Structural and functional studies in indanomycin biosynthesis (360G-Wellcome-105214_Z_14_Z)

Polyketides represent a broad and diverse class of natural products which includes many pharmaceutically-relevant compounds. Historically, identification of novel polyketides relied on natural screening methods; however, rational engineering of polyketide synthases (PKS) represents a powerful tool to create libraries of ‘unNatural’ products to be screened for novel therapeutic properties. The project’s key goals are 1) Elucidating the structure of the indanomycin PKS, starting with the first subunit, IdmL By elucidating the structure of indanomycin PKS, we will increase our understanding of the interfaces between the functional domains and the rules governing the successful rearrangement of polyketide assembly lines. 2) Engineering mutant and chimeric IdmL for the production of novel polyketides By employing synthetic biology approaches, we will investigate the potential for engineering the indanomycin gene cluster to produce novel polyketides. 3) Characterising the structure and function of the post-PKS cyclase IdmH To expand a synthetic biologist’s toolkit of natural product modifying enzymes, we aim to elucidate the structure and reaction mechanism of this novel enzyme. These goals will increase our knowledge of the assembly of the PKS complexes as well as the chemistry involved in the generation of mature polyketide and bring us closer to rational engineering of these systems.