Tracer metabolomics reveals the role of aldose reductase in glycosylation.
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ABSTRACT:
SUBMITTER: Radenkovic S
PROVIDER: S-EPMC10313913 | biostudies-literature | 2023 Jun
REPOSITORIES: biostudies-literature
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Tracer metabolomics reveals the role of aldose reductase in glycosylation.
Radenkovic Silvia S Ligezka Anna N AN Mokashi Sneha S SS Driesen Karen K Dukes-Rimsky Lynn L Preston Graeme G Owuocha Luckio F LF Sabbagh Leila L Mousa Jehan J Lam Christina C Edmondson Andrew A Larson Austin A Schultz Matthew M Vermeersch Pieter P Cassiman David D Witters Peter P Beamer Lesa J LJ Kozicz Tamas T Flanagan-Steet Heather H Ghesquière Bart B Morava Eva E
Cell reports. Medicine 20230530 6
Abnormal polyol metabolism is predominantly associated with diabetes, where excess glucose is converted to sorbitol by aldose reductase (AR). Recently, abnormal polyol metabolism has been implicated in phosphomannomutase 2 congenital disorder of glycosylation (PMM2-CDG) and an AR inhibitor, epalrestat, proposed as a potential therapy. Considering that the PMM2 enzyme is not directly involved in polyol metabolism, the increased polyol production and epalrestat's therapeutic mechanism in PMM2-CDG ...[more]
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Project description: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 mum. 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.
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