PMM2-CDG, a disease caused by mutations in phosphomannomutase-2, is the most common congenital disorder of glycosylation. Yet, it still lacks a cure. Targeting phosphomannomutase-2 with pharmacological chaperones or inhibiting the phosphatase activity of phosphomannomutase-1 to enhance intracellular glucose-1,6-bisphosphate have been proposed as therapeutical approaches. We used Recombinant Bacterial Thermal Shift Assay to assess the binding of a substrate analog to phosphomannomutase-2 and the specific binding to phosphomannomutase-1 of an FDA-approved drug - clodronate. We also deepened the clodronate binding by enzyme activity assays and in silico docking. Our results confirmed the selective binding of clodronate to phosphomannomutase-1 and shed light on such binding.

Exploring ligand interactions with human phosphomannomutases using recombinant bacterial thermal shift assay and biochemical validation / Monticelli, Maria; Hay Mele, Bruno; Wright, Demi Marie; Guerriero, Simone; Andreotti, Giuseppina; Cubellis, Maria Vittoria. - In: BIOCHIMIE. - ISSN 0300-9084. - (2024). [10.1016/j.biochi.2024.02.011]

Exploring ligand interactions with human phosphomannomutases using recombinant bacterial thermal shift assay and biochemical validation

Hay Mele, Bruno
Secondo
;
Cubellis, Maria Vittoria
Ultimo
2024

Abstract

PMM2-CDG, a disease caused by mutations in phosphomannomutase-2, is the most common congenital disorder of glycosylation. Yet, it still lacks a cure. Targeting phosphomannomutase-2 with pharmacological chaperones or inhibiting the phosphatase activity of phosphomannomutase-1 to enhance intracellular glucose-1,6-bisphosphate have been proposed as therapeutical approaches. We used Recombinant Bacterial Thermal Shift Assay to assess the binding of a substrate analog to phosphomannomutase-2 and the specific binding to phosphomannomutase-1 of an FDA-approved drug - clodronate. We also deepened the clodronate binding by enzyme activity assays and in silico docking. Our results confirmed the selective binding of clodronate to phosphomannomutase-1 and shed light on such binding.
2024
Exploring ligand interactions with human phosphomannomutases using recombinant bacterial thermal shift assay and biochemical validation / Monticelli, Maria; Hay Mele, Bruno; Wright, Demi Marie; Guerriero, Simone; Andreotti, Giuseppina; Cubellis, Maria Vittoria. - In: BIOCHIMIE. - ISSN 0300-9084. - (2024). [10.1016/j.biochi.2024.02.011]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/954865
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