE4	COMPLETED	Study of Alendronate to Prevent and Treat Osteoporosis in Cystic Fibrosis Patients
NCT00208078	PHASE4	TERMINATED	Effect of Non-Invasive Ventilation in Cystic Fibrosis Patient With Chronic Respiratory Failure.
NCT00244270	PHASE4	COMPLETED	Cystic Fibrosis and Totally Implantable Vascular Access Devices
NCT00333385	PHASE4	TERMINATED	Continuous Versus Short Infusions of Ceftazidime in Cystic Fibrosis
NCT00411736	PHASE4	COMPLETED	Scandinavian Cystic Fibrosis Azithromycin Study
NCT00418470	PHASE4	TERMINATED	Prolonging the Duration of Peripheral Venous Catheters in Cystic Fibrosis People
NCT00431964	PHASE4	COMPLETED	Effect of Azithromycin on Lung Function in 6-18 Year-olds With Cystic Fibrosis (CF) Not Infected With P. Aeruginosa
NCT00434278	PHASE4	TERMINATED	A Trial of Pulmozyme Withdrawal on Exercise Tolerance in Cystic Fibrosis Subjects With Severe Lung Disease (TOPIC)
NCT00483769	PHASE4	COMPLETED	One Year Glargine Treatment in CFRD Children and Adolescents
NCT00528190	PHASE4	COMPLETED	Treatment of Aspergillus Fumigatus (a Fungal Infection) in Patients With Cystic Fibrosis
NCT00557089	PHASE4	COMPLETED	The Effect of rhDNase on Ventilation Inhomogeneity in Patients With Cystic Fibrosis
NCT00572975	PHASE4	COMPLETED	Malabsorption Blood Test:Toward a Novel Approach to Quantify Steatorrhea
NCT00680316	PHASE4	TERMINATED	A Study of Pulmozyme® (Dornase Alpha) in 3- to 5-Year-Old Patients With Cystic Fibrosis
NCT00685035	PHASE4	COMPLETED	Comparison of Airway Clearance Therapy in Cystic Fibrosis Using the Same VEST Therapy Device But With Different Settings
NCT00744250	PHASE4	TERMINATED	Intraduodenal Aspiration Study to Assess the Bioavailability of Oral Pancrecarb® Compared to Placebo Control
NCT00787917	PHASE4	TERMINATED	An Exploratory Study to Assess Multiple Doses of Omalizumab in Patients With Cystic Fibrosis Complicated by Acute Bronchopulmonary Aspergillosis (ABPA)
NCT00843817	PHASE4	COMPLETED	RhDNase and Biodistribution of PMN Serine Proteases in Cystic Fibrosis Sputum
NCT00890370	PHASE4	COMPLETED	Should Any One Airway Clearance Technique be Recommended for People With Cystic Fibrosis?
NCT00996424	PHASE4	TERMINATED	The Effect of Inhaled N-Acetylcysteine Compared to Normal Saline on Sputum Rheology and Lung Function
NCT01044719	PHASE4	UNKNOWN	Duration of Antibiotics in Infective Exacerbations of Cystic Fibrosis
NCT01100606	PHASE4	COMPLETED	A Study to Evaluate the Mode of Administration and Safety of EUR-1008 (APT-1008) in Infants 1 to 12 Months of Age
NCT01131507	PHASE4	COMPLETED	PR-018: An Open-Label, Safety Extension of Study PR-011
NCT01207245	PHASE4	COMPLETED	Circadian Rhythm In Tobramycin Elimination In Cystic Fibrosis
NCT01323101	PHASE4	COMPLETED	Doxycycline Effects on Inflammation in Cystic Fibrosis
NCT01327703	PHASE4	COMPLETED	Control of Steatorrhea in Participants With Cystic Fibrosis and Exocrine Pancreatic Insufficiency
NCT01377792	PHASE4	COMPLETED	Study of Long-term Treatment With Hypertonic Saline in Patients With Cystic Fibrosis
NCT01400750	PHASE4	COMPLETED	Comparison of 2 Treatment Regimens for Eradication of P Aeruginosa Infection in Children With Cystic Fibrosis
NCT01429259	PHASE4	COMPLETED	Population Pharmacokinetics of Prolonged Infusion Meropenem in Cystic Fibrosis (CF) Children
NCT01608555	PHASE4	COMPLETED	Tobramycin 300 mg Once-a-day (o.d.) Aerosol in Adults With Cystic Fibrosis
NCT01667094	PHASE4	UNKNOWN	A Study Comparing Continuous Infusion Antibiotics to Standard Treatment for Lung Infections in Cystic Fibrosis
NCT01694069	PHASE4	TERMINATED	Continuous Infusion Piperacillin-tazobactam for the Treatment of Cystic Fibrosis
NCT01702415	PHASE4	WITHDRAWN	Zoledronic Acid in Cystic Fibrosis
NCT01712334	PHASE4	COMPLETED	A Study of the Comparable Efficacy and Safety of Pulmozyme (Dornase Alfa) Delivered by the eRapid Nebulizer System in Patients With Cystic Fibrosis
NCT01737983	PHASE4	COMPLETED	Effect of Lactobacillus Reuteri in Cystic Fibrosis
NCT01844778	PHASE4	COMPLETED	Ease of Use and Microbial Contamination of Tobramycin Inhalation Powder (TIP) Versus Nebulised Tobramycin Inhalation Solution (TIS) and Nebulised Colistimethate (COLI)
NCT01880346	PHASE4	COMPLETED	Comparison of Absorption of Vitamin D in Cystic Fibrosis
NCT01882400	PHASE4	COMPLETED	Assessment of Response to Treatment of Osteoporosis With Oral Bisphosphonates in Patients With Muscular Dystrophy
NCT01937325	PHASE4	UNKNOWN	CPET in CF Patients With One G551D Mutation Taking VX770
NCT02015663	PHASE4	TERMINATED	Tobramycin Inhalation Powder (TIP) Administered Once Daily Continuously Versus TIP Administered BID in 28 Day on / 28 Day Off Cycles
NCT02048592	PHASE4	UNKNOWN	Impact of Immunonutrition on the Patients With Cystic Fibrosis