Reversible dissociation of gamma-glutamylcysteine synthetase into two subunits.

Seelig, G F; Simondsen, R P; Meister, Alton

doi:10.1016/s0021-9258(17)42703-7

Cited by 196 publications

(24 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, in HeLa cells, overexpression of the ␥-GCS-LS alone appears to be sufficient to increase ␥-GCS activity and GSH levels (48), suggesting a role for both subunits in GSH synthesis. For rat or human ␥-GCS, about 30%-70% is stabilized by an intersubunit disulfide bond as well as noncovalent bonds (49). The formation of this intersubunit disulfide bond may be regulated by cellular redox status as influenced by depletion or repletion of GSH (50).…”

Section: Discussionmentioning

confidence: 99%

OxLDL induces macrophage γ-GCS-HS protein expression: a role for oxLDL-associated lipid hydroperoxide in GSH synthesis

Shen

Sevanian

2001

Journal of Lipid Research

View full text Add to dashboard Cite

Oxidized LDL (oxLDL) produced a rapid depletion of intracellular glutathione (GSH) followed by an adaptive increase in J774 A.1 macrophages. OxLDL also induced a transient increase in the levels of ␥ -glutamylcysteine synthetase heavy subunit ( ␥ -GCS-HS), representing the catalytic subunit of the rate-limiting enzyme for de novo GSH synthesis. The induction took place within 3 h, with maximum levels observed by 10 h of treatment. Pretreatment of oxLDL with ebselen inhibited GSH depletion and attenuated the ␥ -GCS-HS induction. OxLDL-associated lipid hydroperoxides and their decomposition product aldehydes are two major components thought to account for GSH depletion in macrophages. Ebselen pretreatment had only a

show abstract

Section: Discussionmentioning

confidence: 99%

OxLDL induces macrophage γ-GCS-HS protein expression: a role for oxLDL-associated lipid hydroperoxide in GSH synthesis

Shen

Sevanian

2001

Journal of Lipid Research

View full text Add to dashboard Cite

show abstract

“…GCL is comprised of both a catalytic (GCLc) and a modulatory (GCLm) subunit. GCLc is responsible for all of the enzyme activity of GCL, which is regulated via feedback inhibition by GSH [ 32 ]. Most GSH is present in the cytoplasm, where it is synthesized in mammalian cells [ 33 ].…”

Section: Oxidative Stress In the Brainmentioning

confidence: 99%

Glutathione in the Brain

Aoyama

2021

IJMS

204

View full text Add to dashboard Cite

Glutathione (GSH) is the most abundant non-protein thiol, and plays crucial roles in the antioxidant defense system and the maintenance of redox homeostasis in neurons. GSH depletion in the brain is a common finding in patients with neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, and can cause neurodegeneration prior to disease onset. Excitatory amino acid carrier 1 (EAAC1), a sodium-dependent glutamate/cysteine transporter that is selectively present in neurons, plays a central role in the regulation of neuronal GSH production. The expression of EAAC1 is posttranslationally controlled by the glutamate transporter-associated protein 3–18 (GTRAP3-18) or miR-96-5p in neurons. The regulatory mechanism of neuronal GSH production mediated by EAAC1 may be a new target in therapeutic strategies for these neurodegenerative diseases. This review describes the regulatory mechanism of neuronal GSH production and its potential therapeutic application in the treatment of neurodegenerative diseases.

show abstract

“…The GCL holoenzyme consists of two separate proteins, a catalytic subunit (GCLC) and a modifier subunit (GCLM) ( Krejsa et al, 2010 ), which are encoded by different genes in humans. GCLC exhibits catalytic activity ( Seelig et al, 1984 ; Lu, 2009 ) and GCLM is enzymatically inactive but plays an important regulatory role by lowering the Km of GCL for glutamate and raising the Ki for GSH ( Huang et al, 1993a , b ). GSH synthesis pathway is severely activated by some stimuli including oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

CREB1 and ATF1 Negatively Regulate Glutathione Biosynthesis Sensitizing Cells to Oxidative Stress

Zhao

Xia

Jiang

2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The cAMP response element binding protein (CREB) family activating transcription factor 1 (ATF1) and cAMP response element binding protein 1 (CREB1) have been reported in a diverse group of tumors, however, the mechanistic basis for this remains unclear. Here we found that CREB1 and ATF1 unexpectedly regulate glutathione (GSH) biosynthesis by suppressing the expression of glutamate-cysteine ligase modifier subunit (GCLM) and glutathione synthase (GSS), two key enzymes of GSH biosynthesis pathway. Mechanistic studies reveal that GCLM and GSS are direct transcriptional targets of CREB1 and ATF1. Through repressing the expression of these two enzymes, CREB1 and ATF1 reduce the GSH biosynthesis and the capability of cells to detoxicate reactive oxygen species (ROS), thereby increasing cellular susceptibility to oxidative stress. Therefore, our findings link CREB1 family to cellular metabolism, and uncover a potential therapeutic approach by targeting GCLM or oxidative stress for the treatment of tumors with relatively high expression of CREB1 family proteins.

show abstract

Reversible dissociation of gamma-glutamylcysteine synthetase into two subunits.

Cited by 196 publications

References 15 publications

OxLDL induces macrophage γ-GCS-HS protein expression: a role for oxLDL-associated lipid hydroperoxide in GSH synthesis

OxLDL induces macrophage γ-GCS-HS protein expression: a role for oxLDL-associated lipid hydroperoxide in GSH synthesis

Glutathione in the Brain

CREB1 and ATF1 Negatively Regulate Glutathione Biosynthesis Sensitizing Cells to Oxidative Stress

Contact Info

Product

Resources

About