Application of the C3-Methyltransferase StspM1 for the Synthesis of the Natural Pyrroloindole Motif

Even though pyrroloindoles are widely present in
natural products with different kinds of biological activities, their
selective synthesis remains challenging with existing tools in organic
chemistry, and there is furthermore a demand for stereoselective and
mild methods to access this structural motif. Nature uses C3-methyltransferases
to form the pyrroloindole framework, starting from the amino acid
tryptophan. In the present study, the SAM-dependent methyltransferase
StspM1 from Streptomyces sp. HPH0547 is used to build
the pyrroloindole structural motif in tryptophan-based diketopiperazines
(DKP). The substrate scope of the enzyme regarding different Trp-Trp-DKP
isomers was investigated on an experimental and computational level.
After further characterization and optimization of the methylation
reaction with a design of experiment approach, a preparative scale
reaction with the immobilized enzyme including a SAM regeneration
system was performed to show the synthetic use of this biocatalytic
tool to access the pyrroloindole structural motif.