Beneficial effects of Glc-1,6-P modulation on mutant phosphomannomutase-2.

The metabolite Glucose-1,6-bisphosphate (Glc-1,6-P) plays a vital role in human metabolism, and is a crucial activator and stabilizer for phosphomannomutase-2 (PMM2) - mutations within this protein propagate the most common congenital disorder of glycosylation (PMM2-CDG). In vivo, Glc-1,6-P is hydrolysed by phosphomannomutase-1 (PMM1), predominantly in the brain, under the influence of inosine monophosphate (IMP). In the present study, we employed knock-out PMM1 in PMM2 patient-derived fibroblasts and investigated the phenotypic improvement. Increased Glc-1,6-P was associated with glycosylation enhancement, confirmed by glycan profiling. Previously identified PMM2-CDG biomarkers, such as LAMP1, PTX3 and lysosomal enzymes showed empirical imrovement- these findings were corroborated by metabolomic and proteomic analysis. Moreover, our results support the potential of Glc-1,6-P modulation for PMM2-CDG, potentiating novel perspectives in drug discovery.