Digging out the Molecular Connections between the Catalytic Mechanism of Human Lysosomal α-Mannosidase and Its Pathophysiology
Human lysosomal α-mannosidase (hLAMAN) is a paradigmatic example of how a few missense mutations can critically affect normal catabolism in the lysosome and cause the severe condition named α-mannosidosis. Here, using extensive quantum mechanical/molecular mechanical metadynamics calculations, we show how four reported pathological orthosteric and allosteric single-point mutations alter substrate puckering in the Michaelis complex and how the D74E mutation doubles the energy barrier of the rate-limiting step compared to the wild-type enzyme.
Authors
- Christoph Nusshold
- Gilbert Reibnegger (ORCID: https://orcid.org/0000-0001-7202-2426)
- Pedro A. Sánchez‐Murcia (ORCID: https://orcid.org/0000-0001-8415-870X)
- Bruno Di Geronimo (ORCID: https://orcid.org/0000-0003-1822-7142)
- Santiago Alonso‐Gil (ORCID: https://orcid.org/0000-0001-7596-8161)
- Bojan Žagrović (ORCID: https://orcid.org/0000-0003-3814-3675)
- Špela Mandl
Institutions
- University of Vienna (AT)
- Medical University of Graz (AT)
- Max Perutz Labs (AT)
- BioTechMed-Graz (AT)
- Vienna Biocenter (AT)
Publication Details
- Journal
- Journal of Chemical Information and Modeling
- Published
- 2025-02-20
- DOI
- https://doi.org/10.1021/acs.jcim.4c02229
- Citations
- 1
- Primary Topic
- Calcium signaling and nucleotide metabolism
- Type
- article
- Field-Weighted Citation Impact
- 1.12
Funders
- Fundación Alfonso Martín Escudero
- Austrian Science Fund
- Medizinische Universität Graz
- H2020 Marie Skłodowska-Curie Actions