Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2028610 | Steroids | 2008 | 12 Pages |
Recent biochemical and clinical evidences unveiled that DHCR24 enzyme (3-β-hydoxysterol-Δ24-reductase, also named seladin-1), which catalyzes the last step of the cholesterol biosynthesis, is implicated in relevant neuroprotective processes by modulating the level of cholesterol in membrane. The present study was undertaken with a view to model the DHCR24 enzyme and its catalytic site, analyzing the substrate recognition at an atomic level. A homology model of the enzyme was obtained based on plant Cytokinin Dehydrogenase, and its active site was found to bind the desmosterol plus a set of post-squalenic intermediates of the cholesterol biosynthesis in a binding mode conducive to catalysis, even if the docking results suggested that the enzyme has a clear preference for the last intermediates of such biosynthetic pathway. Since DHCR24 possesses a putative transmembrane segment, the enzyme was, then, inserted in a suitable membrane model and the membrane-anchored structure in complex with desmosterol and cholesterol underwent 10 ns MD simulations. Such simulations evidenced a clearly different behavior between substrate and product since the product only completely leaves the catalytic cavity whereas desmosterol firmly conserves its pivotal interactions during all simulation time. This is one of the first reports documenting the enzymatic product egress using simple MD simulations in which all atoms are free to move.