TY - JOUR
T1 - Tracer metabolomics reveals the role of aldose reductase in glycosylation
AU - Radenkovic, Silvia
AU - Ligezka, Anna N.
AU - Mokashi, Sneha S.
AU - Driesen, Karen
AU - Dukes-Rimsky, Lynn
AU - Preston, Graeme
AU - Owuocha, Luckio F.
AU - Sabbagh, Leila
AU - Mousa, Jehan
AU - Lam, Christina
AU - Edmondson, Andrew
AU - Larson, Austin
AU - Schultz, Matthew
AU - Vermeersch, Pieter
AU - Cassiman, David
AU - Witters, Peter
AU - Beamer, Lesa J.
AU - Kozicz, Tamas
AU - Flanagan-Steet, Heather
AU - Ghesquière, Bart
AU - Morava, Eva
N1 - Publisher Copyright:
© 2023 The Author(s)
PY - 2023/6/20
Y1 - 2023/6/20
N2 - 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.
AB - 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.
KW - aldose reductase
KW - aldose reductase inhibition
KW - congenital disorder of glycosylation
KW - glycosylation
KW - phoshomannomutase-2 deficiency
KW - polyol metabolism
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U2 - 10.1016/j.xcrm.2023.101056
DO - 10.1016/j.xcrm.2023.101056
M3 - Article
C2 - 37257447
AN - SCOPUS:85162138860
SN - 2666-3791
VL - 4
JO - Cell Reports Medicine
JF - Cell Reports Medicine
IS - 6
M1 - 101056
ER -