|Rebets Y, Nadmid S, Paulus C, Dalem C, Hermann J, Hübner H, Rückert C, Kiemer A, Gmeiner P, Kalinowski J, Müller R, Luzhetskyy A
|Perquinolines A-C: Unprecedented Bacterial Tetrahydroisoquinolines Involving an Intriguing Biosynthesis
|Angew Chem Int Ed Engl
| tetrahydroisoquinoline natural products biosynthetic gene cluster heterologous expression streptomyces
|Metabolic profiling of Streptomyces sp. IB2014/016-6 led to the identification of three new tetrahydroisoquinoline natural products, perquinolines A-C (1-3). Labelled precursor feeding studies and the cloning of the pqr biosynthetic gene cluster revealed that 1-3 are assembled by the action of several unusual enzymes. The biosynthesis starts with the condensation of succinyl-CoA and L-phenylalanine catalysed by the amino-7-oxononanoate synthase-like enzyme PqrA, representing rare chemistry in natural product assembly. The second condensation and cyclization events are conducted by PqrG resembling an acyl-CoA ligase. Last, ATP-grasp RimK-type ligase PqrI completes the biosynthesis by transferring a γ-aminobutyric acid or β-alanine moiety. The discovered pathway represents a new paradigm for assembly of the tetrahydroisoquinoline cores of natural products.