Phospholipid Hydroxyperoxide Glutathione Peroxidase

Phospholipid Hydroxyperoxide Glutathione Peroxidase
	Existing structural data : 2gs3 , 2obi
Properties of human protein
Mass / length primary structure	<198 amino acids
Secondary to quaternary structure	Monomer
Cofactor	selenium
Isoforms	Cyt., With., Nucl.
Identifier
Gene name	GPX4
External IDs	OMIM : 138322 ; UniProt : P36969 ;
Enzyme classification
EC, category	1.11.1.12 , oxidoreductase
Substrate	Glutathione + lipid hydroperoxide
Products	Glutathione disulfide + lipid + H 2 O
Occurrence
Homology family	Glutathione peroxidase
Parent taxon	Creature
	Orthologue

The phospholipid-hydroxyperoxide-glutathione-peroxidase (PHGPx) ( gene : GPX4 ) is one of four known glutathione peroxidases which, as part of the antioxidant protection system, degrades the complex hydroperoxides that can arise through the action of free radicals . PHGPx is produced in all chordates and occurs in several tissue types in humans, but especially in the testes. Three isoforms , which are localized in the cytosol , in the mitochondria and in the cell nucleus , are known. Embryos without PHGPx die, and mutations in GPX4 can cause male infertility.

In mice, the tissue types with the highest expression of PHGPx are, in order, testes, heart, brain, small intestine, stomach, liver, duodenum, epididymis. In humans this is not yet well known.

function

PHGPx catalyzes the oxidation of glutathione by lipid hydroperoxides. This reaction step makes the reactive (and therefore dangerous) peroxide harmless, but reduces the reductive pool that has to be replenished by glutathione reductase . PHGPx is indispensable for the development of neurons in the embryo, but also after traumatic brain injury. Mice producing only half of PHGPx (heterozygous knockout) were more sensitive to oxidative stress, but lived longer.

In addition to its enzyme function, PHGPx has functions as a structural protein in sperm.

The expression of PHGPx is upregulated by C / EBPε, induced by TNFα . PHGPx has a self-inhibiting effect on NF-κB activation and at several points in prostaglandin synthesis .

history

The enzyme was discovered in 1982 by Fulvio Ursini and Mathilde Maiorino from the University of Padua . Genetic studies by Regina Brigelius-Flohé in Potsdam ( DIfE ) provided evidence in 1993 that it is an independent enzyme .

Individual evidence

↑ UniProt P36969
↑ ^a ^b Savaskan NE, Ufer C, Kühn H, Borchert A: Molecular biology of glutathione peroxidase 4: from genomic structure to developmental expression and neural function . In: Biol. Chem. . 388, No. 10, October 2007, pp. 1007-17. doi : 10.1515 / BC.2007.126 . PMID 17937614 .
↑ ^a ^b Brigelius-Flohé R: Glutathione peroxidases and redox-regulated transcription factors . In: Biol. Chem. . 387, No. 10-11, 2006, pp. 1329-35. doi : 10.1515 / BC.2006.166 . PMID 17081103 .
↑ Baek IJ, Seo DS, Yon JM, et al : Tissue expression and cellular localization of phospholipid hydroperoxide glutathione peroxidase (PHGPx) mRNA in male mice . In: J. Mol. Histol. . 38, No. 3, June 2007, pp. 237-44. doi : 10.1007 / s10735-007-9092-7 . PMID 17503194 .
^ Conrad M, Schneider M, Seiler A, Bornkamm GW: Physiological role of phospholipid hydroperoxide glutathione peroxidase in mammals . In: Biol. Chem. . 388, No. 10, October 2007, pp. 1019-25. doi : 10.1515 / BC.2007.130 . PMID 17937615 .
↑ Ran Q, Liang H, Ikeno Y, et al : Reduction in glutathione peroxidase 4 increases life span through increased sensitivity to apoptosis . In: J. Gerontol. A Biol. Sci. Med. Sci. . 62, No. 9, September 2007, pp. 932-42. PMID 17895430 .
↑ Suzuki-Toyota F, Ito C, Toyama Y, et al : Factors maintaining normal sperm tail structure during epididymal maturation studied in Gopc - / - mice . In: Biol. Reprod. . 77, No. 1, July 2007, pp. 71-82. doi : 10.1095 / biolreprod.106.058735 . PMID 17360959 .
↑ Hattori H, Imai H, Kirai N, et al : Identification of a responsible promoter region and a key transcription factor, CCAAT / enhancer-binding protein epsilon, for up-regulation of PHGPx in HL60 cells stimulated with TNF alpha . In: Biochem. J. . 408, No. 2, December 2007, pp. 277-86. doi : 10.1042 / BJ20070245 . PMID 17688422 . PMC 2267347 (free full text).

[1] UniProt P36969

[r1-2] Savaskan NE, Ufer C, Kühn H, Borchert A: Molecular biology of glutathione peroxidase 4: from genomic structure to developmental expression and neural function . In: Biol. Chem. . 388, No. 10, October 2007, pp. 1007-17. doi : 10.1515 / BC.2007.126 . PMID 17937614 .

[r2-3] Brigelius-Flohé R: Glutathione peroxidases and redox-regulated transcription factors . In: Biol. Chem. . 387, No. 10-11, 2006, pp. 1329-35. doi : 10.1515 / BC.2006.166 . PMID 17081103 .

[4] Baek IJ, Seo DS, Yon JM, et al : Tissue expression and cellular localization of phospholipid hydroperoxide glutathione peroxidase (PHGPx) mRNA in male mice . In: J. Mol. Histol. . 38, No. 3, June 2007, pp. 237-44. doi : 10.1007 / s10735-007-9092-7 . PMID 17503194 .

[5] Conrad M, Schneider M, Seiler A, Bornkamm GW: Physiological role of phospholipid hydroperoxide glutathione peroxidase in mammals . In: Biol. Chem. . 388, No. 10, October 2007, pp. 1019-25. doi : 10.1515 / BC.2007.130 . PMID 17937615 .

[6] Ran Q, Liang H, Ikeno Y, et al : Reduction in glutathione peroxidase 4 increases life span through increased sensitivity to apoptosis . In: J. Gerontol. A Biol. Sci. Med. Sci. . 62, No. 9, September 2007, pp. 932-42. PMID 17895430 .

[7] Suzuki-Toyota F, Ito C, Toyama Y, et al : Factors maintaining normal sperm tail structure during epididymal maturation studied in Gopc - / - mice . In: Biol. Reprod. . 77, No. 1, July 2007, pp. 71-82. doi : 10.1095 / biolreprod.106.058735 . PMID 17360959 .

[8] Hattori H, Imai H, Kirai N, et al : Identification of a responsible promoter region and a key transcription factor, CCAAT / enhancer-binding protein epsilon, for up-regulation of PHGPx in HL60 cells stimulated with TNF alpha . In: Biochem. J. . 408, No. 2, December 2007, pp. 277-86. doi : 10.1042 / BJ20070245 . PMID 17688422 . PMC 2267347 (free full text).