gcs-1

UniProt ID: Q20117
Organism: Caenorhabditis elegans
Review Status: COMPLETE
📝 Provide Detailed Feedback

Gene Description

GCS-1 is the C. elegans glutamate-cysteine ligase (gamma-glutamylcysteine synthetase) catalytic subunit, which catalyses the ATP-dependent ligation of L-glutamate and L-cysteine to gamma-glutamylcysteine, the first and rate-limiting step of glutathione biosynthesis. It is predicted to associate with the modifier subunit GCLM-1 (E01A2.1) in a heterodimeric glutamate-cysteine ligase. gcs-1 is a canonical phase II detoxification target of the transcription factor SKN-1: it is expressed constitutively in the ASI neurons and is induced in the intestine by oxidants, arsenite and pathogen-generated reactive oxygen species. Loss of gcs-1 sensitises animals to arsenite and arsenate, a defect rescued by exogenous glutathione, and glutathione made by GCS-1 also supports disulfide reduction of cuticle components during molting.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0000302 response to reactive oxygen species
IEP
PMID:16166371
The C. elegans p38 MAPK pathway regulates nuclear localizati... 		KEEP AS NON CORE
Summary: gcs-1 transcription is induced in intestine via PMK-1/SKN-1 upon oxidative stress.
Reason: Expression-based response annotation. GCS-1 does contribute work to the oxidative stress defence (by making glutathione), but this row records induction; non-core relative to its enzymatic role. Abstract-only cache; deferring to curator.
Supporting Evidence:
PMID:16166371
In response to oxidative stress, PMK-1 phosphorylates SKN-1, leading to its accumulation in intestine nuclei, where SKN-1 activates transcription of gcs-1, a phase II detoxification enzyme gene.
GO:0000302 response to reactive oxygen species
IMP
PMID:23593298
The glutathione reductase GSR-1 determines stress tolerance ... 		KEEP AS NON CORE
Summary: gcs-1(RNAi) animals were tested against pro-oxidants; GCS-1 was required for arsenite tolerance but hardly affected juglone sensitivity.
Reason: The phenotype is specific to arsenite rather than general ROS stress (juglone tolerance largely unaffected), so the term is a broad reading of the data; retained as non-core as GCS-1-derived glutathione does participate in oxidant defence.
Supporting Evidence:
PMID:23593298
Remarkably, protection against this stressor required the presence of the GSH synthesis enzyme gcs-1
PMID:23593298
In contrast to that, RNAi-mediated inhibition of GCS-1 hardly altered the susceptibility to juglone.
GO:0000303 response to superoxide
IEP
PMID:12869585
SKN-1 links C. elegans mesendodermal specification to a cons... 		KEEP AS NON CORE
Summary: SKN-1-dependent induction of gcs-1 in intestine under oxidative stress.
Reason: Expression response; abstract-only cache does not name the oxidant, defer to the curator who read the full text. Non-core.
Supporting Evidence:
PMID:12869585
During postembryonic stages, SKN-1 regulates a key Phase II detoxification gene through constitutive and stress-inducible mechanisms in the ASI chemosensory neurons and intestine, respectively.
GO:0000303 response to superoxide
IEP
PMID:16166371
The C. elegans p38 MAPK pathway regulates nuclear localizati... 		KEEP AS NON CORE
Summary: gcs-1 induction under oxidative stress via PMK-1/SKN-1.
Reason: Expression response annotation; non-core. Abstract-only cache.
Supporting Evidence:
PMID:16166371
In response to oxidative stress, PMK-1 phosphorylates SKN-1, leading to its accumulation in intestine nuclei, where SKN-1 activates transcription of gcs-1, a phase II detoxification enzyme gene.
GO:0003824 catalytic activity
IEA
GO_REF:0000002 		MODIFY
Summary: Generic catalytic activity from InterPro glutamine synthetase-like catalytic domain.
Reason: Too general; GCS-1 is a glutamate-cysteine ligase (EC 6.3.2.2).
Supporting Evidence:
file:worm/gcs-1/gcs-1-uniprot.txt
Reaction=L-cysteine + L-glutamate + ATP = gamma-L-glutamyl-L-cysteine + ADP + phosphate + H(+)
GO:0004357 glutamate-cysteine ligase activity
IBA
GO_REF:0000033 		ACCEPT
Summary: IBA to glutamate-cysteine ligase activity.
Reason: Core enzymatic activity, conserved from yeast to mammals; GCS-1 genetic data and glutathione rescue are consistent.
Supporting Evidence:
PMID:16333752
Gamma-glutamylcysteine synthetase (gamma-GCS) catalyzes the first, rate-limiting step in the biosynthesis of glutathione (GSH).
file:worm/gcs-1/gcs-1-uniprot.txt
Reaction=L-cysteine + L-glutamate + ATP = gamma-L-glutamyl-L-cysteine + ADP + phosphate + H(+)
GO:0004357 glutamate-cysteine ligase activity
IEA
GO_REF:0000120 		ACCEPT
Summary: Automated (InterPro/Rhea/EC) assignment to glutamate-cysteine ligase activity.
Reason: Correct; duplicates the IBA.
Supporting Evidence:
file:worm/gcs-1/gcs-1-uniprot.txt
Reaction=L-cysteine + L-glutamate + ATP = gamma-L-glutamyl-L-cysteine + ADP + phosphate + H(+)
GO:0005515 protein binding
IPI
PMID:14704431
A map of the interactome network of the metazoan C. elegans. 		REMOVE
Summary: Large-scale yeast two-hybrid interaction with E01A2.1 (Q966L2, GCLM-1, the glutamate-cysteine ligase modifier subunit).
Reason: Protein binding is uninformative. The partner is the GCL modifier subunit, so the interaction supports membership of the glutamate-cysteine ligase complex (GO:0017109, already annotated by IBA) rather than a distinct molecular function.
GO:0006750 glutathione biosynthetic process
IBA
GO_REF:0000033 		ACCEPT
Summary: IBA to glutathione biosynthetic process.
Reason: GCS-1 catalyses the first, rate-limiting step.
Supporting Evidence:
PMID:16333752
Gamma-glutamylcysteine synthetase (gamma-GCS) catalyzes the first, rate-limiting step in the biosynthesis of glutathione (GSH).
file:worm/gcs-1/gcs-1-uniprot.txt
PATHWAY: Sulfur metabolism; glutathione biosynthesis; glutathione from L-cysteine and L-glutamate: step 1/2.
GO:0006750 glutathione biosynthetic process
IEA
GO_REF:0000120 		ACCEPT
Summary: Automated assignment to glutathione biosynthetic process.
Reason: Correct.
Supporting Evidence:
file:worm/gcs-1/gcs-1-uniprot.txt
PATHWAY: Sulfur metabolism; glutathione biosynthesis; glutathione from L-cysteine and L-glutamate: step 1/2.
GO:0006750 glutathione biosynthetic process
IMP
PMID:16333752
Caenorhabditis elegans gcs-1 confers resistance to arsenic-i... 		ACCEPT
Summary: gcs-1 mutants are arsenic-hypersensitive and rescued by exogenous GSH.
Reason: Worm genetic evidence that GCS-1 is needed for GSH synthesis.
Supporting Evidence:
PMID:16333752
These results indicate that GCS-1 is essential for the synthesis of intracellular GSH in C. elegans and consequently that the intracellular GSH status plays a critical role in protection of C. elegans from arsenic-induced oxidative stress.
GO:0009408 response to heat
IEP
PMID:12869585
SKN-1 links C. elegans mesendodermal specification to a cons... 		KEEP AS NON CORE
Summary: IEP to response to heat from the SKN-1/gcs-1 reporter study.
Reason: Expression-based; heat induction is not described in the cached abstract, so the curator's full-text reading is deferred to. Peripheral to the enzymatic role.
Supporting Evidence:
PMID:12869585
During postembryonic stages, SKN-1 regulates a key Phase II detoxification gene through constitutive and stress-inducible mechanisms in the ASI chemosensory neurons and intestine, respectively.
GO:0017109 glutamate-cysteine ligase complex
IBA
GO_REF:0000033 		ACCEPT
Summary: IBA placing GCS-1 in the glutamate-cysteine ligase complex.
Reason: C. elegans encodes a GCL modifier subunit (GCLM-1, E01A2.1) that interacts with GCS-1 in the worm interactome, consistent with the conserved heterodimeric holoenzyme.
Supporting Evidence:
file:worm/gcs-1/gcs-1-uniprot.txt
Q20117; Q966L2: E01A2.1; NbExp=2
GO:0046685 response to arsenic-containing substance
IMP
PMID:16333752
Caenorhabditis elegans gcs-1 confers resistance to arsenic-i... 		KEEP AS NON CORE
Summary: gcs-1 mutants are hypersensitive to arsenite and arsenate.
Reason: Well supported (also confirmed by RNAi in PMID:23593298); a physiological output of GSH synthesis, not the core activity.
Supporting Evidence:
PMID:16333752
gcs-1 mutant nematodes are more sensitive to arsenic toxicity than that of wild-type animals
PMID:23593298
Remarkably, protection against this stressor required the presence of the GSH synthesis enzyme gcs-1

