Two homologous meroterpenoid gene clusters consisting of contiguous genes encoding polyketide synthase (PKS), prenyltransferase (PT), terpenoid cyclase (TC) and other tailoring enzymes were identified from two phylogenetically distinct fungi through computational analysis. Media optimization guided by reverse‐transcription PCR (RT‐PCR) enabled two strains to produce eight new and two known meroterpenoids (1–10). Using gene inactivation, heterologous expression, and biochemical analyses, we revealed a new polyketide‐terpenoid assembly line that utilizes a pair of PKSs to synthesize 2,4‐dihydroxy‐6‐alkylbenzoic acid, followed by oxidative decarboxylation, farnesyl transfer, and terpene cyclization to construct the meroterpenoid scaffold. In addition, two of the isolated meroterpenoids (3 and 17 d) showed immunosuppressive bioactivity. Our work reveals a new strategy for meroterpenoid natural products discovery, and reveals the biosynthetic pathway for compounds 1–10.

中文翻译：

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两种系统发育独特真菌类萜类化合物的基因组挖掘和比较生物合成

通过计算分析，从两个系统发育不同的真菌中鉴定出两个同源的类萜金属类基因簇，它们由编码聚酮化合物合酶（PKS），异戊二烯基转移酶（PT），萜类环化酶（TC）和其他剪裁酶的连续基因组成。逆转录PCR（RT-PCR）指导的培养基优化使两种菌株产生了八种新的和两种已知的类萜（1 – 10）。利用基因失活，异源表达和生化分析，我们揭示了一条新的聚酮-萜类组装生产线，该生产线利用一对PKS合成2,4-二羟基-6-烷基苯甲酸，然后进行氧化脱羧，法呢基转移和萜烯环化建造金属萜类支架。此外，其中两个孤立的类萜3和17d）显示出免疫抑制生物活性。我们的工作揭示了发现类萜金属天然产物的新策略，并揭示了化合物1 – 10的生物合成途径。