Global genome mining reveals multiprenylated cyclodipeptides with enhanced neuroprotective activity Jessie James Limlingan Malit 1,2 , Chuanhai Wu 1,2 , Xueying Tian 1,2 , Wenchao Liu 1,2 , Duli Huang 1,2 , Herman H.-Y. Sung 1,4 , Ling-Li Liu 3 , Ian D. Williams 1,4 and Pei-Yuan Qian 1,2 1 Southern Marine Science and Engineering Guangdong Laboratory, China, 2 Department of Ocean Science, The Hong Kong University of Science and Technology, Hong Kong HKG, China, 3 Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, China, 4 Department of Chemistry, The Hong Kong University of Science and Technology, Hong Kong HKG, China Prenylation has been shown to impart improved pharmacological activities on bioactive compounds [1,2]. To identify novel prenylated natural products, we employed global genome mining using antiSMASH [3] on 223,815 bacterial genomes. We targeted for prenyltransferase-associated cyclodipeptide (CDP) synthase biosynthesis gene clusters (BGCs), as CDP scaffolds exhibit diverse bioactivities. BGC networking analysis through BiG-SCAPE [4] revealed a gczABC BGC from Streptomyces griseocarneus 132, which contained two prenyltransferase genes downstream of the CDP synthase gene. Heterologous expression and compound purification led to the identification of griseocazines, a novel family of multiprenylated CDPs. Structural elucidation and biotransformation analyses showed that the prenyltransferases found in the BGC catalyzed the stereospecific addition of prenyl, geranyl, and farnesyl groups to cyclo-L-Trp-L-Trp. The prenylated CDPs exhibited an improved neuroprotective activity than their nonprenylated counterpart based on a glutamate-induced excitotoxicity assay. This study has leveraged the use of large-scale genome mining and a targeted biosynthesis logic to discover novel compounds with good bioactivity. References 1. Šmejkal, K. Cytotoxic Potential of C-Prenylated Flavo-noids. Phytochem. Rev. 2014, 13 (1), 245–275. 2. Santos, C. M. M.; Silva, A. M. S. The Antioxidant Activity of Prenylflavonoids. Molecules 2020, 25 (3), 696. 3. Blin, K.; Shaw, S.; Kloosterman, A. M.; Charlop-Powers, Z.; van Wezel, G. P.; Medema, M. H.; Weber, T. An-tiSMASH 6.0: Improving Cluster Detection and Compari-son Capabilities. Nucleic Acids Res. 2021, 49 (W1), W29–W35. 4. Navarro-Muñoz, J. C.; Selem-Mojica, N.; Mullowney, M. W.; Kautsar, S. A.; Tryon, J. H.; Parkinson, E. I.; De Los Santos, E. L. C.; Yeong, M.; Cruz-Morales, P.; Abubucker, S.; Roeters, A.; Lokhorst, W.; Fernandez-Guerra, A.; Cap-pelini, L. T. D.; Goering, A. W.; Thomson, R. J.; Metcalf, W. W.; Kelleher, N. L.; Barona-Gomez, F.; Medema, M. H. A Computational Framework to Explore Large-Scale Bio-synthetic Diversity. Nat. Chem. Biol. 2020, 16 (1), 60–68.
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