Understanding and exploiting oxidative modifications by modular polyketide synthases – PKSOx

The modular polyketide synthases (PKSs) of bacteria assemble a wealth of complex natural products of high clinical value. These giant multifunctional proteins contain enzyme modules, each of which sequentially elongates the polyketide chain and introduces a particular functional group. While textbook modular PKSs mainly employ fatty acid synthase-related biochemistry to construct polyketides, the remarkable trans-acyltransferase (AT) PKS class incorporates an unparalleled diversity of biosynthetic modules that expand the structural scope of polyketides, but remains poorly studied. This project will focus on recently discovered modules with oxygenase domains that catalyze oxygen insertion into growing polyketide chains. A particularly notable oxygenation module introduces an oxime functionality, a bioorthogonal moiety amenable to semi-synthesis approaches, such as polyketide tagging. The aim of this Swiss/French collaborative project is to biochemically characterize in detail the identified types of oxygenation modules, by drawing on the combined expertise of the partners in analytical chemistry, in vitro protein biochemistry, mechanistic enzymology, synthesis, structural biology, and biophysical approaches. This knowledge will be leveraged toward generating a synthetic biology platform for oxygen insertion into high-interest polyketide structures.