Rearrangements in the mechanisms of the indole alkaloid prenyltransferases

The indole prenyltransferases are a family of metal-independent enzymes that catalyze the transfer of a prenyl group from dimethylallyl diphosphate (DMAPP) onto the indole ring of a tryptophan residue. These enzymes are remarkable in their ability to direct the prenyl group in either a “normal” or “reverse” fashion to positions with markedly different nucleophilicity. The enzyme 4-dimethylallyltryptophan synthase (4-DMATS) prenylates the non-nucleophilic C-4 position of the indole ring in free tryptophan. Evidence is presented in support of a mechanism that involves initial ion pair formation followed by a reverse prenylation at the nucleophilic C-3 position. A Cope rearrangement then generates the C-4 normal prenylated intermediate and deprotonation rearomatizes the indole ring. The enzyme tryprostatin B synthase (FtmPT1) catalyzes the normal C-2 prenylation of the indole ring in brevianamide F (cyclo-L-Trp-L-Pro). It shares high structural homology with 4-DMATS, and evidence is presented in favor of an initial C-3 prenylation (either normal or reverse) followed by carbocation rearrangements to give product. The concept of a common intermediate that partitions to different products via rearrangements can help to explain how these evolutionarily related enzymes can prenylate different positions on the indole ring.