PEARL mediated biosynthesis: a novel pathway to aromatic amines

Aromatic amines are common functional groups found in several metabolites. The biosynthesis of aromatic amines canonically involves amino group installation prior to aromatization. We report a fundamentally distinct pathway to aromatic amines by conversion of phenolic groups to amines. Recent studies identified the use of short, catalytic scaffold peptides for the biosynthesis of amino acid derived natural products. During this process, a peptide‐amino acyl tRNA ligase (PEARL) appends amino acids to the C‐terminus of a ribosomally synthesized peptide in an ATP‐ and tRNA‐dependent manner. We report two pathways in which the short, ribosomally synthesized peptides serve as the scaffold for downstream enzymes to modify a PEARL‐appended tryptophan into a pyrroloiminoquinone. These pathways feature previously unknown biochemical processes using a ribosomally synthesized peptide as a scaffold for non‐ribosomal peptide extension and chemical modification to generate an amino acid derived natural product. These pathways showcase a new use for PEARLs resulting in the amination of indoles.