Natural products have a major impact on drug discovery. They have contributed to approximately 50% of new chemical entities between 1940 and 2006, because they offer a unique richness in structural skeletons combined with a high degree of chirality that has the potential to selectively match bio-receptors. Natural products have been particularly useful for the treatment of cancer and infectious diseases, nonetheless new drugs are urgently needed because current drug regimens inevitably lose their effectiveness due to resistance mechanisms. Many important natural product drugs are generated by polyketide synthases (PKS, multiple enzyme complexes), and various frame-modifying reactions, called post-PKS tailoring steps. Type II PKSs assembling multicyclic aromatic intermediates together with the respective tailoring enzymes are responsible for the generation of important drugs, such as the clinically used tetracycline antibiotics, or anthracycline and aureolic acid anticancer drugs. While type II PKSs are well studied, the post-PKS steps are much less understood, although the frame modifying enzymes typically render an inert scaffold into a bioactive drug. The primary goal of this proposal is to functionally and mechanistically characterize uniquely reacting and organized frame modifying post-PKS enzymes involved in the biosynthesis of anticancer polyketide drugs of the angucycline and aureolic acid groups. It is our expectation that uncovering the molecular details of catalysis will help to evolve these critical enzymes, so that they can be exploited to modify type II PKS scaffolds. This could lead to novel, second-generation 'unnatural' natural products and/or derivatives of natural products via combinatorial biosynthesis, mutasynthesis, or chemo-enzymatic synthetic strategies. The studies also will help to generate new mithramycin and gilvocarcin analogues that will be useful to further study and steer the interactions of these drugs with their recently discovered specific targets.
The proposed work aims to study key enzymes and enzyme complexes of the type II post-polyketide synthase (PKS) machinery found in the biosynthesis of natural product anticancer drugs, which are essential to turn primary polyketide scaffolds into bioactive drugs. Uncovering the molecular details of catalysis will help to evolve these critical enzymes, so that they can be exploited to modify primary PKS scaffolds. This could lead to novel, second-generation 'unnatural' natural products and/or derivatives of natural products via combinatorial biosynthesis, mutasynthesis, or chemo-enzymatic synthetic strategies. The studies also will help to generate new mithramycin and gilvocarcin analogues that will be useful to further study and steer the interactions of these drugs with their recently discovered specific targets.
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