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As a thioesterase in type\u2010I polyketide synthase, <jats:italic>pimTE<\/jats:italic> controls the 26\u2010m\u2010r macrolide main chain release in pimaricin biosynthesis. In this work, we sought to determine whether the 6\u2010m\u2010r hemiketal formation was linked to <jats:italic>pimTE<\/jats:italic>\u2010catalyzed 26\u2010m\u2010r lactonization. Compared to non\u2010hemiketal TEs, <jats:italic>pimTE<\/jats:italic> is characterized by an aspartic acid residue (D179) accessible to the U\u2010turn motif in the acyl\u2010enzyme intermediate. Both the covalent docking and molecular dynamics simulations demonstrate that the reactive conformations for macrocyclic lactonization are drastically promoted by the 6\u2010m\u2010r hemiketal. Moreover, the small\u2010model quantum mechanistic calculations suggest that protic residues can significantly accelerate the 6\u2010m\u2010r hemiketal cyclization. In addition, the post\u2010hemiketal molecular dynamic simulations demonstrate that hydrogen\u2010bonding networks surrounding the substrate U\u2010turn of the hairpin\u2010shaped conformation changes significantly when the 6\u2010m\u2010r hemiketal is formed. In particular, the <jats:italic>R<\/jats:italic>\u2010hemiketal intermediate is not only catalyzed by the D179 residue, but also twists the hairpin structure to the 26\u2010m\u2010r lactonizing pre\u2010reaction state. By contrast, the <jats:italic>S\u2010<\/jats:italic>hemiketal formation is unlikely catalyzed by D179, which twists the hairpin in an opposite direction. Our results propose that <jats:italic>pimTE<\/jats:italic> could be a bi\u2010functional enzyme, which can synergistically catalyze tandem 6\u2010m\u2010r and 26\u2010m\u2010r formations during the main\u2010chain release of pimaricin biosynthesis.<\/jats:p>","DOI":"10.1002\/asia.202201229","type":"journal-article","created":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T23:41:17Z","timestamp":1675899677000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Theoretical Studies of Mutual Effects between 6\u2010m\u2010r Hemiketalization and 26\u2010m\u2010r Lactonization in Pimaricin Thioesterase"],"prefix":"10.1002","volume":"18","author":[{"given":"Chuchu","family":"Jiang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Microbial Metabolism Joint International Research Laboratory of Metabolic and Developmental Sciences School of Life Sciences and Biotechnology Shanghai Jiao Tong University  Shanghai 200240 P.\u2005R. 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