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Updated: Jun 13, 2025

Formation of Covalent DNA Adducts by Enzymatically Activated Carcinogens and Drugs In Vitro and Their Determination by 32P-postlabeling
Published on: March 20, 2018
Multifunctional cytochrome P450 orchestrates radical cleavage and non-radical cyclization in 5-oxaindolizidine
Kaijin Zhang1,2, Jingxian Sun1,2, Wencai Song1,2
1Key Laboratory of Marine Drugs, Ministry of Education, Ocean University of China Qingdao 266003 China dehaili@ouc.edu.cn.
Abstract:
Penicilactam A (1), a fungal alkaloid featuring a rare 5-oxaindolizidine scaffold, has long eluded biosynthetic characterization despite recent advances in microbial genomics. Through retro-biosynthetic analysis of Penicillium citrinum HDN11-186, we identified the pnlt gene cluster governing its production. This pathway ultilizes a hybrid polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) system to assemble the prolinol-containing precursor scalusamide A (2). The multifunctional cytochrome P450 enzyme PnltC then orchestrates two mechanistically distinct reactions: radical-mediated C-C bond cleavage followed by iminium-driven cyclization. Combined structural and computational analyses unveil PnltC's unprecedented catalytic logic, merging radical oxidation with non-radical cyclization within a single active site, which challenges existing paradigms of P450 enzymology. Our findings expand the functional repertoire of oxygenases in natural products (NPs) biosynthesis, revealing nature's sophisticated strategies for constructing complex nitrogen heterocycles.
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