Peroxiredoxin6 in Endothelial Signaling

Abstract

Peroxiredoxins (Prdx) are a ubiquitous family of highly conserved antioxidant enzymes with a cysteine residue that participate in the reduction of peroxides. This family comprises members Prdx1–6, of which Peroxiredoxin 6 (Prdx6) is unique in that it is multifunctional with the ability to neutralize peroxides (peroxidase activity) and to produce reactive oxygen species (ROS) via its phospholipase (PLA2) activity that drives assembly of NADPH oxidase (NOX2). From the crystal structure, a C47 residue is responsible for peroxidase activity while a catalytic triad (S32, H26, and D140) has been identified as the active site for its PLA2 activity. This paradox of being an antioxidant as well as an oxidant generator implies that Prdx6 is a regulator of cellular redox equilibrium (graphical abstract). It also indicates that a fine-tuned regulation of Prdx6 expression and activity is crucial to cellular homeostasis. This is specifically important in the endothelium, where ROS production and signaling are critical players in inflammation, injury, and repair, that collectively signal the onset of vascular diseases. Here we review the role of Prdx6 as a regulator of redox signaling, specifically in the endothelium and in mediating various pathologies.

Peroxiredoxin 6 mediates protective function of astrocytes in Aβ proteostasis

“…PRDX6 also is widely recognized for cellular signaling owing to its PLA 2 activity, and this functionality is triggered by various cellular stressors requiring oxidative, inflammatory, and mechanical stress response [5,7]. PRDX6/PLA 2 activity can engage several signaling pathways including down-stream activation of NADPH oxidase 2 (NOX2), which is a member of the NOX/DuOX enzyme family generating O 2…”

“…PRDX6 is a dual function enzyme with independent glutathione peroxidase (Gpx) and phospholipase A2 (PLA 2 ) activities, which is highly expressed by several cell lineages outside the CNS including alveolar epithelium, endothelium, and macrophages [5]. The PLA 2 activity distinguishes PRDX6 from other peroxiredoxins and enables replacement of peroxidatively damaged cell membrane lipids, and cellular signaling [6,7]. In the CNS, PRDX6 is expressed by astrocytes but no other type of glial cells [8,9] and its exact function remains largely unexplored.…”

Proteome characteristics of liver tissue from patients with parenteral nutrition-associated liver disease

“…Second, various antioxidant factors are downregulated in PNALD. For example, peroxiredoxin-6 (PRDX6, downregulated) is a peroxiredoxin that primarily functions as an antioxidant to scavenge peroxides in biological systems [38], regucalcin (RGN, downregulated) is an antioxidant [39], delta-aminolevulinic acid dehydratase (ALAD, downregulated) is an important antioxidant enzyme, whose inhibition may result in the accumulation of its substrate d-ALA, which in turn is associated with the overproduction of ROS [40], inhibition of PHGDH (downregulated) impairs the synthesis of heme, resulting in the impairment of oxidative phosphorylation and escape of electrons to molecular oxygen generating more ROS [41], inhibition of aspartate aminotransferase (GOT1, downregulated) inhibits the synthesis of the NADPH antioxidan t [42], and DDAH1 (downregulated) deficiency significantly enhances cellular oxidative stress [43]. , Third, we found histidine metabolism-associated proteins (AMDHD1, HNMT, FTCD, HAL, and UROC1) to be downregulated in PNALD.…”

Proteome Characteristics of Liver Tissue from Patients with Parenteral Nutrition-Associated Liver Disease

“…Second, various antioxidant factors are downregulated in PNALD. For example, peroxiredoxin-6 (PRDX6, downregulated) is a peroxiredoxin that primarily functions as an antioxidant to scavenge peroxides in biological systems [38], regucalcin (RGN, downregulated) is an antioxidant [39], delta-aminolevulinic acid dehydratase (ALAD, downregulated) is an important antioxidant enzyme, whose inhibition may result in the accumulation of its substrate d-ALA, which in turn is associated with the overproduction of ROS [40], inhibition of PHGDH (downregulated) impairs the synthesis of heme, resulting in the impairment of oxidative phosphorylation and escape of electrons to molecular oxygen generating more ROS [41], inhibition of aspartate aminotransferase (GOT1, downregulated) inhibits the synthesis of the NADPH antioxidant [42], and DDAH1 (downregulated) deficiency significantly enhances cellular oxidative stress [43]. Third, we found histidine metabolismassociated proteins (AMDHD1, HNMT, FTCD, HAL, and UROC1) to be downregulated in PNALD.…”