Aldose Reductase-catalyzed Reduction of Aldehyde Phospholipids

Abstract

Oxidation of unsaturated phospholipids results in the generation of aldehyde side chains that remain esterified to the phospholipid backbone. Such "core" aldehydes elicit immune responses and promote inflammation. However, the biochemical mechanisms by which phospholipid aldehydes are metabolized or detoxified are not well understood. In the studies reported here, we examined whether aldose reductase (AR), which reduces hydrophobic aldehydes, metabolizes phospholipid aldehydes. Incubation with AR led to the reduction of 5-oxovaleroyl, 7-oxo-5-heptenoyl, 5-hydroxy-6-oxo-caproyl, and 5-hydroxy-8-oxo-6-octenoyl phospholipids generated upon oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PAPC). The enzyme also catalyzed the reduction of phospholipid aldehydes generated from the oxidation of 1-alkyl, and 1-alkenyl analogs of PAPC, and 1-palmitoyl-2-arachidonoyl phosphatidic acid or phosphoglycerol. Aldose reductase catalyzed the reduction of chemically synthesized 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphatidylcholine (POVPC) with a K m of 10 M. Addition of POVPC to the culture medium led to incorporation and reduction of the aldehyde in COS-7 and THP-1 cells. Reduction of POVPC in these cells was prevented by the AR inhibitors sorbinil and tolrestat and was increased in COS-7 cells overexpressing AR. Together, these observations suggest that AR may be a significant participant in the metabolism of several structurally diverse phospholipid aldehydes. This metabolism may be a critical regulator of the pro-inflammatory and immunogenic effects of oxidized phospholipids.

Autoimmunity in Membranous Nephropathy Targets Aldose Reductase and SOD2

“…17 The enzyme also catalyzes the transformation of aldehydes, generated upon oxidation of unsaturated fatty acids. 18 Localization of AR within the normal kidney is limited to tubular epithelial cells of the medulla, and it is absent in normal glomeruli. 19,20 SOD2 is a crucial component of the extensive antioxidant cell protective system, transforming toxic superoxide ions into H 2 O 2 and diatomic oxygen.…”

Reductive metabolism increases the proinflammatory activity of aldehyde phospholipids

“…Solvents and other analytical grade reagents were obtained from Sigma Chemical Co. (St. Louis, MO). POVPC, PHVPC, POVPE [1-palmitoyl-2-(5 ′ -oxo-valeroyl)-sn -glycero-3-phosphoethanolamine], and PHVPE [1-palmitoyl-2-(5 ′ -hydroxy-valeroyl)-sn -glycero-3-phosphoethanolamine] were synthesized as described previously ( 17 ). Purity of the phospholipid aldehydes was established by ESI + /MS.…”

“…Nevertheless, it is not known whether metabolism via AR regulates the biological activity of phospholipid aldehydes. Accordingly, the current study was designed to develop a better under-oligo(dT) [12][13][14][15][16][17][18] primers and AMV Reverse Transcriptase. qRT PCR were performed in iCycler equipment (Bio-Rad) using SYBR Green detection.…”

“…For synthesizing 14 C-POVPC, 4-bromo-1-1-dimethoxy butane (0.45 mmol) was stirred with 0.5 mmol C-5,5-dimethoxy pentanoic acid was confi rmed by NMR spectroscopy. The 14 C-5,5-dimethoxypentanoic acid was coupled with lyso-phosphatidylcholine (lyso-PC) to obtain 14 C-POVPC acetal as described previously ( 15,17 ). Prior to use the 14 C-POVPC acetal was hydrolyzed by amberlite-15 (in acetone:water; 6:1 v/v) to yield 14 C-POVPC.…”

Selective Enzymatic Reduction of Aldehydes

“…in the reduction of ketones [2][3][4][5]. In contrast, there are few examples where an enzymatic reaction has been applied to selectively reduce aldehydes.…”