@article{2c5635075189406f8826195af10197b8,
title = "Didepside Formation by the Nonreducing Polyketide Synthase Preu6 of Preussia isomera Requires Interaction of Starter Acyl Transferase and Thioesterase Domains",
abstract = "Orsellinic acid (OA) derivatives are produced by filamentous fungi using nonreducing polyketide synthases (nrPKSs). The chain-releasing thioesterase (TE) domains of such nrPKSs were proposed to also catalyze dimerization to yield didepsides, such as lecanoric acid. Here, we use combinatorial domain exchanges, domain dissections and reconstitutions to reveal that the TE domain of the lecanoric acid synthase Preu6 of Preussia isomera must collaborate with the starter acyl transferase (SAT) domain from the same nrPKS. We show that artificial SAT-TE fusion proteins are highly effective catalysts and reprogram the ketide homologation chassis to form didepsides. We also demonstrate that dissected SAT and TE domains of Preu6 physically interact, and SAT and TE domains of OA-synthesizing nrPKSs may co-evolve. Our work highlights an unexpected domain–domain interaction in nrPKSs that must be considered for the combinatorial biosynthesis of unnatural didepsides, depsidones, and diphenyl ethers.",
keywords = "Biosynthesis, Dimerization, Enzyme Catalysis, Polyketides, Protein-Protein Interactions",
author = "Qingpei Liu and Dan Zhang and Shuaibiao Gao and Xianhua Cai and Ming Yao and Yao Xu and Yifu Gong and Ke Zheng and Yigui Mao and Liyan Yang and Dengfeng Yang and Istv{\'a}n Moln{\'a}r and Xiaolong Yang",
note = "Funding Information: We express special thanks to the members of the Dr. Shengxiong Huang (Kunming Institute of Botany, Chinese Academy of Sciences) laboratories for useful discussions. We also thank Dr. Chen Wang (Biotechnology Research Institute, Chinese Academy of Agricultural Sciences) for his help with the phylogenetic analysis of TE and SAT domains. This research was supported by the National Natural Science Foundation of China (82073714 to X.Y., 22007102 to Q.L.); the Knowledge Innovation Program of Wuhan‐Shuguang Project (2022020801020406 to Q.L.); The National Civil Affairs Commission's young and middle‐aged talents training program (MZR20008 to X.Y.); the Key project at central government level: The ability establishment of sustainable use for valuable Chinese medicine resources (2060302) (2060302‐2101‐20 to Q.L.); the Fundamental Research Funds for the Central Universities, South‐Central Minzu University (YZZ19007 to Q.L.); the USDA National Institute of Food and Agriculture (Hatch project ARZT‐1361640‐H12‐224 to I. M.); and VTT Technical Research Centre of Finland (to I. M.). ",
year = "2023",
month = feb,
day = "1",
doi = "10.1002/anie.202214379",
language = "English",
volume = "62",
journal = "Angewandte Chemie: International Edition",
issn = "1433-7851",
publisher = "Wiley",
number = "6",
}