GCLC

Protein identityUniProt · HPA

UniProt accession

P48506

Gene

GCLC

Ensembl

ENSG00000001084

Chromosome

6

Canonical length

637 aa

Protein class

Disease related genes, Enzymes, Human disease related genes, Metabolic proteins, Plasma proteins, Potential drug targets, Predicted intracellular proteins

Subcellular location

Nucleoplasm,Nucleoli,Cytosol

OverviewNCBI Gene

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.[provided by RefSeq, Oct 2010]

Canonical amino-acid sequenceUniProt

637 residues, UniProt reviewed canonical sequence.

>P48506|GCLC
     1  MGLLSQGSPL SWEETKRHAD HVRRHGILQF LHIYHAVKDR HKDVLKWGDE VEYMLVSFDH
    61  ENKKVRLVLS GEKVLETLQE KGERTNPNHP TLWRPEYGSY MIEGTPGQPY GGTMSEFNTV
   121  EANMRKRRKE ATSILEENQA LCTITSFPRL GCPGFTLPEV KPNPVEGGAS KSLFFPDEAI
   181  NKHPRFSTLT RNIRHRRGEK VVINVPIFKD KNTPSPFIET FTEDDEASRA SKPDHIYMDA
   241  MGFGMGNCCL QVTFQACSIS EARYLYDQLA TICPIVMALS AASPFYRGYV SDIDCRWGVI
   301  SASVDDRTRE ERGLEPLKNN NYRISKSRYD SIDSYLSKCG EKYNDIDLTI DKEIYEQLLQ
   361  EGIDHLLAQH VAHLFIRDPL TLFEEKIHLD DANESDHFEN IQSTNWQTMR FKPPPPNSDI
   421  GWRVEFRPME VQLTDFENSA YVVFVVLLTR VILSYKLDFL IPLSKVDENM KVAQKRDAVL
   481  QGMFYFRKDI CKGGNAVVDG CGKAQNSTEL AAEEYTLMSI DTIINGKEGV FPGLIPILNS
   541  YLENMEVDVD TRCSILNYLK LIKKRASGEL MTVARWMREF IANHPDYKQD SVITDEMNYS
   601  LILKCNQIAN ELCECPELLG SAFRKVKYSG SKTDSSN

LocalizationUniProt · AlphaFold · HPA

Whether an antibody against GCLC can act on the native protein depends on physical access: surface and secreted proteins are reachable by circulating antibodies, intracellular proteins usually are not.

Antibody reachability

Intracellular

Secreted

No

Transmembrane segments

0

Mean surface accessibility (rSASA)

0.22

Highest tissue expression

142 nTPM

Expression across tissuesHPA

DiseaseUniProt · ClinVar · IEDB · PubMed

Four sources answering four different questions about GCLC.

Disease | AllUniProt

Conditions GCLC is implicated in, by any mechanism.

• Anemia, congenital, non-spherocytic hemolytic, 7 (CNSHA7) MIM:230450

Disease | GeneticClinVar

2 pathogenic / likely-pathogenic of 234 ClinVar records.

Conditions with pathogenic or likely-pathogenic variants.

• Gamma-glutamylcysteine synthetase deficiency

Genetic constraint and essentialitygnomAD · DepMap

Does the body need this protein intact? Low LOEUF or a strong DepMap dependency means loss or blockade of the protein is likely to be felt.

gnomAD LOEUF (loss-of-function intolerance)

0.4

gnomAD pLI

0.43

gnomAD missense Z

2.55

DepMap mean gene effect

-0.07

DepMap dependency class

selective

Cancer expressionTCGA

Across TCGA tumor cohorts, this protein is over-expressed in roughly 5% of surveyed tumor types (aggregate summary; per-cohort expression, alteration, and survival load in the interactive view).

OntologyGO

Biological processes

• blood vessel diameter maintenance
• cell redox homeostasis
• cellular response to fibroblast growth factor stimulus
• cellular response to follicle-stimulating hormone stimulus
• cellular response to glucose stimulus
• cellular response to hepatocyte growth factor stimulus
• cellular response to insulin stimulus
• cellular response to mechanical stimulus
• cellular response to thyroxine stimulus
• cysteine metabolic process
• glutamate metabolic process
• glutathione biosynthetic process
• L-ascorbic acid metabolic process
• negative regulation of apoptotic process
• negative regulation of DNA-templated transcription
• negative regulation of extrinsic apoptotic signaling pathway
• negative regulation of hepatic stellate cell activation
• negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway
• negative regulation of neuron apoptotic process
• negative regulation of protein ubiquitination
• positive regulation of proteasomal ubiquitin-dependent protein catabolic process
• regulation of mitochondrial depolarization
• response to activity
• response to arsenic-containing substance
• response to cadmium ion
• response to heat
• response to hormone
• response to human chorionic gonadotropin
• response to interleukin-1
• response to nitrosative stress
• response to nutrient
• response to oxidative stress
• response to xenobiotic stimulus

Molecular functions

• ADP binding
• ATP binding
• glutamate binding
• glutamate-cysteine ligase activity
• magnesium ion binding
• protein-containing complex binding

Cellular components

• cytosol
• glutamate-cysteine ligase complex
• mitochondrion

Protein domainsUniProt · Pfam · InterPro

• Glutamine synthetase/guanido kinase, catalytic domain
• Glutamate-cysteine ligase catalytic subunit
• Glutamate-cysteine ligase

KeywordsUniProt

• Acetylation
• ATP-binding
• Glutathione biosynthesis
• Hereditary hemolytic anemia
• Ligase
• Nucleotide-binding
• Phosphoprotein

InteractionsUniProt · HPA

Protein binding partners of GCLC in the human serome: UniProt-annotated complex subunits plus reported interactors. Each links to its own Seroatlas record.

• GCLM