INVESTIGATION ON THE SQUALENE CYCLASE ON THE BASES OF ORGANIC CHEMISTRY AND MOLECULAR BIOLOGY

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This investigation was carried out to gain insight into the squalene cyclization mechanism by using the substrate analogs and by site-directed mutagenesis experiments. We established the initiation site of the cyclization and the stabilization sites as follows. The amino acid alignment of DXDDTA motif, the acidity being enhanced by His 451, is responsible for the initiation and Phe365, Phe601 and Phe605 residues stabilize the cationic intermediates. Incubation experiments of 10-desmethylsqualene analog showed the methyl group at 10-position is most critical to the completion of squalene cyclization.