GCLM glutamate-cysteine ligase modifier subunit [Homo sapiens (human)] - Gene

Summary

Official Symbol: GCLMprovided by HGNC
Official Full Name: glutamate-cysteine ligase modifier subunitprovided by HGNC
Primary source: HGNC:HGNC:4312
See related: Ensembl:ENSG00000023909 MIM:601176; AllianceGenome:HGNC:4312
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: GLCLR
Summary: 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. Gamma glutamylcysteine synthetase deficiency has been implicated in some forms of hemolytic anemia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]
Expression: Ubiquitous expression in liver (RPKM 13.0), thyroid (RPKM 9.9) and 24 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 1p22.1

Exon count:: 9

Annotation release	Status	Assembly	Chr	Location
RS_2024_08	current	GRCh38.p14 (GCF_000001405.40)	1	NC_000001.11 (93885199..93909430, complement)
RS_2024_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	1	NC_060925.1 (93733450..93757695, complement)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	1	NC_000001.10 (94350755..94374986, complement)

Chromosome 1 - NC_000001.11 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Glutamate-cysteine ligase catalytic and its modifier function as novel immunotargets in gastric adenocarcinoma.
Title: Glutamate-cysteine ligase catalytic and its modifier function as novel immunotargets in gastric adenocarcinoma.
Association of Polymorphisms of Glutamate Cysteine Ligase Genes GCLC C-129 T and GCLM C-588 T with Risk of Polycystic Ovary Syndrome in Chinese Women.
Title: Association of Polymorphisms of Glutamate Cysteine Ligase Genes GCLC C-129 T and GCLM C-588 T with Risk of Polycystic Ovary Syndrome in Chinese Women.
Association of glutamate cystein ligase (GCL) activity Peroxiredoxin 4 (prxR4) and apelin levels in women with preeclampsia.
Title: Association of glutamate cystein ligase (GCL) activity Peroxiredoxin 4 (prxR4) and apelin levels in women with preeclampsia.
Genetic variants in glutamate cysteine ligase confer protection against type 2 diabetes.
Title: Genetic variants in glutamate cysteine ligase confer protection against type 2 diabetes.
Glutathione biosynthesis during the lipopolysaccharide-induced inflammatory response in THP-1 macrophages is tightly and differentially regulated via GCLC and GCLM subunits of glutamate cysteine ligase.
Title: Temporal changes in glutathione biosynthesis during the lipopolysaccharide-induced inflammatory response of THP-1 macrophages.
Two promoter polymorphisms of GCLM (-588C/T) and GCLC (-128T/C) are associated with an increased risk of ischemic heart disease in Kazakhstan population.
Title: Association of GCLM -588C/T and GCLC -129T/C Promoter Polymorphisms of Genes Coding the Subunits of Glutamate Cysteine Ligase with Ischemic Heart Disease Development in Kazakhstan Population.
High GCLM expression is associated with chemotherapy resistance in breast cancer.
Title: Nrf2 is the key to chemotherapy resistance in MCF7 breast cancer cells under hypoxia.
Glutaminolysis is activated in ES2 and OVCAR3, though ES2 exclusively synthesizes amino acids and GSH. ES2 cells are more resistant to carboplatin than OVCAR3 and the abrogation of GSH production by BSO sensitizes ES2 to carboplatin. HNF1beta regulates the expression of GCLC, but not GCLM, and consequently GSH production in ES2
Title: HNF1β drives glutathione (GSH) synthesis underlying intrinsic carboplatin resistance of ovarian clear cell carcinoma (OCCC).
Data suggest gene expression in vascular endothelium is altered by dietary factors; aged garlic extract induces expression of HMOX1 (heme oxygenase-1) and GCLM via activation of NRF2-ARE (nuclear factor erythroid 2-antioxidant response element) signaling.
Title: Aged garlic extract enhances heme oxygenase-1 and glutamate-cysteine ligase modifier subunit expression via the nuclear factor erythroid 2-related factor 2-antioxidant response element signaling pathway in human endothelial cells.
miR-433 targets both catalytic (GCLc) and regulatory (GCLm) subunits of GCL.
Title: Targeting of Gamma-Glutamyl-Cysteine Ligase by miR-433 Reduces Glutathione Biosynthesis and Promotes TGF-β-Dependent Fibrogenesis.

