The phospholipase A2 activity of peroxiredoxin 6 [S]

Abstract

Peroxiredoxin 6 (Prdx6) is a Ca 2+ -independent intracellular phospholipase A 2 (called aiPLA 2 )that is localized to cytosol, lysosomes, and lysosomal-related organelles. Activity is minimal at cytosolic pH but is increased significantly with enzyme phosphorylation, at acidic pH, and in the presence of oxidized phospholipid substrate; maximal activity with phosphorylated aiPLA 2 is ~2 µmol/min/mg protein. Prdx6 is a "moonlighting" protein that also expresses glutathione peroxidase and lysophosphatidylcholine acyl transferase activities.The catalytic site for aiPLA 2 activity is an S32-H26-D140 triad; S32-H26 is also the phospholipid binding site. Activity is inhibited by a serine "protease" inhibitor (diethyl p-nitrophenyl phosphate),an analogue of the PLA 2 transition state (1-hexadecyl-3-(trifluoroethyl)-sn-glycero-2-phosphomethanol, MJ33), and by two naturally occurring proteins (surfactant protein A and p67 phox ), but not by bromoenol lactone. aiPLA 2 activity has important physiological roles in the turnover (synthesis and degradation) of lung surfactant phospholipids, in the repair of peroxidized cell membranes, and in the activation of NADPH oxidase (NOX2). The enzyme has been implicated in acute lung injury, carcinogenesis, neurodegenerative diseases, diabetes, male infertility, and sundry other conditions although its specific roles have not been well defined. Protein mutations and animal models are now available to further investigate the roles of Prdx6-aiPLA 2 activity in normal and pathological physiology.

Updating Phospholipase A2 Biology

“…The aiPLA 2 activity of Prdx6 has important physiological roles in the turnover (synthesis and degradation) of lung surfactant phospholipids [ 196 ], protection against LPS-induced lung injury [ 197 ], repair of peroxidized cell membranes [ 198 ], and sperm fertilizing competence [ 199 ]. The properties and functions of LPLA 2 and Prdx6/aiPLA 2 have been summarized in recent reviews [ 200 , 201 ].…”

Ginkgolic Acid Rescues Lens Epithelial Cells from Injury Caused by Redox Regulated-Aberrant Sumoylation Signaling by Reviving Prdx6 and Sp1 Expression and Activities

“…Prdx6 is a unique member of the Prdx family, as it contains glutathione (GSH) peroxidase and calcium independent phospholipase A 2 (PLA 2 ) activities, and multifunctional proteins. [ 34 , 35 , 36 , 37 ]. Prdx6 is widely expressed throughout all organs with especially high concentrations in the eye lens, lung, brain, liver, kidney and testis [ 12 , 34 , 38 ], wherein Prdx6 maintains cellular homeostasis by maintaining ROS levels.…”

Regulation of Prdx6 by Nrf-2 is mediated through aiPLA2 in white matter reperfusion injury

“…Furthermore, the role of aiPLA2 activity of Prdx6 in white matter reperfusion injury was investigated by inhibiting it with a serine "protease" inhibitor, MJ33 [39]. Previous reports suggested important physiological roles of aiPLA2 activity in the turnover of phospholipids, repair of peroxidized cell membranes, and activation of NOX2 (NADPH oxidase 2) [40]. We observed inhibition of hypoxia-induced upregulation of Prdx6 after MJ33 treatment, whereas expression of Prdx6 in reperfusion injury remains upregulated (Fig.…”

“…activity. In fact, aiPLA2 activity with oxidized substrates is similar at acidic and neutral pH [40], which suggests the role of this enzyme in the repair of peroxidized cell membranes. Nrf2 protein expression shows a similar pattern as observed with Prdx6 protein after MJ33 treatment ( Fig.…”

“…These results could be attributed to the differential activity of aiPLA2 at different pH levels. In basal conditions (sham), a major fraction of intracellular Prdx6 is localized to the cytosol where the neutral pH supports neither aiPLA2 binding to membranes nor its enzymatic activity [40,41]. Under acidic conditions (hypoxia), aiPLA2 activity increased by increased binding of Prdx6 to phospholipids.…”