Di Geronimo Bruno, Mandl Špela, Alonso-Gil Santiago, Žagrović Bojan, Reibnegger Gilbert, Nusshold Christoph, Sánchez-Murcia Pedro A
Laboratory of Computer-Aided Molecular Design, Division of Medicinal Chemistry, Otto-Loewi Research Center, Medical University of Graz, Neue Stiftingtalstr. 6/III, A-8010 Graz, Austria.
Max Perutz Labs, Vienna Biocenter Campus (VBC), Campus Vienna Biocenter 5, 1030 Vienna, Austria.
J Chem Inf Model. 2025 Mar 10;65(5):2650-2659. doi: 10.1021/acs.jcim.4c02229. Epub 2025 Feb 20.
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.
人类溶酶体α-甘露糖苷酶（hLAMAN）是一个典型例子，展示了几个错义突变如何严重影响溶酶体中的正常分解代谢，并导致名为α-甘露糖苷贮积症的严重病症。在此，我们通过广泛的量子力学/分子力学元动力学计算，展示了四个已报道的病理性正构和别构单点突变如何改变米氏复合物中的底物褶皱，以及与野生型酶相比，D74E突变如何使限速步骤的能量屏障增加一倍。