Submit: New GeneRIF Correction See all GeneRIFs (42)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Myocardial infarction, susceptibility to MedGen: C1832662 OMIM: 608446 GeneReviews: Not available	Compare labs

EBI GWAS Catalog

Description
Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

HIV-1 interactions

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Replication interactions

Interaction	Pubs
Knockdown of glutamate-cysteine ligase, modifier subunit (GCLM) by shRNA library screening inhibits HIV-1 replication in cultured Jurkat T-cells	PubMed

Go to the HIV-1, Human Interaction Database

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

D1S3247 (e-PCR)
- UniSTS:39172

G66720 (e-PCR)
- UniSTS:166928

G66719 (e-PCR)
- UniSTS:166929

D8S2279 (e-PCR)
- UniSTS:473907

D15S1477 (e-PCR)
- UniSTS:474482

D1S1425 (e-PCR)
- UniSTS:149621

GCLM_3987 (e-PCR)
- UniSTS:462210

D1S3412 (e-PCR)
- UniSTS:28861

RH69046 (e-PCR)
- UniSTS:74457

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
contributes_to glutamate-cysteine ligase activity	IMP Inferred from Mutant Phenotype more info	PubMed
enables glutamate-cysteine ligase catalytic subunit binding	IBA Inferred from Biological aspect of Ancestor more info
enables glutamate-cysteine ligase catalytic subunit binding	IPI Inferred from Physical Interaction more info	PubMed
enables glutamate-cysteine ligase regulator activity	IBA Inferred from Biological aspect of Ancestor more info
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein-containing complex binding	IEA Inferred from Electronic Annotation more info

Process	Evidence Code	Pubs
involved_in apoptotic mitochondrial changes	IEA Inferred from Electronic Annotation more info
involved_in blood vessel diameter maintenance	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in cellular response to fibroblast growth factor stimulus	IEA Inferred from Electronic Annotation more info
involved_in cellular response to follicle-stimulating hormone stimulus	IEA Inferred from Electronic Annotation more info
involved_in cellular response to glucose stimulus	IEA Inferred from Electronic Annotation more info
involved_in cellular response to hepatocyte growth factor stimulus	IEA Inferred from Electronic Annotation more info
involved_in cellular response to leukemia inhibitory factor	IEA Inferred from Electronic Annotation more info
involved_in cellular response to thyroxine stimulus	IEA Inferred from Electronic Annotation more info
involved_in cysteine metabolic process	IEA Inferred from Electronic Annotation more info
involved_in glutamate metabolic process	IDA Inferred from Direct Assay more info	PubMed
involved_in glutathione biosynthetic process	IBA Inferred from Biological aspect of Ancestor more info
involved_in glutathione biosynthetic process	IDA Inferred from Direct Assay more info	PubMed
involved_in glutathione biosynthetic process	IEA Inferred from Electronic Annotation more info
involved_in glutathione biosynthetic process	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in hepatic stellate cell activation	IEA Inferred from Electronic Annotation more info
involved_in negative regulation of extrinsic apoptotic signaling pathway	IEA Inferred from Electronic Annotation more info
involved_in negative regulation of neuron apoptotic process	IEA Inferred from Electronic Annotation more info
involved_in regulation of mitochondrial depolarization	IEA Inferred from Electronic Annotation more info
involved_in response to activity	IEA Inferred from Electronic Annotation more info
involved_in response to human chorionic gonadotropin	IEA Inferred from Electronic Annotation more info
involved_in response to nitrosative stress	IEA Inferred from Electronic Annotation more info
involved_in response to nutrient	IEA Inferred from Electronic Annotation more info
involved_in response to oxidative stress	IDA Inferred from Direct Assay more info	PubMed
involved_in response to xenobiotic stimulus	IDA Inferred from Direct Assay more info	PubMed

Component	Evidence Code	Pubs
located_in cytosol	NAS Non-traceable Author Statement more info	PubMed
located_in cytosol	TAS Traceable Author Statement more info
part_of glutamate-cysteine ligase complex	IBA Inferred from Biological aspect of Ancestor more info
part_of glutamate-cysteine ligase complex	IDA Inferred from Direct Assay more info	PubMed

General protein information

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Preferred Names: glutamate--cysteine ligase regulatory subunit

Names: GCS light chain; GSC light chain; gamma-ECS regulatory subunit; gamma-glutamylcysteine synthetase regulatory subunit; glutamate-cysteine ligase (gamma-glutamylcysteine synthetase), regulatory (30.8kD); glutamate-cysteine ligase modifier subunit delta2 alternative splicing; glutamate-cysteine ligase regulatory protein

NP_001295182.1

EC 6.3.2.2

NP_002052.1

EC 6.3.2.2

XP_011539563.1

EC 6.3.2.2

XP_047273987.1

EC 6.3.2.2

XP_054192028.1

EC 6.3.2.2

XP_054192029.1

EC 6.3.2.2

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_012072.1 RefSeqGene

Range

5027..29258

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_001308253.2 → NP_001295182.1 glutamate--cysteine ligase regulatory subunit isoform 2

See identical proteins and their annotated locations for NP_001295182.1

Status: REVIEWED

Description

Transcript Variant: This variant (2) lacks an alternate in-frame exon in the 5' coding region, compared to variant 1. It encodes isoform 2 which has the same N- and C-termini, but is shorter than isoform 1.

Source sequence(s)

AB809606, BC041809, BF513627, BG501583, BM982562, BQ049850, BU754400, CB123306, CN272168, CN422503, N53134

Consensus CDS

CCDS81352.1

Related

ENSP00000484507.1, ENST00000615724.1

Conserved Domains (1) summary

cl00470
Location:64 → 189

AKR_SF; Aldo-keto reductase (AKR) superfamily
NM_002061.4 → NP_002052.1 glutamate--cysteine ligase regulatory subunit isoform 1

See identical proteins and their annotated locations for NP_002052.1

Status: REVIEWED

Description

Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1).

Source sequence(s)

AK290449, BC041809, BF513627, BM982562, BQ049850, BU754400, CB123306, CN272168, CN422503, N53134

Consensus CDS

CCDS746.1

UniProtKB/Swiss-Prot

A8K334, D3DT45, M5A959, P48507, Q6FHC1, Q9NPX9, Q9NU74

Related

ENSP00000359258.3, ENST00000370238.8

Conserved Domains (1) summary

cl00470
Location:86 → 211

AKR_SF; Aldo-keto reductase (AKR) superfamily

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

NC_000001.11 Reference GRCh38.p14 Primary Assembly

Range

93885199..93909430 complement

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_011541261.3 → XP_011539563.1 glutamate--cysteine ligase regulatory subunit isoform X2

Conserved Domains (1) summary

cl00470
Location:29 → 123

Aldo_ket_red; Aldo-keto reductases (AKRs) are a superfamily of soluble NAD(P)(H) oxidoreductases whose chief purpose is to reduce aldehydes and ketones to primary and secondary alcohols. AKRs are present in all phyla and are of importance to both health and industrial ...
XM_047418031.1 → XP_047273987.1 glutamate--cysteine ligase regulatory subunit isoform X1

Alternate T2T-CHM13v2.0

Genomic

NC_060925.1 Alternate T2T-CHM13v2.0

Range

93733450..93757695 complement

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_054336054.1 → XP_054192029.1 glutamate--cysteine ligase regulatory subunit isoform X2
XM_054336053.1 → XP_054192028.1 glutamate--cysteine ligase regulatory subunit isoform X1