Natural products play an important role in drug discovery. About 50% of all newly approved drugs between 1981 and 2006 derive either directly from natural products or are inspired by their structures.1 It is well accepted that the evolutionary privileged structures of natural products make them superior leads, starting from which the probability to find drug candidates is much higher than from non-natural compounds.
Besides fermentative processes, chemical synthesis displays a potential route to natural products and their derivatives. Natural Product Chemistry has taken an impressive development within the last decades. Given sufficient time and resources, every desired target structure can nowadays be accessed by chemical means. However, due to the structural complexity of natural products, total syntheses are often not economic and accordingly, the way to derivatives also remains obstructed. Organic Chemistry is furthermore challenged with shrinking resources and the need to serve a growing population in a more environmentally friendly and efficient way.
For developing more environmentally benign alternatives to natural product synthesis, it is obvious to learn from the way how nature makes these important molecules. Progress in the understanding of the genetics and the enzymology of natural product biosynthetic pathways has paved the way for novel strategies to access natural products and their derivatives.
Besides semisynthesis, mutasynthesis and pathway engineering, one promising strategy is the use of enzymes from secondary metabolism as biocatalysts. If made applicable on a preparative scale, their integration into synthetic routes might lead to improved total syntheses that combine nature’s efficiency with the flexibility of Organic Chemistry.
Our group follows a multidisciplinary approach, applying methods from Molecular Biology, Enzymology and Organic Chemistry, to exploit knowledge about biosynthetic pathways for chemical synthesis. We are particularly interested in the application of enzymes from polyketide biosynthesis. Nature assembles polyketides by polyketide synthases (PKSs) (Figure 2). These megaenzymes assemble linear backbones, which are then further processed by so-called tailoring enzymes to yield the final products. Polyketide natural product pathways harbour plenty of interesting enzymology and are therefore a source of tools to access molecular diversity.
1Newman D.J.; Cragg G.M. J. Nat. Pro. 2007, 70, 461-477.
2Cortés J.; Haydock S.F.; Roberts G.A.; Bevitt D.J.; Leadlay, P.F. Nature 1990, 348, 176-178.