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| - Molecular Analysis of the Benastatin Biosynthetic Pathwayand Genetic Engineering of Altered Fatty Acid−PolyketideHybrids
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| - The entire gene locus encoding the biosynthesis of the potent glutathione-S-transferase inhibitorsand apoptosis inducers benastatin A and B has been cloned and sequenced. The cluster identity wasunequivocally proven by deletion of flanking regions and heterologous expression in S. albus and S. lividans.Inactivation and complementation experiments revealed that a KSIII component (BenQ) similar to FabH iscrucial for providing and selecting the rare hexanoate PKS starter unit. In the absence of BenQ, severalnovel penta- and hexacyclic benastatin derivatives with antiproliferative activities are formed. In total, fivenew compounds were isolated and fully characterized, and the chemical analysis was confirmed byderivatization. The most intriguing observation is that the ben PKS can utilize typical straight and branchedfatty acid synthase primers. If shorter straight-chain starters are utilized, the length of the polyketide backboneis increased, resulting in the formation of an extended, hexacyclic ring system reminiscent of proposedintermediates in the griseorhodin and fredericamycin pathways. Analysis and manipulation of the hybridfatty acid polyketide pathway provides strong support for the hypothesis that the number of chain elongationsis dependent on the total size of the polyketide chain that is accommodated in the PKS enzyme cavity.Our results also further substantiate the potential of metabolic engineering toward polyphenols with alteredsubstituents and ring systems.
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