Discovery and Characterization of a cis-Casbene Diterpene Synthase from Streptomyces paromomycinus

IF 3.6 2区生物学 Q2 CHEMISTRY, MEDICINAL

Journal of Natural Products Pub Date : 2025-09-30 DOI:10.1021/acs.jnatprod.5c00870

Xinru Sun, , , Fang-Ru Li, , , Qian Yang, , , Xingming Pan, , , Hui-Min Xu, , and , Liao-Bin Dong*,

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Abstract

Casbene-type diterpenoids are important bioactive natural products, but all known examples possess exclusively trans-configured double bonds. Here, we report the discovery of SpTS1 from Streptomyces paromomycinus, a diterpene synthase that produces the first naturally occurring cis-casbene. Through heterologous expression and in vitro characterization, we isolated four novel cis-diterpenes from the substrate nerylneryl diphosphate (NNPP): (1S,2Z,6Z,10Z,14S)-casbene (1) featuring the characteristic bicyclo[12.1.0]pentadecane scaffold, 14-membered macrocyclic diterpene 2, and two monocyclic diterpenes 3 and 4. The absolute configurations of 1 and 2 were established through ECD spectroscopy and quantum calculations. Notably, SpTS1 also accepts trans-substrate geranylgeranyl diphosphate (GGPP) to produce cembrene-type diterpenes, demonstrating unusual substrate promiscuity. This discovery not only fills an important gap in casbene natural product diversity but also reveals new possibilities for engineering stereochemically diverse terpenoids.

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巨巨链霉菌中顺式casbene二萜合成酶的发现和鉴定。

casbene型二萜是重要的生物活性天然产物，但所有已知的例子都具有完全反构型双键。在这里，我们报道了从paromomycinus链霉菌中发现的SpTS1，一种产生第一个自然存在的顺式casbene的二萜合成酶。通过异源表达和体外鉴定，我们从底物nerylneryl diphosphate （NNPP）中分离出4个新的顺式二萜：(1S,2Z,6Z,10Z,14S)-casbene(1)，具有典型的双环[12.1.0]十五烷支架，14元大环二萜2，以及两个单环二萜3和4。通过ECD光谱和量子计算建立了1和2的绝对构型。值得注意的是，SpTS1也接受反底物香叶二磷酸（GGPP）产生烯型二萜，表现出不寻常的底物乱交。这一发现不仅填补了casbene天然产物多样性的重要空白，而且揭示了工程立体化学多样化萜类化合物的新可能性。

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

Journal of Natural Products 生物-药学

CiteScore

9.10

自引率

5.90%

发文量

294

审稿时长

2.3 months

期刊介绍： The Journal of Natural Products invites and publishes papers that make substantial and scholarly contributions to the area of natural products research. Contributions may relate to the chemistry and/or biochemistry of naturally occurring compounds or the biology of living systems from which they are obtained. Specifically, there may be articles that describe secondary metabolites of microorganisms, including antibiotics and mycotoxins; physiologically active compounds from terrestrial and marine plants and animals; biochemical studies, including biosynthesis and microbiological transformations; fermentation and plant tissue culture; the isolation, structure elucidation, and chemical synthesis of novel compounds from nature; and the pharmacology of compounds of natural origin. When new compounds are reported, manuscripts describing their biological activity are much preferred. Specifically, there may be articles that describe secondary metabolites of microorganisms, including antibiotics and mycotoxins; physiologically active compounds from terrestrial and marine plants and animals; biochemical studies, including biosynthesis and microbiological transformations; fermentation and plant tissue culture; the isolation, structure elucidation, and chemical synthesis of novel compounds from nature; and the pharmacology of compounds of natural origin.