engleski

Molecular biology of polyketide biosynthesis

Streptomyces species and related genera synthesize a large number of secondary metabolites many of which are biologically active. Among them polyketides are the largest class. Polyketides are a structurally diverse family of natural products with a broad range of biological activities and pharmacological properties. Polyketide antibiotics, antifungals, antiparasitics, animal growth promotants, natural insecticides, cytostatics, immunosuppressants and anticholesterolemics are in com-mercial use. The evidences accumulated up till now have indicated a substantial analogy between the formation of long chain fatty acids and biosynthesis of polyketides carried out by Type I and Type II polyketide synthases (Hopwood, Chem. Rev., 97, 2465, 1997). During the last decade many polyketide gene-clusters have been cloned and sequenced. DNA sequencing showed considerable DNA homology hence they originated from the same ancestor. This allowed the use of combinatorial biology in creation of novel chemical entities. Combinatorial biology aims to create biodiversity by engineering the way the natural molecules are formed to generate "natural" substances that Nature never imagined. In principal, two approaches have been used: targeted manipulation (e.g. disruption and replacement of certain genes involved in the biosynthetic pathway ; McDaniel et al., Proc. Natl. Acad. Sci. USA, 96, 1846, 1999) and random approach (e.g. gene shuffling technology ; Del Cardayre et al., WO 00/4190). In PLIVA, the targeted approach that generated several novel scaffolds by the manipu-lation of the S. rimosus oxytetreacycline gene-cluster has been used (Petković et al., J. Biol. Chem., 274, 32829, 1999 ; Perić et al., P-990153A). In this talk the latest data from this field will be presented.

Streptomyces; polyketides; polyketide biosynthesis; combinatorial biology

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