Exploring Post-Type II PKS Frame Modifications

Many important natural product drugs are generated by polyketide synthases (PKS, multiple enzyme complexes) and various frame-modifying follow-up reactions, called post-PKS tailoring steps. Type II PKSs are responsible for the generation of important drugs such as the tetracycline antibiotics and clinically used anthracycline and aureolic acid anticancer drugs. The PKSs are resposnsible for the initial formation of multicyclic aromatic intermediates, which are then further converted into the biologically active drugs by the post-PKS enzymes. While PKSs are well studied, the post-PKS steps are much lesser understood, although they are frame modifying enzymes that provide the biological activities. To understand and evolve these enzymes offers to utilize these for the generation of novel cancer drugs and antibiotics by embedding them in combinatorial biosynthesis, mutasynthesis or chemo-enzymatic synthesis strategies. Both new anticancer drugs and new antibiotics are urgently needed, because current drug regimens lose their effectiveness due to resistance mechanisms. Cancer remains a leading cause of death in the US and worldwide. Infectious diseases are an increasing threat, surpassing recently the death rates of AIDS. The goal of this proposal is to study the frame modifying post-PKS steps of the biosyntheses of highly active, promising polyketide drugs of the gilvocarcin and aureolic acid groups, and consequently to evolve analogues that have the potential to become valuable additions to current regimens of cancer and antibacterial chemotherapies.