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


RESULTS
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.


CONCLUSIONS
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.
Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, Asturias, 33006, Oviedo, Spain.
Raúl García
RG
Salcedo
Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, Asturias, 33006, Oviedo, Spain.
Carlos
C
Olano
Drug Discovery Area, PharmaMar S.A., Avda. de los Reyes, Colmenar Viejo, 128770, Madrid, Spain.
Rogelio
R
Fernández
Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, Asturias, 33006, Oviedo, Spain.
Alfredo F
AF
Braña
Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, Asturias, 33006, Oviedo, Spain.
Carmen
C
Méndez
Drug Discovery Area, PharmaMar S.A., Avda. de los Reyes, Colmenar Viejo, 128770, Madrid, Spain.
Fernando
F
de la Calle
Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, Asturias, 33006, Oviedo, Spain. jasalas@uniovi.es.
José A
JA
Salas
D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D017353:Gene Deletion; D005818:Genetic Engineering / Q000379:methods*; D006031:Glycosylation; D016695:Glycosyltransferases / Q000235:genetics / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D018942:Macrolides / Q000378:metabolism* / Q000494:pharmacology; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D018942:Macrolides; C000614291:PM100117; C000614292:PM100118; D016695:Glycosyltransferases
Antitumor; Deoxysugar; Glycosyltranferase; Structural analogue