Fungal indole prenyltransferases are important enzymes involved in the  biosynthesis of a range of prenylated indole derivatives. FtmPT1 is a typical fungal indole prenyltransferase that prenylates Brevianamide F to form the antitumor agent Tryprostatin B. Interestingly, a single point mutation, Gly 115 to Thr, leads to a new cyclized product, which shows the potential for FtmPT1 to be modified to synthesize novel prenylated products. We describe quantum mechanical and molecular mechanical (QM/MM) MD studies, which match the experimental energy barriers, and we show that the prenyl transfer reaction follows a SN1 reaction pathway for both the wild type and mutant enzymes. The rate-determining step is the formation of the carbocation from dimethylallyl diphosphate. The intermediate carbocation and its local environment then determine the final selection of the prenylation product. The proton transfer step, which completes the reaction, is facile and involves the transfer of the proton to an active site water followed by transfer to Glu 102. For the wild type enzyme a direct proton transfer step is followed, while for the G115T mutated enzyme, ring formation along with a proton transfer occurs simultaneously.

Quantum mechanics and molecular dynamics studies on the indole prenyltransferase FtmPT1

246th National Meeting (2013)

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