Beneficial effects of Glc-1,6-P2 modulation on mutant phosphomannomutase-2
The metabolite Glucose-1,6-bisphosphate (Glc-1,6-P<sub>2</sub>) 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<sub>2</sub> 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 <sup>Arg141His/Phe119Leu</sup>PMM2 patient-derived fibroblasts and investigated the phenotypic improvement. Increased Glc-1,6-P<sub>2</sub> 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<sub>2</sub> modulation for PMM2-CDG, potentiating novel perspectives in drug discovery.
Authors
- Maria Vittoria Cubellis (ORCID: https://orcid.org/0000-0001-6147-6553)
- Marek Nemčovič (ORCID: https://orcid.org/0000-0002-1702-4952)
- Maria Chiara Monti (ORCID: https://orcid.org/0000-0002-1337-2909)
- Debora Paris (ORCID: https://orcid.org/0000-0003-4526-8353)
- Giuseppina Andreotti (ORCID: https://orcid.org/0000-0002-1594-0156)
- Rebeka Kodríková (ORCID: https://orcid.org/0000-0002-3342-3486)
- Maria Monticelli (ORCID: https://orcid.org/0000-0003-3136-2138)
- Elva Morretta (ORCID: https://orcid.org/0000-0002-7244-0297)
- Zuzana Pakanová (ORCID: https://orcid.org/0000-0001-5422-7110)
Institutions
- Institute of Chemistry of the Slovak Academy of Sciences (SK)
- Slovak Academy of Sciences (SK)
- Istituto Nazionale di Fisica Nucleare, Sezione di Napoli (IT)
- Federico II University Hospital (IT)
- Institute for Complex Systems (IT)
- National Research Council (IT)
- University of Naples Federico II (IT)
Publication Details
- Journal
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
- Published
- 2025-04-01
- DOI
- https://doi.org/10.1016/j.bbamcr.2025.119948
- Citations
- 1
- Primary Topic
- Glycosylation and Glycoproteins Research
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Slovenská Akadémia Vied
- European Commission
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Consiglio Nazionale delle Ricerche
- Ministero dell'Università e della Ricerca