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On April 3, 2017. You Delin Research Team of Deng Zixin Group from National Key Lab of Microbial Metabolism at School of Life Science and Biotechnology (SLSB) of Shanghai Jiao Tong University (SJTU) and Yit-Heng Chooi's lab from University of Western Australia collaborated in publishing the article entitled "Biosynthesis of the pyrrolidine protein synthesis inhibitor anisomycin involves novel gene ensemble and cryptic biosynthetic steps" in Proceedings of the National Academy of Sciences of the United States of America (PNAS).

The protein synthesis inhibitor anisomycin features a unique benzylpyrrolidine system and exhibits diverse biological and pharmacological activities. However, its biosynthetic origin has remained obscure for over 60 years.

In this article, Delin You's team reports the identification of the biosynthetic gene cluster (BGC) of anisomycin in Streptomyces hygrospinosus var. beijingensis by a bioactivity-guided high-throughput screening method. Using a combination of bioinformatic analysis, reverse genetics, chemical analysis and in vitro biochemical assays, They identified a core four-gene ensemble responsible for the synthesis of the pyrrolidine system in anisomycin: aniQ encoding a aminotransferase that catalyzes an initial deamination and a later reamination steps, aniP encoding a novel transketolase implicated to bring together an glycolysis intermediate with 4-hydroxyphenylpyruvic acid to form the anisomycin molecular backbone, aniO encoding a glycosyltransferase that catalyzes a cryptic glycosylation crucial for downstream enzyme processing, and aniN encoding a bifunctional dehydrogenase that mediates multistep pyrrolidine formation.

Their results revealed a novel class of BGC for pyrrolidine alkaloid biosynthesis, which is distinct from known bacterial alkaloid pathways, and provided the signature sequences that will facilitate the discovery of BGCs encoding novel pyrrolidine alkaloids in bacterial genomes. The biosynthetic insights revealed further set the foundation for biosynthetic engineering of pyrrolidine antibiotics.

PhD student Xiaoqing Zheng is the first author of this article.  This research was supported by grants from the National Science Foundation of China, the Ministry of Science and Technology, Shanghai Pujiang Program from the Shanghai Municipal Council of Science and Technology.

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