Genome Mining and Comparative Biosynthesis of Meroterpenoids from Two Phylogenetically Distinct Fungi
Genome Mining and Comparative Biosynthesis of Meroterpenoids from Two Phylogenetically Distinct Fungi
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两种系统发育不同真菌中类萜的基因组挖掘和比较生物合成
DOI：
10.1002/anie.201804317
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发表时间：
2018-07-02
影响因子：
16.6
通讯作者：
Ge, Hui Ming
中科院分区：
文献类型：
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作者：
Zhang, Xuan;Wang, Ting Ting;Ge, Hui Ming
通过计算分析，从两种不同真菌中鉴定出两个同源的部分萜类基因簇，它们由编码聚酮合成酶（PKS）、异戊烯基转移酶（PT）、萜类环化酶（TC）和其他剪裁酶的连续基因组成。通过逆转录PCR（RT-PCR）引导的培养基优化使得两个菌株能够产生八个新的和两个已知的部分萜类化合物（1-10）。利用基因失活、异源表达和生化分析，我们揭示了一种新的聚酮-萜类组装线，其利用一对PKS合成2，4-二羟基-6-烷基苯甲酸，然后通过氧化脱羧、法呢基转移和萜环化来构建部分萜类支架。此外，两个分离的部分萜类化合物（3和17天）显示免疫抑制活性。我们的工作揭示了一个新的策略，为meroterpenoid天然产物的发现，并揭示了化合物1-10的生物合成途径。
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 17d) showed immunosuppressive bioactivity. Our work reveals a new strategy for meroterpenoid natural products discovery, and reveals the biosynthetic pathway for compounds 1-10.