Monticelli Maria, Paris Debora, Monti Maria Chiara, Morretta Elva, Pakanova Zuzana, Nemcovic Marek, Kodrikova Rebeka, Cubellis Maria Vittoria, Andreotti Giuseppina
Institute of Biomolecular Chemistry, National Research Council of Italy, Comprensorio Olivetti, via Campi Flegrei 34, 80078 Pozzuoli, Italy; Dept. Biology, University of Napoli "Federico II", Complesso Universitario Monte Sant'Angelo, via Cinthia, 80126 Naples, Italy.
Institute of Biomolecular Chemistry, National Research Council of Italy, Comprensorio Olivetti, via Campi Flegrei 34, 80078 Pozzuoli, Italy.
Biochim Biophys Acta Mol Cell Res. 2025 Jun;1872(5):119948. doi: 10.1016/j.bbamcr.2025.119948. Epub 2025 Mar 30.
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.
代谢物葡萄糖-1,6-二磷酸（Glc-1,6-P）在人体新陈代谢中起着至关重要的作用，是磷酸甘露糖变位酶-2（PMM2）的关键激活剂和稳定剂——该蛋白内的突变会引发最常见的糖基化先天性疾病（PMM2-CDG）。在体内，Glc-1,6-P在肌苷单磷酸（IMP）的影响下，主要在大脑中被磷酸甘露糖变位酶-1（PMM1）水解。在本研究中，我们在源自PMM2患者的成纤维细胞中敲除PMM1，并研究了表型改善情况。糖基化分析证实，Glc-1,6-P增加与糖基化增强相关。先前确定的PMM2-CDG生物标志物，如LAMP1、PTX3和溶酶体酶显示出经验性改善——代谢组学和蛋白质组学分析证实了这些发现。此外，我们的结果支持了Glc-1,6-P调节对PMM2-CDG的潜力，为药物发现带来了新的视角。
