Fatty acid synthases (FASs) enable access to new-to-nature compounds Martin Grininger 1 , Alexander Rittner 1 , Mirko Joppe 1 , Jennifer Schmidt 2 , Simon Reiners 1 ,
Franziska Stegemann 1 , Jan Gajewski 1 and David Sherman 2 1 Goethe University Frankfurt, Germany, 2 University of Michigan, USA
Multienzyme type I fatty acid (FASs) and polyketide synthases (PKSs) catalyze C-C bond forming reactions in compartmentalized space. Compartmentalization is largely achieved by the transacylation function of FASs and PKSs, i.e. the enzymatic reaction responsible for selecting substrates from the bulk cytoplasm, and further relies on a specific protein architecture as well as the shuttled distribution of substrates between the enzymatic domains. Controlling the transacylation function of FASs and PKSs is a powerful mean to modulate the product output of these proteins for access to technologically and medicinally relevant compounds. 1,2 Two examples for transacylation-based engineering will be presented in this talk: (i)We employed fungal FAS for the custom synthesis of commodity products, among them short-chain fatty acids, methylketones and lactones 3-5 . For increasing complexity of synthesized compounds, FAS constructs were modulated in transferase function for acting in sequence. (ii) The mammalian FAS features high transacylation rates for a wide range of substrates 2 . We inserted the mammalian FAS transferase domain (MAT) into modular PKSs to enable the in vitro semisynthesis of new polyketides, including fluorinated 12- and 14-membered macrolactones with the same fluoro-methyl motif as in the next-generation antibiotic solithromycin 6 . References 1. F. Stegemann, M. Grininger, ChemCatChem 2021 , 13 , 2771-2782 . 2. A. Rittner, K. S. Paithankar, K. V. Huu, M. Grininger, ACS Chem Biol 2018 , 13 , 723-732. 3. J. Gajewski, F. Buelens, S. Serdjukow, M. Janssen, N. Cortina, H. Grubmuller, M. Grininger, Nat Chem Biol 2017 , 13 , 363–365. 4. Z. Zhu, Y. J. Zhou, A. Krivoruchko, M. Grininger, Z. K. Zhao, J. Nielsen, Nat Chem Biol 2017 , 13 , 360-362. 5. J. Gajewski, R. Pavlovic, M. Fischer, E. Boles, M. Grininger, Nat Commun 2017 , 8 , 14650. 6. A. Rittner, M. Joppe, J. J. Schmidt, L. M. Mayer, E. Heid, D. H. Sherman M. Grininger, bioRxiv 2021 , https://doi. org/10.1101/2021.07.30.454469.
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