A novel lysophosphatidylcholine acyl transferase activity is expressed by peroxiredoxin 6

Abstract

as short chain hydroperoxides) using GSH as an electron donor and for hydrolysis of phospholipids; i.e., it exhibits both GSH peroxidase (GPx) and phospholipase A 2 (PLA 2 ) activities ( 1 ). These activities require the binding of Prdx6 to phospholipids in a specifi c orientation in relation to cys47, the active site for GPx activity, and to S32-H26-D140, the catalytic triad for PLA 2 activity ( 2, 3 ). The GPx activity of Prdx6 plays a key role in the antioxidant defense of the lung, as well as other organs ( 4-8 ), and has been shown recently to participate in the repair of peroxidized cell membranes by reduction of phospholipid hydroperoxides ( 3, 9 ). The PLA 2 activity of Prdx6 also participates in the repair of peroxidized cell membranes by liberating the sn -2 oxidized fatty acid to generate lysophosphatidylcholine (LPC) ( 9, 10 ). Additionally, the PLA 2 activity participates in the turnover of lung surfactant phospholipids with a major function in phospholipid remodeling to generate the dipalmitoylphosphatidylcholine (DPPC) that is the surface-active lipid component of the lung surfactant (11)(12)(13)(14)(15). Both the repair of peroxidized cell membrane phospholipids and a pathway for DPPC synthesis require the combined activity of PLA 2 followed by a LPC acyl transferase (LPCAT) activity in order to either regenerate a reduced membrane phospholipid or to remodel phosphatidylcholine (PC) to produce DPPC . This pathway that combines PLA 2 activity followed by LPCAT activity has been designated as the remodeling pathway for PC synthesis (Lands cycle) ( 16 ).These metabolic functions of PLA 2 that are associated with phospholipid turnover and membrane repair are clearly compartmentalized within cells. While DPPC synthesis via the de novo (Kennedy) pathway occurs in the Peroxiredoxin (Prdx)6 is a 1-cys member of the Prdx family that has the unique combination of activities for both reduction of phospholipid hydroperoxides (as well

The phospholipase A2 activity of peroxiredoxin 6 [S]

“…These effects, discussed in detail below, include alterations of lung phospholipid turnover, altered cell membrane repair in oxidative stress, and failure of NADPH oxidase (NOX2) activation. Specificity for the role of the PLA 2 activity of Prdx6 in the altered physiology has been confirmed by specific mutation of the PLA 2 active site in Prdx6 (2,10,(54)(55)(56).…”

“… D31A---mutation abolishes LPCAT activity but there is no effect on aiPLA 2 or peroxidase activities (10).…”

“… S32A or H26A-these mutations prevent binding of the protein to phospholipids, thereby abolishing PLA 2 (and phospholipid hydroperoxide peroxidase) activities; peroxidase activity with small peroxides such as H 2 O 2 is unaffected (6,10,55).…”

“…i.e.,phospholipase A 2 activity (PLA 2 ) (4, 9); and c) transfer a fatty acyl CoA into the sn-2 position of lysophosphatidylcholine (LPC), i.e., LPC acyl transferase (LPCAT) activity (10).…”

Peroxiredoxin 6 in the repair of peroxidized cell membranes and cell signaling

“…Prdx6 also demonstrates a third distinct activity, namely the ability to acylate lysophosphatidylcholine with a free fatty acid (CoA derivative); this activity is called lysoPC-acyl CoA transferase (LPCAT) [84]. Prdx6 exhibits one of the motifs, 26 HxxxxD 31 , that characterize LPCAT activity [85,86] (Fig.…”