Synthetic Biology of Natural Products
Dr. Kenan Bozhüyük
Natural products are obtained from living organisms and comprise structurally diverse and bioactive molecules with low molecular weight (<3000), which occupy chemical property space beyond Lipinski’s rule of five. Especially bacterial natural products produced by modular biosynthetic assembly-lines, i.e., polyketide synthases (PKSs), non-ribosomal peptide synthetases (NRPSs), and hybrids thereof are not only at the heart of our research but, provide the scaffolds for a majority of our essential clinical agents. Examples include well known antibacterial molecules such as the polyketide insecticide spinosyn and NRPS derived penicillins.
Essentially, PKS and NRPS modular megasynth(et)ases act as machines, with many moving parts and reaction centres that all work together. They follow an elegant sort of logic in which subsections, referred to as modules, facilitate sequential well-orchestrated reactions that give rise to highly functionalised biopolymers from a broad variety of monomers, called extender units. Hundreds of extender units have been reported, typically derived from malonate in the case of PKSs or amino acids in the case of NRPSs. The resulting complex chemical structures and enormous pharmaceutical potential make the respective biosynthetic gene clusters key targets for bioengineering to build new therapeutics from new combinations of extender units.
Our scientific vision is the development of all necessary tools to enable the biosynthesise of any natural product-like peptide/polyketide derivatives and new-to-nature peptides/polyketides – beyond the limitations of chemical synthesis. Although our contributions to the very field delineated guidelines for successful NRPS engineering, it also showed the limitations. For this reason, and to make the structural diversity of NRPSs and PKSs derived bacterial natural products amenable to drug development purposes, we are combining state-of-the-art in silico (genome mining, comparative genomics, homology modelling, protein networks, molecular docking, molecular dynamics), in vitro (activity assays), and in vivo (heterologous expression of recombined biosynthetic pathways, comparative metabolomics) methods to push the boundaries of what already is possible even further.
Bozhüyük, K. A. J., Watzel, J., Abbood, N., Bode, H. B. (2021)
Synthetic Zippers as an Enabling Tool for Engineering of Non-Ribosomal Peptide Synthetases. Angew. Chem. Int. Ed., 60(32), 17531-17538. doi: 10.1002/anie.202102859
Bozhüyük, K. A. J., Micklefield, J., Wilkinson, B. (2019)
Engineering Enzymatic Assembly Lines to Produce New Antibiotics. Curr. Opin. Microbiol., 51, 88–96. doi: 10.1016/j.mib.2019.10.007.
Bozhüyük, K. A. J., Linck, A., Tietze, A., Kranz, J., Wesche, F., Nowak, S., Fleischhacker, F., Shi, Y., Grün, P., Bode, H. B. (2019)
Modification and de novo design of non-ribosomal peptide synthetases (NRPS) using specific assembly points within condensation domains. Nat. Chem., 11(7), 653-661. doi: 10.1038/s41557-019-0276-z.
Bozhüyük, K. A. J., Fleischhacker, F., Linck, A., Wesche, F., Tietze, A., Niesert, C. P., Bode, H. B. (2018)
De novo design and engineering of non-ribosomal peptide synthetases. Nat. Chem., 10(3), 275-281. doi: 10.1038/nchem.2890.
Bozhüyük, K. A. J., Zhou, Q., Engel, Y., Heinrich, A., Perez, A., Bode, H. B. (2017)
Natural Products from Photorhabdus and Other Entomopathogenic Bacteria. Curr Top Microbiol Immunol., 402, 55-79. doi: 10.1007/82_2016_24.