Digging out theMolecular Connections between theCatalytic Mechanism of Human Lysosomal α‑Mannosidaseand 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.