A Streptomyces Cytochrome P450 Enzyme Catalyzes Regiospecific C2-Guaninylation for the Synthesis of Diverse Guanitrypmycin Analogs

Heterologous expression of a cdps-p450 locus from Streptomyces sp. NRRL S-1521 led to the identification of guanitrypmycin D1, a new guaninylated diketopiperazine. The cytochrome P450 GutD1521 catalyzed the regiospecific transfer of guanine to C-2 of the indole ring of cyclo-(l-Trp-l-Tyr) via a C–C linkage and represents a new chemical transformation within this enzyme class. Furthermore, GutD1521 efficiently accepts several other tryptophan-containing cyclodipeptides or derivatives for regiospecific coupling with guanine, thus generating different guanitrypmycin analogs.