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Author Spotlight: Discovering New Alkaloids in Plants with Advanced Mass Spectrometry Techniques
Published on: March 8, 2024
Cytochrome P450-mediated structural diversification of diketopiperazine alkaloids
Guangzheng Wei1, Wenya Tian1, Yeqing Du1
1State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China; Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai 201203, China.
Abstract:
2,5-Diketopiperazines (DKPs), the smallest cyclic dipeptides, serve as privileged scaffolds in natural product biosynthesis and drug discovery due to their stable conformation, metabolic stability, and diverse pharmacological properties. Cytochrome P450 enzymes significantly expand DKP structural diversity through various oxidative modifications, generating complex bioactive natural products. This review focuses on recent progress in P450-catalyzed DKP functionalization, particularly their catalytic diversity beyond hydroxylation to include dimerization, nucleobase coupling, and intramolecular cyclization. We also explore emerging strategies using engineered P450 variants for the sustainable biosynthesis of bioactive DKP frameworks, integrating natural product biosynthesis with synthetic biology to drive innovation in DKP-based drug discovery.
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