Literature summary for 1.11.1.12 extracted from

Corteselli, E.M.; Gibbs-Flournoy, E.; Simmons, S.O.; Bromberg, P.; Gold, A.; Samet, J.M.
Long chain lipid hydroperoxides increase the glutathione redox potential through glutathione peroxidase 4 (2019), Biochim. Biophys. Acta, 1863, 950-959 .

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Activating Compound

Activating Compound	Comment	Organism	Structure
9-hydroperoxy-10E,12Z-octadecadienoic acid	9-HpODE, induces a dose-dependent intracellular increase in GSH oxidation that is independent of intracellular H2O2 production and is mediated by glutathione peroxidase 4 (GPx4) in BEAS-2B cells. Glucose deprivation potentiates the oxidative effect of 9-HpODE on GSH and inhibits its recovery	Homo sapiens

Cloned(Commentary)

Cloned (Comment)	Organism
recombinant enzyme expression in HEK-293T cells	Homo sapiens

Protein Variants

Protein Variants	Comment	Organism
additional information	enzyme silencing of glutathione peroxidase 4 by shRNA hairpin oligonucleotides, designed by selecting an 18-nt site from the human GPx4 complete mRNA (NCBI Accession: BC046163.1) optimized for siRNA targeting of GPx4 mRNA (S080) or a random 18-nt sequence (scramble) with no predicted homology to human genomic or transcript sequences. The cloning strategy nests the shRNA fragments between 5' and 3' miRNA30 adaptors within the 3' untranslated region of a polycistronic red fluorescent protein reporter gene under the control of a CMV promoter. Stable expression of the GPx4 knockdown, and stable expression of genetically encoded fluorescent reporters attained via lentiviral transduction of BEAS-2B cells. Lentivirus encoding roGFP2 or HyPer is incubated for 4 hr with wild-type BEAS-2B cells in keratinocyte basal media (KBM) using a multiplicity of infection of 2-5	Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
2 glutathione + a hydroperoxy-fatty-acyl-[lipid]	Homo sapiens	-	glutathione disulfide + a hydroxy-fatty-acyl-[lipid] + H2O	-	?

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	P36969	-	-

Purification (Commentary)

Purification (Comment)	Organism
recombinant enzyme partially from HEK-293T cells by ultrafiltration	Homo sapiens

Source Tissue

Source Tissue	Comment	Organism	Textmining
BEAS-2B cell	subclone s6, SV40 large T antigen-transformed human airway epithelial cells	Homo sapiens	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
2 glutathione + a hydroperoxy-fatty-acyl-[lipid]	-	Homo sapiens	glutathione disulfide + a hydroxy-fatty-acyl-[lipid] + H2O	-	?
additional information	different isomers of the hydroperoxide hydroperoxy-octadecadienoic acid (HpODE) are formed depending on whether linoleic acid is subjected to enzymatic, free radical, or non-radical attack	Homo sapiens	?	-	-

Synonyms

Synonyms	Comment	Organism
glutathione peroxidase 4	-	Homo sapiens
GPx4	-	Homo sapiens

General Information

General Information	Comment	Organism
metabolism	glutathione (GSH) is the most abundant intracellular antioxidant, with millimolar concentrations present in the cytosol of most cell types. The ratio of oxidized (GSSG) to reduced glutathione, which defines the glutathione redox potential (EGSH) in the Nernst equation, is an important indicator of overall cellular oxidative state. Under homeostatic conditions, the EGSH reflects a ratio of GSH:GSSG of 100:1. roGFP is a genetically encoded fluorogenic sensor that has been used in a variety of cell types for real-time assessments of the EGSH. roGFP has been shown to equilibrate with EGSH through a redox relay that is initiated by hydrogen peroxide (H2O2) and involves the participation of the enzymes GPx, glutaredoxin (Grx), and glutathione reductase (GR)	Homo sapiens
physiological function	linoleic acid is present in the surfactant lining the airway epithelium, where it is a target of lipid peroxidation by oxidizing air pollutants such as ozone. 9-hydroperoxy-10E,12Z-octadecadienoic acid (9-HpODE) is a product of linoleic acid peroxidation that can be generated enzymatically or via radical or non-radical mediated oxidation. Exposure of human airway epithelial cells (HAEC) to 9-HpODE results in an alteration of intracellular EGSH. Enzyme glutathione peroxidase 4, GPx4, is involved in the initiation of GSH oxidation in human aortic endothelial cells (HAEC) by 9-hydroperoxy-10E,12Z-octadecadienoic acid (9-HpODE), but not in GSH oxidation induction by H2O2 or the low molecular weight alkyl tert-butyl hydroperoxide (TBH). 9-Hydroperoxy-10E,12Z-octadecadienoic acid (9-HpODE) is a product of linoleic acid peroxidation that can be generated enzymatically or via radical or non-radical mediated oxidation. Long chain lipid hydroperoxides can directly alter cytosolic EGSH independent of secondary lipid oxidation products or H2O2 production. NADPH has a protective role against 9-HpODE induced EGSH changes. GPx4 is involved specifically in the reduction of long-chain lipid hydroperoxides, leading to GSH oxidation. The same concentration of 9-hydroxy-10E,12Z-octadecadienoic acid (9-HODE), the reduced product of 9-HpODE, does not result in GSH oxidation, as reported by roGFP, over the same period. Exposure to 9-HpODE causes a dose-dependent increase in GSH oxidation in HAEC that is independent of intracellular or extracellular H2O2 production and is exacerbated by NADPH depletion	Homo sapiens

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Release 2023.1 (January 2023)