Divergent Biosynthesis of Bridged Polycyclic Sesquiterpenoids by a Minimal Fungal Biosynthetic Gene Cluster,Journal of Natural Products

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Divergent Biosynthesis of Bridged Polycyclic Sesquiterpenoids by a Minimal Fungal Biosynthetic Gene Cluster
Journal of Natural Products ( IF 3.3 ) Pub Date : 2024-02-28 , DOI: 10.1021/acs.jnatprod.3c01161
Meng-Meng Zhang ₁ , Yi Long ₁ , Yuxin Li ₂ , Jiao-Jiao Cui ₁ , Tinghong Lv ₁ , Shangwen Luo ₁ , Kun Gao ₁ , Shi-Hui Dong ₁

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The bridged polycyclic sesquiterpenoids derived from sativene, isosativene, and longifolene have unique structures, and many chemical synthesis approaches with at least 10 steps have been reported. However, their biosynthetic pathway remains undescribed. A minimal biosynthetic gene cluster (BGC), named bip, encoding a sesquiterpene cyclase (BipA) and a cytochrome P450 (BipB) is characterized to produce such complex sesquiterpenoids with multiple carbon skeletons based on enzymatic assays, heterologous expression, and precursor experiments. BipA is demonstrated as a versatile cyclase with (−)-sativene as the dominant product and (−)-isosativene and (−)-longifolene as minor ones. BipB is capable of hydroxylating different enantiomeric sesquiterpenes, such as (−)-longifolene and (+)-longifolene, at C-15 and C-14 in turn. The C-15- or both C-15- and C-14-hydroxylated products are then further oxidized by unclustered oxidases, resulting in a structurally diverse array of sesquiterpenoids. Bioinformatic analysis reveals the BipB homologues as a discrete clade of fungal sesquiterpene P450s. These findings elucidate the concise and divergent biosynthesis of such intricate bridged polycyclic sesquiterpenoids, offer valuable biocatalysts for biotransformation, and highlight the distinct biosynthetic strategy employed by nature compared to chemical synthesis.

中文翻译：

最小真菌生物合成基因簇对桥连多环倍半萜类化合物的不同生物合成

衍生自香麻草烯、异香麻草烯和长叶烯的桥联多环倍半萜类化合物具有独特的结构，并且已经报道了许多至少有10个步骤的化学合成方法。然而，它们的生物合成途径仍未被描述。最小生物合成基因簇 (BGC)，称为bip ，编码倍半萜环化酶 (BipA) 和细胞色素 P450 (BipB)，基于酶测定、异源表达和前体实验，其特征在于产生具有多个碳骨架的复杂倍半萜类化合物。 BipA 被证明是一种多功能环化酶，其中 (−)-sativene 为主要产物，(−)-isosativene 和 (−)-longifoline 为次要产物。 BipB 能够在 C-15 和 C-14 处依次羟基化不同的对映体倍半萜，例如 (−)-长叶烯和 (+)-长叶烯。然后，C-15-或C-15-和C-14-羟基化产物被非簇氧化酶进一步氧化，产生结构多样的倍半萜类化合物。生物信息学分析揭示 BipB 同源物是真菌倍半萜 P450 的一个离散分支。这些发现阐明了这种复杂的桥连多环倍半萜类化合物的简明而发散的生物合成，为生物转化提供了有价值的生物催化剂，并强调了与化学合成相比，大自然采用的独特的生物合成策略。

更新日期：2024-02-28

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