RGD Reference Report - Differential regulation of glutamate-cysteine ligase subunit expression and increased holoenzyme formation in response to cysteine deprivation. - Rat Genome Database

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Differential regulation of glutamate-cysteine ligase subunit expression and increased holoenzyme formation in response to cysteine deprivation.

Authors: Lee, JI  Kang, J  Stipanuk, MH 
Citation: Lee JI, etal., Biochem J. 2006 Jan 1;393(Pt 1):181-90.
RGD ID: 1582663
Pubmed: PMID:16137247   (View Abstract at PubMed)
PMCID: PMC1383676   (View Article at PubMed Central)
DOI: DOI:10.1042/BJ20051111   (Journal Full-text)

GCL (glutamate-cysteine ligase) is a heterodimer of a GCLC (GCL catalytic subunit) that possesses all of the enzymatic activity and a GCLM (GCL modifier subunit) that alters the K(i) of GCLC for GSH. We hypothesized that the expression of GCLM and the association of GCLM with GCLC were responsible for the apparent increase in GCL activity state observed in the liver of rats fed low-protein diets or in hepatocytes cultured in low-sulphur amino acid-containing medium. Therefore we conducted a series of studies using rats and a human hepatoma (HepG2/C3A) cell line to assess the role of GCLM and holoenzyme formation in the regulation of GCL activity in response to sulphur amino acid intake or availability. Increases in GCL activity in rat liver, as well as in HepG2 cells, were due to the additive effects of changes in the amount of GCLC and the kcat for GCLC. The increase in the kcat for GCLC was associated with increased holoenzyme formation, which was associated with an increase in the molar ratio of GCLM to GCLC. Furthermore, our results indicate that the GCLM level in rat liver is always limiting and that up-regulation of the GCLM level results in increased holoenzyme formation and an increase in the kcat. This is the first report demonstrating that the catalytic efficiency of rat GCL is increased by holoenzyme formation and the first demonstration of differential up-regulation of the GCL subunits in response to cysteine deprivation.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
GclmRatpositive regulation of glutamate-cysteine ligase activity  IDA  RGD 

Cellular Component

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
GclcRatglutamate-cysteine ligase complex  IDA  RGD 
GclmRatglutamate-cysteine ligase complex  IDA  RGD 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
GclmRatglutamate-cysteine ligase catalytic subunit binding  IDA  RGD 
GclcRatprotein-containing complex binding  IDA heterodimerizationRGD 
GclmRatprotein-containing complex binding  IDA heterodimerizationRGD 

Molecular Pathway Annotations    Click to see Annotation Detail View

RGD Manual Annotations


  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
GclcRatglutathione metabolic pathway  IDA  RGD 
GclmRatglutathione metabolic pathway  IDA  RGD 
Objects Annotated

Genes (Rattus norvegicus)
Gclc  (glutamate-cysteine ligase, catalytic subunit)
Gclm  (glutamate cysteine ligase, modifier subunit)


Additional Information