AL4BIOCH SIGNED

Project "AL4BIOCH" data sheet

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 Partnership

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 Project objective

Polyketide Synthases (PKS) are biological factories for the production of potent natural products, including antibiotics, anti‐cancer drugs, statins and further drugs. The exceptional chemical diversity generated by PKS is encoded in their modular architecture. The domains required for one step of precursor elongation and modification are combined into a functional polypeptide module. PKS modules can either act iteratively (iPKS) or in a linearly organized assembly line of multiple modules (modPKS). The collinearity between synthesis and protein sequence in modPKS promised the opportunity for rational re‐engineering of PKS at the genetic level in order to produce novel compounds. However, information on functional protein-protein interactions and substrate transfer in PKS beyond the level of isolated domains is sparse and divergent architectural models of module organization have been proposed. In the AL2BIOCH project, we aim to reveal the fundamental intermodular assembly line organization underlying the unique biosynthetic generation of chemical diversity by modPKS. For this purpose, we employ cryo-electron microscopy to comprehensively study the organization of modPKS bimodules as minimal representations of assembly lines organization. In combination with functional analysis, biophysical studies and chemoenzymatic trapping we address the architectures underlying directed substrate transfer. The research builds on modern and rapidly evolving techniques, including cryo electron microscopy, advanced optical imaging and biophysics, as well as chemical probes, which are most relevant for front-line molecular biology research. Success in this project will allow the host lab and organization to establish new collaborations for translating insights on modPKS architecture for the design of novel or re-engineered assembly lines for the generation of advanced chemical compounds and drug candidates.