Developing a polyketide synthase module-centered multi-enzyme cascade for chemoenzymatic synthesis of antifungal polyketides Jörg Stang, Prof. Dr. Frank Hahn University of Bayreuth, Germany Increasing efforts are put into the development of new antimycotics due to the spread of drug-resistant fungal pathogens.[1] Despite this, only a few groups of antifungal agents are currently available for human treatment. Myxobacterial secondary metabolites are known to exhibit remarkable biological activity and are therefore of high pharmacological interest. These include the related polyketide families of the ambruticins and jerangolids isolated from Sorangiumcellulosum strains Soce10 and Soce307, respectively.[2,3] They display antimycotic activity against a broad range of pathogenic fungi with low toxicity in humans. Nonetheless, availability of ambruticins and jerangolids is impeded by their structural complexity. A combinatorial approach of enzymatic transformations and organic synthesis has proven to be an effective strategy for the preparation of bioactive small molecules. We have previously investigated the role of two multifunctional dehydratase domains AmbDH3 and AmbDH4 as well as the C ‑methyltransferase (CMT) AmbM in the biosynthesis of the conserved pharmacophoric eastern fragment of the ambruticins and revealed their biocatalytic potential.[4,5,6] We now strive to exploit these enzymes for efficient chemoenzymatic syntheses of the ambruticins and jerangolids.
Figure1. Multi-enzyme cascade for the synthesis of the ambruticin and jerangolid eastern fragment. For this purpose, we intend to establish an invitro multi-enzyme cascade that centers around the polyketide synthase modules 4 and which provides straight-forward access to the advanced intermediate 3 starting from the biomimetic tetraketide surrogate 1 (Figure1). Synthetic gain and convenience of product isolation will be maximised by also integrating a tetrahydropyran-forming cyclase, a CMT as well as a suitable thioesterase into this cascade. References 1. Howard K. C.; Dennis E. K.; Watt D. S.; Garneau-Tsodikova S. Chem. Soc. Rev. 2020 , 49 , 2426–2480. 2. Gerth K.; Washausen P.; Hofle G.; Irschik H.; Reichenbach H. J. Antibiot. 1996 , 49 , 71-75. 3. Ringel S. M.; Greenough R. C.; Roemer S.; Connor D.; Gutt A. L.; Blair B.; Kanter G.; von Strandtmann M. J. Antibiot 1977 , 30 , 371–375. 4. Berkhan G.; Hahn F. Angew. Chem. Int. Ed. 2014 , 53 , 14240–14244. 5. Berkhan G.; Merten C.; Holec C.; Hahn F. Angew. Chem. Int. Ed. 2016 , 55 , 13589-13592. 6. Hollmann T.; Berkhan G.; Wagner L.; Sung K. H.; Kolb S.; Geise H.; Hahn F. ACS Catal . 2020 , 10 , 4973‑4982.
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