PUBLICATION
Tracer metabolomics reveals the role of aldose reductase in glycosylation
- Authors
- Radenkovic, S., Ligezka, A.N., Mokashi, S.S., Driesen, K., Dukes-Rimsky, L., Preston, G., Owuocha, L.F., Sabbagh, L., Mousa, J., Lam, C., Edmondson, A., Larson, A., Schultz, M., Vermeersch, P., Cassiman, D., Witters, P., Beamer, L.J., Kozicz, T., Flanagan-Steet, H., Ghesquière, B., Morava, E.
- ID
- ZDB-PUB-230601-39
- Date
- 2023
- Source
- Cell reports. Medicine 4(6): 101056 (Journal)
- Registered Authors
- Flanagan-Steet, Heather
- Keywords
- aldose reductase, aldose reductase inhibition, congenital disorder of glycosylation, glycosylation, phoshomannomutase-2 deficiency, polyol metabolism
- MeSH Terms
-
- Aldehyde Reductase*/genetics
- Aldehyde Reductase*/metabolism
- Animals
- Glycosylation
- Mannose/metabolism
- Metabolomics
- Zebrafish*/metabolism
- PubMed
- 37257447 Full text @ Cell Rep Med
Citation
Radenkovic, S., Ligezka, A.N., Mokashi, S.S., Driesen, K., Dukes-Rimsky, L., Preston, G., Owuocha, L.F., Sabbagh, L., Mousa, J., Lam, C., Edmondson, A., Larson, A., Schultz, M., Vermeersch, P., Cassiman, D., Witters, P., Beamer, L.J., Kozicz, T., Flanagan-Steet, H., Ghesquière, B., Morava, E. (2023) Tracer metabolomics reveals the role of aldose reductase in glycosylation. Cell reports. Medicine. 4(6):101056.
Abstract
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 remained elusive. PMM2-CDG, caused by PMM2 deficiency, presents with depleted GDP-mannose and abnormal glycosylation. Here, we show that, apart from glycosylation abnormalities, PMM2 deficiency affects intracellular glucose flux, resulting in polyol increase. Targeting AR with epalrestat decreases polyols and increases GDP-mannose both in patient-derived fibroblasts and in pmm2 mutant zebrafish. Using tracer studies, we demonstrate that AR inhibition diverts glucose flux away from polyol production toward the synthesis of sugar nucleotides, and ultimately glycosylation. Finally, PMM2-CDG individuals treated with epalrestat show a clinical and biochemical improvement.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping