Identification of a key prenyltransferase involved in biosynthesis of the most abundant fungal meroterpenoids derived from 3,5-dimethylorsellinic acid.

Destroying aromaticity: A novel prenyltransferase (Trt2) involved in fungal meroterpenoid biosynthesis was shown to catalyze an unusual aromatic addition reaction onto a fully substituted aromatic ring. The prenylated product serves as a key intermediate in the biosynthesis of the most abundant series of meroterpenoids in fungi.

Reconstitution of a fungal meroterpenoid biosynthesis reveals the involvement of a novel family of terpene cyclases.

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.