Post‐Translational Formation of Aminomalonate by a Promiscuous Peptide‐Modifying Radical SAM Enzyme

Abstract

AbstractAminomalonate (Ama) is a widespread structural motif in Nature, whereas its biosynthetic route is only partially understood. In this study, we show that a radical S‐adenosylmethionine (rSAM) enzyme involved in cyclophane biosynthesis exhibits remarkable catalytic promiscuity. This enzyme, named three‐residue cyclophane forming enzyme (3‐CyFE), mainly produces cyclophane in vivo, whereas it produces formylglycine (FGly) as a major product and barely produce cyclophane in vitro. Importantly, the enzyme can further oxidize FGly to produce Ama. Bioinformatic study revealed that 3‐CyFEs have evolved from a common ancestor with anaerobic sulfatase maturases (anSMEs), and possess a similar set of catalytic residues with anSMEs. Remarkably, the enzyme does not need leader peptide for activity and is fully active on a truncated peptide containing only 5 amino acids of the core sequence. Our work discloses the first ribosomal path towards Ama formation, providing a possible hint for the rich occurrence of Ama in Nature.