Terpene cyclases are responsible for the initial cyclization cascade in the multistep synthesis of a large number of terpenes. CotB2 is a diterpene cyclase from Streptomyces melanosporofaciens, which synthesizes the formation of cyclooctat-9-en-7-ol, a precursor to the next-generation anti-inflammatory drug, cyclooctatin. In this work, we present evidence for a significant role of the active site residues in CotB2 on the reaction energetics using quantum mechanics calculations in an active site cluster model. The results using the active site model reveal the significant effect of the active site residues on the relative electronic energy of the intermediates and transition state (TS) structures with respect to gas phase data. A detailed understanding of the role of the enzyme environment on the CotB2 reaction cascade can provide important information towards a biosynthetic strategy for cyclooctatin and the biomanufacturing of related terpene structures.
Keywords: Diterpene; quantum mechanics; CotB2 cyclase; mechanism; active site
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Raz, K.; Driller, R.; Brück, T.; Loll, B.; Major, D. T. Beilstein Arch. 2019, 2019108. doi:10.3762/bxiv.2019.108.v1
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