A stable GH31 α-glucosidase as a model system for the study of mutations leading to human glycogen storage disease type II
GH31 glycosidases are widespread across organisms, but remarkably, less than 1% of them have been biochemically characterised to date. Among them, human lysosomal acid α-glucosidase (GAA) stands out due to its link to Pompe disease, a rare lysosomal storage disorder caused by its deficiency. This di...
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Taylor & Francis Group
2025-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2025.2468859 |
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| author | Roberta Iacono Francesca Maria Pia Paragliola Andrea Strazzulli Marco Moracci |
| author_facet | Roberta Iacono Francesca Maria Pia Paragliola Andrea Strazzulli Marco Moracci |
| author_sort | Roberta Iacono |
| collection | DOAJ |
| description | GH31 glycosidases are widespread across organisms, but remarkably, less than 1% of them have been biochemically characterised to date. Among them, human lysosomal acid α-glucosidase (GAA) stands out due to its link to Pompe disease, a rare lysosomal storage disorder caused by its deficiency. This disease results in glycogen accumulation, severe cellular damage, motor impairment, and premature death. Structural and functional studies of GAA mutants are challenging due to their instability and lack of activity, hindering their expression and purification. The GH31 enzyme MalA from a hyperthermophilic archaeon is explored here as a stable homolog of GAA. MalA is highly expressible, easy to purify, and structurally characterised. The R400H mutant in MalA, corresponding to the pathogenic GAA R600H mutation, revealed here a 1200-fold drop in specificity constant and >8 °C reduction in thermal stability. We propose MalA’s as a robust model for studying GAA mutations and developing therapeutic chaperones. |
| format | Article |
| id | doaj-art-37c1ba31559242339bb114e3e7eeecfa |
| institution | OA Journals |
| issn | 1475-6366 1475-6374 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
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| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj-art-37c1ba31559242339bb114e3e7eeecfa2025-08-20T01:56:41ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742025-12-0140110.1080/14756366.2025.2468859A stable GH31 α-glucosidase as a model system for the study of mutations leading to human glycogen storage disease type IIRoberta Iacono0Francesca Maria Pia Paragliola1Andrea Strazzulli2Marco Moracci3Department of Biology, University of Naples “Federico II”, Naples, ItalyDepartment of Biology, University of Naples “Federico II”, Naples, ItalyDepartment of Biology, University of Naples “Federico II”, Naples, ItalyDepartment of Biology, University of Naples “Federico II”, Naples, ItalyGH31 glycosidases are widespread across organisms, but remarkably, less than 1% of them have been biochemically characterised to date. Among them, human lysosomal acid α-glucosidase (GAA) stands out due to its link to Pompe disease, a rare lysosomal storage disorder caused by its deficiency. This disease results in glycogen accumulation, severe cellular damage, motor impairment, and premature death. Structural and functional studies of GAA mutants are challenging due to their instability and lack of activity, hindering their expression and purification. The GH31 enzyme MalA from a hyperthermophilic archaeon is explored here as a stable homolog of GAA. MalA is highly expressible, easy to purify, and structurally characterised. The R400H mutant in MalA, corresponding to the pathogenic GAA R600H mutation, revealed here a 1200-fold drop in specificity constant and >8 °C reduction in thermal stability. We propose MalA’s as a robust model for studying GAA mutations and developing therapeutic chaperones.https://www.tandfonline.com/doi/10.1080/14756366.2025.2468859Pompe diseaseextremozymesenzymatic modelpharmacological chaperon therapy |
| spellingShingle | Roberta Iacono Francesca Maria Pia Paragliola Andrea Strazzulli Marco Moracci A stable GH31 α-glucosidase as a model system for the study of mutations leading to human glycogen storage disease type II Journal of Enzyme Inhibition and Medicinal Chemistry Pompe disease extremozymes enzymatic model pharmacological chaperon therapy |
| title | A stable GH31 α-glucosidase as a model system for the study of mutations leading to human glycogen storage disease type II |
| title_full | A stable GH31 α-glucosidase as a model system for the study of mutations leading to human glycogen storage disease type II |
| title_fullStr | A stable GH31 α-glucosidase as a model system for the study of mutations leading to human glycogen storage disease type II |
| title_full_unstemmed | A stable GH31 α-glucosidase as a model system for the study of mutations leading to human glycogen storage disease type II |
| title_short | A stable GH31 α-glucosidase as a model system for the study of mutations leading to human glycogen storage disease type II |
| title_sort | stable gh31 α glucosidase as a model system for the study of mutations leading to human glycogen storage disease type ii |
| topic | Pompe disease extremozymes enzymatic model pharmacological chaperon therapy |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2025.2468859 |
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