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SHR Neuro Cancer Cardio Lipid Metab Microb

Di, Geronimo, B; Mandl, Š; Alonso-Gil, S; Žagrović, B; Reibnegger, G; Nusshold, C; Sánchez-Murcia, PA.
Digging out the Molecular Connections between the Catalytic Mechanism of Human Lysosomal α-Mannosidase and Its Pathophysiology.
J Chem Inf Model. 2025; Doi: 10.1021/acs.jcim.4c02229 [OPEN ACCESS]
Web of Science PubMed FullText FullText_MUG

Leading authors Med Uni Graz: Di Geronimo Quintero Bruno; Sánchez Murcia Pedro Alejandro
Co-authors Med Uni Graz: Mandl Spela; Nusshold Christoph; Reibnegger Gilbert
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Abstract:: 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.