Multifunctional Cytochrome P450 Orchestrates Radical Cleavage and Non-radical Cyclization in 5-Oxaindolizidine Biosynthesis

IF 7.6 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Chemical Science Pub Date : 2025-05-10 DOI:10.1039/d4sc07174c

Kaijin Zhang, Jingxian Sun, Wencai Song, Junyu Liu, Chuanteng Ma, Ying-Han Chen, Yan Guan, Yuting Liu, Zilin Ren, Qian Che, Guojian Zhang, Yankai Liu, Tianjiao Zhu, Dehai Li

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引用次数: 0

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 repertore of oxygenases in natural products (NPs) biosynthesis, revealing nature’s sophisticated strategies for constructing complex nitrogen heterocycles.

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多功能细胞色素P450在5-氧苯多利嗪生物合成中协调自由基切割和非自由基环化

Penicilactam A(1)是一种真菌生物碱，具有罕见的5-oxaindolizidine支架，尽管最近微生物基因组学取得了进展，但长期以来一直无法进行生物合成表征。通过对柑橘青霉HDN11-186的逆转录生物合成分析，我们确定了控制其生产的pnlt基因簇。该途径利用杂化聚酮合成酶-非核糖体肽合成酶（PKS-NRPS）系统组装含有脯氨酸醇的前体scalusamide a(2)。然后，多功能细胞色素P450酶PnltC协调两个机制不同的反应：自由基介导的C-C键切割，然后是最小驱动的环化。结合结构和计算分析揭示了PnltC前所未有的催化逻辑，将自由基氧化与非自由基环化结合在一个活性位点上，这挑战了P450酶学的现有范式。我们的发现扩展了天然产物（NPs）生物合成中加氧酶的功能库，揭示了自然界构建复杂氮杂环的复杂策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Chemical Science CHEMISTRY, MULTIDISCIPLINARY-

CiteScore

14.40

自引率

4.80%

发文量

1352

审稿时长

2.1 months

期刊介绍： Chemical Science is a journal that encompasses various disciplines within the chemical sciences. Its scope includes publishing ground-breaking research with significant implications for its respective field, as well as appealing to a wider audience in related areas. To be considered for publication, articles must showcase innovative and original advances in their field of study and be presented in a manner that is understandable to scientists from diverse backgrounds. However, the journal generally does not publish highly specialized research.