Elucidation of the glycosylation steps during biosynthesis of antitumor macrolides PM100117 and PM100118 and engineering for novel derivatives

Raúl García Salcedo, Carlos Olano, Rogelio Fernández, Alfredo F. Braña, Carmen Méndez, Fernando de la Calle, José A. Salas

Antitumor compounds PM100117 and PM100118 are glycosylated polyketides derived from the marine actinobacteria Streptomyces caniferus GUA-06-05-006A. The organization and characterization of the PM100117/18 biosynthesis gene cluster has been recently reported. Based on the preceding information and new genetic engineering data, we have outlined the pathway by which PM100117/18 are glycosylated. Furthermore, these genetic engineering experiments have allowed the generation of novel PM100117/18 analogues. Deletion of putative glycosyltranferase genes and additional genes presumably involved in late biosynthesis steps of the three 2,6-dideoxysugars appended to the PM100117/18 polyketide skeleton, resulted in the generation of a series of intermediates and novel derivatives. Isolation and identification of the novel compounds constitutes an important contribution to our knowledge on PM100117/18 glycosylation, and set the basis for further characterization of specific enzymatic reactions, additional genetic engineering and combinatorial biosynthesis approaches.