Abstract
The cleavage of the magnesium-assisted diphosphate group (the PPi group) is one significant and prevalent rate-limiting step triggering the enzyme catalysis synthesis of terpenoid natural products. However, the PPi cleavage procedure has been rarely studied in most theoretical research of the terpenoid biosynthetic mechanism. In this work, QM(DFT)/MM MD simulations were employed to illuminate the detailed PPi cleavage mechanism in three different enzyme systems (ATAS, TEAS, and FPPS). We found that the most rational protonation state of the PPi group is highly dependent on the Mg2+ coordination modes and the enzyme classes. The deprotonation of PPi is favorable for triggering the catalysis reaction in ATAS, while monoprotonation in FPPS and biprotonation in TEAS are advantageous. As a result, similar PPi cleavage occurs by means of nucleophilic substitution reactions in TEAS/FPPS/ATAS but presents an SN1, SN2, and borderline mechanism, respectively. Finally, the alternative functions of PPi protonation an...
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