Genome Mining of Alkaloidal Terpenoids from a Hybrid Terpene and Nonribosomal Peptide Biosynthetic Pathway

Biosynthetic
pathways containing multiple core enzymes have potential
to produce structurally complex natural products. Here we mined a
fungal gene cluster that contains two predicted terpene cyclases (TCs)
and a nonribosomal peptide synthetase (NRPS). We showed the flv pathway produces flavunoidine 1, an alkaloidal
terpenoid. The core of 1 is a tetracyclic, cage-like,
and oxygenated sesquiterpene that is connected to dimethylcadaverine
via a C–N bond and is acylated with 5,5-dimethyl-l-pipecolate. The roles of all flv enzymes are established
on the basis of metabolite analysis from heterologous expression.