Discovery of unprecedented prenylated indole piperazines and pyrazines through cryptic biosynthetic gene cluster heterologous expression

IF 5.8 3区化学 Q1 CHEMISTRY, MEDICINAL

Natural Products and Bioprospecting Pub Date : 2026-04-03 DOI:10.1007/s13659-026-00601-7

Ziou Zha, Dan He, Jianguo Song, Zhenhua Guan, Jiapei Han, Chang Liu, Xinyu Wang, Yongchun Zhu, Hucheng Zhu, Wencai Ye, Qin Li, Yonghui Zhang, Yuan Zhou

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引用次数: 0

Abstract

Prenylation modifications of natural products typically introduce greater structural complexity and enhance their biological activities. Yet, the modification of piperazine alkaloids by dimethylallyl tryptophan synthases (DMATS) remains unreported. In this study, we identified and activated a silent DMATS-containing piperazine biosynthetic gene cluster (BGC), flz, in Aspergillus flavipes via heterologous expression and in vitro enzymatic assay, leading to the isolation and identification of sixteen metabolites. Among these, twelve are new, including five tryptophan-valine-derived alkaloids (2–6) and seven previously unreported prenylated analogs (8–13, 17). Notably, 8 and 9 represent novel prenylated piperazines featuring a unique 6-5-5-6 ring system. Most significantly, we uncovered a versatile DMATS, FlzE, capable of catalyzing mono-prenylation on flexible substrates, such as piperazine, pyrazine, and diketopiperazine, at multiple sites in either regular or reverse manners. This study not only expands the chemical space of indole alkaloid derivatives but also provides a versatile and engineerable biocatalyst for the prenylation of both natural and synthetic products.

Graphical Abstract

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通过隐式生物合成基因簇异源表达发现前所未有的戊基化吲哚哌嗪和吡嗪

天然产物的前置酰化修饰通常会引入更大的结构复杂性并增强其生物活性。然而，二甲基丙烯基色氨酸合酶修饰哌嗪类生物碱的研究尚未见报道。本研究通过异源表达和体外酶法，在黄曲霉中鉴定并激活了一个含dmats的沉默哌嗪生物合成基因簇（BGC） flz，分离鉴定了16个代谢物。其中12种是新发现的，包括5种色氨酸缬氨酸衍生的生物碱（2-6）和7种以前未报道的戊酰化类似物（8 - 13,17）。值得注意的是，8和9代表具有独特6-5-5-6环体系的新型戊基化哌嗪。最重要的是，我们发现了一种多功能DMATS FlzE，它能够在灵活的底物（如哌嗪、吡嗪和双酮哌嗪）上以规则或反向的方式在多个位点催化单戊烯酰化。这项研究不仅拓展了吲哚生物碱衍生物的化学空间，而且为天然和合成产物的戊烯酰化提供了一种通用的、可工程的生物催化剂。图形抽象

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

Natural Products and Bioprospecting CHEMISTRY, MEDICINAL-

CiteScore

8.30

自引率

2.10%

发文量

审稿时长

13 weeks

期刊介绍： Natural Products and Bioprospecting serves as an international forum for essential research on natural products and focuses on, but is not limited to, the following aspects: Natural products: isolation and structure elucidation Natural products: synthesis Biological evaluation of biologically active natural products Bioorganic and medicinal chemistry Biosynthesis and microbiological transformation Fermentation and plant tissue cultures Bioprospecting of natural products from natural resources All research articles published in this journal have undergone rigorous peer review. In addition to original research articles, Natural Products and Bioprospecting publishes reviews and short communications, aiming to rapidly disseminate the research results of timely interest, and comprehensive reviews of emerging topics in all the areas of natural products. It is also an open access journal, which provides free access to its articles to anyone, anywhere.