Problems, progress and holy-grails in natural product sciences.

Microbes are responsible for a remarkable array of secondary metabolites. Over the past three decades enormous progress has been made to understand the large multifunctional polyketide synthase (PKS) proteins that assemble large macrolactone rings that are critical structural components in numerous antibiotics and anticancer agents. Our work has focused on studying these systems using advanced polyketide chain elongation intermediates to understand the selectivity parameters of individual catalytic domains within modular PKS systems. New structural insights gained through x-ray crystallography and cryo-electron microscopy are enabling fascinating insights into the inner workings of these spectacular biosynthetic molecular machines.

More recently, we have been exploring natural product pathways that possess polycyclic ring systems bearing the [2.2.2] diazaoctane core and other indole alkaloids. These enzymes are mined from an array of biosynthetic gene clusters derived from numerous bacterial and fungal genomes. Highlights from our current studies relating to a diverse range of biosynthetic transformations and mechanisms will be discussed.