Core Functions

Catalytic subunit of glutamate-cysteine ligase, making gamma-glutamylcysteine in the rate-limiting step of glutathione synthesis; a SKN-1-induced phase II gene whose product supports defence against arsenic and oxidants.

Molecular Function:
glutamate-cysteine ligase activity
Directly Involved In:
glutathione biosynthetic process
In Complex:
glutamate-cysteine ligase complex
Supporting Evidence:
  • PMID:16333752
    Gamma-glutamylcysteine synthetase (gamma-GCS) catalyzes the first, rate-limiting step in the biosynthesis of glutathione (GSH).
  • PMID:16333752
    These results indicate that GCS-1 is essential for the synthesis of intracellular GSH in C. elegans and consequently that the intracellular GSH status plays a critical role in protection of C. elegans from arsenic-induced oxidative stress.
  • file:worm/gcs-1/gcs-1-uniprot.txt
    Reaction=L-cysteine + L-glutamate + ATP = gamma-L-glutamyl-L-cysteine + ADP + phosphate + H(+)

References

Loading supporting content…

Download this section (compressed HTML)

Suggested Questions for Experts

Q: Does GCLM-1 modulate GCS-1 kinetics (Km for glutamate, GSH feedback inhibition) as the mammalian modifier subunit does?

Suggested Experiments

Experiment: Recombinant GCS-1 with and without GCLM-1 to measure gamma-glutamylcysteine formation kinetics and GSH feedback inhibition.

Deep Research

WormBase

(gcs-1-deep-research-wormbase.md)

Loading supporting content…

Download this section (compressed HTML)

📚 Additional Documentation

Notes

(gcs-1-notes.md)

Loading supporting content…

Download this section (compressed HTML)

📄 View Raw YAML

Loading supporting content…

Download this section (compressed HTML)