Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan.
Nat Chem. 2010 Oct;2(10):858-64. doi: 10.1038/nchem.764. Epub 2010 Aug 1.
Meroterpenoids are hybrid natural products of both terpenoid and polyketide origin. We identified a biosynthetic gene cluster that is responsible for the production of the meroterpenoid pyripyropene in the fungus Aspergillus fumigatus through reconstituted biosynthesis of up to five steps in a heterologous fungal expression system. The cluster revealed a previously unknown terpene cyclase with an unusual sequence and protein primary structure. The wide occurrence of this sequence in other meroterpenoid and indole-diterpene biosynthetic gene clusters indicates the involvement of these enzymes in the biosynthesis of various terpenoid-bearing metabolites produced by fungi and bacteria. In addition, a novel polyketide synthase that incorporated nicotinyl-CoA as the starter unit and a prenyltransferase, similar to that in ubiquinone biosynthesis, was found to be involved in the pyripyropene biosynthesis. The successful production of a pyripyropene analogue illustrates the catalytic versatility of these enzymes for the production of novel analogues with useful biological activities.
倍半萜烯是萜烯类和聚酮类天然产物的杂种。我们通过在异源真菌表达系统中重新构建多达五个步骤的生物合成，鉴定了一个生物合成基因簇，该基因簇负责在真菌烟曲霉中产生倍半萜烯吡嗪吡咯烯。该簇揭示了一种以前未知的萜烯环化酶，其具有不寻常的序列和蛋白质一级结构。该序列在其他倍半萜烯和吲哚二萜生物合成基因簇中的广泛存在表明这些酶参与了真菌和细菌产生的各种含萜类代谢物的生物合成。此外，还发现了一种新型聚酮合酶，它以烟酰辅酶 A 作为起始单元，并发现了一种类似于泛醌生物合成的 prenyltransferase，参与了吡嗪吡咯烯的生物合成。成功地生产了一种吡嗪吡咯烯类似物，说明了这些酶在产生具有有用生物活性的新型类似物方面的催化多功能性。
