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Open AccessArticle

β-Glucose-1,6-Bisphosphate Stabilizes Pathological Phophomannomutase2 Mutants In Vitro and Represents a Lead Compound to Develop Pharmacological Chaperones for the Most Common Disorder of Glycosylation, PMM2-CDG

1
Dipartimento di Biologia, Università Federico II, 80126 Napoli, Italy
2
Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Università degli Studi della Campania “Luigi Vanvitelli”, 81100 Caserta, Italy
3
Istituto di Chimica Biomolecolare—CNR, 80078 Pozzuoli, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(17), 4164; https://doi.org/10.3390/ijms20174164
Received: 15 July 2019 / Revised: 13 August 2019 / Accepted: 22 August 2019 / Published: 26 August 2019
(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies (II))
A large number of mutations causing PMM2-CDG, which is the most frequent disorder of glycosylation, destabilize phosphomannomutase2. We looked for a pharmacological chaperone to cure PMM2-CDG, starting from the structure of a natural ligand of phosphomannomutase2, α-glucose-1,6-bisphosphate. The compound, β-glucose-1,6-bisphosphate, was synthesized and characterized via 31P-NMR. β-glucose-1,6-bisphosphate binds its target enzyme in silico. The binding induces a large conformational change that was predicted by the program PELE and validated in vitro by limited proteolysis. The ability of the compound to stabilize wild type phosphomannomutase2, as well as frequently encountered pathogenic mutants, was measured using thermal shift assay. β-glucose-1,6-bisphosphate is relatively resistant to the enzyme that specifically hydrolyses natural esose-bisphosphates. View Full-Text
Keywords: PMM2-CDG; pharmacological chaperone; glucose-1,6-bisphosphate PMM2-CDG; pharmacological chaperone; glucose-1,6-bisphosphate
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Monticelli, M.; Liguori, L.; Allocca, M.; Andreotti, G.; Cubellis, M.V. β-Glucose-1,6-Bisphosphate Stabilizes Pathological Phophomannomutase2 Mutants In Vitro and Represents a Lead Compound to Develop Pharmacological Chaperones for the Most Common Disorder of Glycosylation, PMM2-CDG. Int. J. Mol. Sci. 2019, 20, 4164.

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