Generation of hybrid elloramycin analogs by combinatorial biosynthesis using genes from anthracycline-type and macrolide biosynthetic pathways.
Elloramycin and oleandomycin are two polyketide compounds produced by Streptomyces olivaceus Tü2353 and Streptomyces antibioticus ATCC11891, respectively. Elloramycin is an anthracycline-like antitumor drug and oleandomycin a macrolide antibiotic. Expression in S. albus of a cosmid (cos16F4) containing part of the elloramycin biosynthetic gene cluster produced the elloramycin non-glycosylated intermediate 8-demethyl-tetracenomycin C. Several plasmid constructs harboring different gene combinations of L-oleandrose (neutral 2,6-dideoxyhexose attached to the macrolide antibiotic oleandomycin) biosynthetic genes of S. antibioticus that direct the biosynthesis of L-olivose, L-oleandrose and L-rhamnose were coexpressed with cos16F4 in S. albus. Three new hybrid elloramycin analogs were produced by these recombinant strains through combinatorial biosynthesis, containing elloramycinone or 12a-demethyl-elloramycinone (= 8-demethyl-tetracenomycin C) as aglycone moiety encoded by S. olivaceus genes and different sugar moieties, coded by the S. antibioticus genes. Among them is L-olivose, which is here described for the first time as a sugar moiety of a natural product.
Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain.
L
L
Rodriguez
C
C
Oelkers
I
I
Aguirrezabalaga
A F
AF
Braña
J
J
Rohr
C
C
Méndez
J A
JA
Salas
D018943:Anthracyclines / Q000378:metabolism; D000880:Anthraquinones / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D003837:Deoxy Sugars / Q000737:chemistry / Q000378:metabolism*; D006031:Glycosylation; D016695:Glycosyltransferases / Q000235:genetics / Q000378:metabolism; D018942:Macrolides / Q000378:metabolism; D009279:Naphthacenes / Q000737:chemistry / Q000378:metabolism; D009827:Oleandomycin / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism
D018943:Anthracyclines; D000880:Anthraquinones; D003837:Deoxy Sugars; D018942:Macrolides; D009279:Naphthacenes; C020938:tetracenomycin C; C047329:elloramycin; D016695:Glycosyltransferases; D009827:Oleandomycin