Molecular basis of regio- and stereo-specificity in biosynthesis of bacterial heterodimeric diketopiperazines

Chenghai Sun, Zhenyao Luo, Wenlu Zhang, Wenya Tian, Haidong Peng, Zhi Lin, Zixin Deng, Bostjan Kobe (), Xinying Jia () and Xudong Qu ()
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Chenghai Sun: Shanghai Jiao Tong University
Zhenyao Luo: The University of Queensland
Wenlu Zhang: Wuhan University School of Pharmaceutical Sciences
Wenya Tian: Shanghai Jiao Tong University
Haidong Peng: Wuhan University School of Pharmaceutical Sciences
Zhi Lin: Shanghai Jiao Tong University
Zixin Deng: Shanghai Jiao Tong University
Bostjan Kobe: The University of Queensland
Xinying Jia: The University of Queensland
Xudong Qu: Shanghai Jiao Tong University

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: Abstract Bacterial heterodimeric tryptophan-containing diketopiperazines (HTDKPs) are a growing family of bioactive natural products. They are challenging to prepare by chemical routes due to the polycyclic and densely functionalized backbone. Through functional characterization and investigation, we herein identify a family of three related HTDKP-forming cytochrome P450s (NasbB, NasS1868 and NasF5053) and reveal four critical residues (Qln65, Ala86, Ser284 and Val288) that control their regio- and stereo-selectivity to generate diverse dimeric DKP frameworks. Engineering these residues can alter the specificities of the enzymes to produce diverse frameworks. Determining the crystal structures (1.70–1.47 Å) of NasF5053 (ligand-free and substrate-bound NasF5053 and its Q65I-A86G and S284A-V288A mutants) and molecular dynamics simulation finally elucidate the specificity-conferring mechanism of these residues. Our results provide a clear molecular and mechanistic basis into this family of HTDKP-forming P450s, laying a solid foundation for rapid access to the molecular diversity of HTDKP frameworks through rational engineering of the P450s.

Date: 2020
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DOI: 10.1038/s41467-020-20022-5

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