Characterization and structural analysis of a versatile aromatic prenyltransferase for imidazole-containing diketopiperazines

Wenxue Wang, Peng Wang, Chuanteng Ma, Kang Li, Zian Wang, Yuting Liu, Lu Wang, Guojian Zhang, Qian Che, Tianjiao Zhu, Yuzhong Zhang (zhangyz@sdu.edu.cn) and Dehai Li (dehaili@ouc.edu.cn)
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Wenxue Wang: Ocean University of China
Peng Wang: Ocean University of China
Chuanteng Ma: Ocean University of China
Kang Li: Ocean University of China
Zian Wang: Ocean University of China
Yuting Liu: Ocean University of China
Lu Wang: Ocean University of China
Guojian Zhang: Ocean University of China
Qian Che: Ocean University of China
Tianjiao Zhu: Ocean University of China
Yuzhong Zhang: Qingdao Marine Science and Technology Center
Dehai Li: Ocean University of China

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: Abstract Prenylation modifications of natural products play essential roles in chemical diversity and bioactivities, but imidazole modification prenyltransferases are not well investigated. Here, we discover a dimethylallyl tryptophan synthase family prenyltransferase, AuraA, that catalyzes the rare dimethylallylation on the imidazole moiety in the biosynthesis of aurantiamine. Biochemical assays validate that AuraA could accept both cyclo-(L-Val-L-His) and cyclo-(L-Val-DH-His) as substrates, while the prenylation modes are completely different, yielding C2-regular and C5-reverse products, respectively. Cryo-electron microscopy analysis of AuraA and its two ternary complex structures reveal two distinct modes for receptor binding, demonstrating a tolerance for altered orientations of highly similar receptors. The mutation experiments further demonstrate the promiscuity of AuraA towards imidazole-C-dimethylallylation. In this work, we also characterize a case of AuraA mutant-catalyzed dimethylallylation of imidazole moiety, offering available structural insights into the utilization and engineering of dimethylallyl tryptophan synthase family prenyltransferases.

Date: 2025
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DOI: 10.1038/s41467-024-55537-8

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