Peroxiredoxin 6: A Bifunctional Enzyme with Glutathione Peroxidase and Phospholipase A₂Activities

Abstract

Peroxiredoxin 6 (Prdx6) is the prototype and the only mammalian 1-Cys member of the Prdx family. Major differences from 2-Cys Prdxs include the use of glutathione (GSH) instead of thioredoxin as the physiological reductant, heterodimerization with pGSH S-transferase as part of the catalytic cycle, and the ability either to reduce the oxidized sn-2 fatty acyl group of phospholipids (peroxidase activity) or to hydrolyze the sn-2 ester (alkyl) bond of phospholipids (phospholipase A 2 [PLA 2 ] activity). The bifunctional protein has separate active sites for peroxidase (C47, R132, H39) and PLA 2 (S32, D140, H26) activities. These activities are dependent on binding of the protein to phospholipids at acidic pH and to oxidized phospholipids at cytosolic pH. Prdx6 can be phosphorylated by MAP kinases at T177, which markedly increases its PLA 2 activity and broadens its pH-activity spectrum. Prdx6 is primarily cytosolic but also is targeted to acidic organelles (lysosomes, lamellar bodies) by a specific targeting sequence (amino acids 31-40). Oxidant stress and keratinocyte growth factor are potent regulators of Prdx6 gene expression. Prdx6 has important roles in both antioxidant defense based on its ability to reduce peroxidized membrane phospholipids and in phospholipid homeostasis based on its ability to generate lysophospholipid substrate for the remodeling pathway of phospholipid synthesis. Antioxid. Redox Signal. 15, 831-844.

2D-DIGE to identify proteins associated with gestational diabetes in omental adipose tissue

“…Removal of ROS by antioxidant enzymes plays an important part in limiting this damage, and indeed, antioxidants can prevent diabetic embryopathy in rat models of diabetes in pregnancy (Higa et al 2012). PRX6 is a cytosolic peroxidase (Fisher 2011) that has been demonstrated to protect various tissues, such as skin, lung and cardiac muscle, against acute oxidative insults, and that has been shown to be down-regulated in diabetes (Johnson et al 2009). HSPs are molecular chaperones that are classified into families according to their molecular weight (Ellis 1999, Hwang et al 2009.…”

Identification and Characterization of Alternatively Transcribed Form of Peroxiredoxin IV Gene That Is Specifically Expressed in Spermatids of Postpubertal Mouse Testis

“…Members of the peroxiredoxin (Prx) 3 family of peroxidases are present in all organisms and reduce peroxides with a catalytic cysteine (Cys) residue serving as the site of oxidation by peroxides (1). Six mammalian Prx isoforms (Prx I-VI) have been identified to date and can be divided into three subgroups: typical 2-Cys (Prx I-IV), atypical 2-Cys (Prx V), and 1-Cys (Prx VI) subgroups (1)(2)(3).…”

“…Six mammalian Prx isoforms (Prx I-VI) have been identified to date and can be divided into three subgroups: typical 2-Cys (Prx I-IV), atypical 2-Cys (Prx V), and 1-Cys (Prx VI) subgroups (1)(2)(3). The 2-Cys Prx enzymes exist as homodimers and possess two conserved Cys residues.…”

The serpentine path to a novel mechanism-based inhibitor of acute inflammatory lung injury

“…Six mammalian peroxiredoxins have been described. Prdx6 has some unique properties compared with the other five (26,69). It is the only 1-cys Prdx6, it uses GSH rather than thioredoxin as the physiological reductant, and it is the only member of the family with PLA 2 activity.…”

“…We have carried out extensive studies of Prdx6 binding to phospholipids and determined that this feature can account for the unique Prdx6 activities (26,58,59). Site-directed amino (59).…”