State Key Laboratory of Pharmaceutical Biotechnology, Institute of Functional Biomolecules, School of Life Sciences, Nanjing University, Nanjing, 210023, China.
State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
Angew Chem Int Ed Engl. 2018 Jul 2;57(27):8184-8188. doi: 10.1002/anie.201804317. Epub 2018 Jun 20.
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.
通过计算分析，从两种系统发育上不同的真菌中鉴定出两个由连续基因编码的同源聚酮合酶（PKS）、 prenyltransferase（PT）、萜烯环化酶（TC）和其他修饰酶的聚酮萜类基因簇。通过逆转录 PCR（RT-PCR）指导的培养基优化，使两个菌株能够产生八种新的和两种已知的聚酮萜类化合物（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装配线，该装配线利用一对 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，构建聚酮萜类支架。此外，分离出的两种聚酮萜类化合物（3 和 17d）表现出免疫抑制的生物活性。我们的工作揭示了一种新的聚酮萜类天然产物发现策略，并揭示了化合物 1-10 的生物合成途径。
