Metal-mediated peptide processing. How copper and iron catalyze diverse peptide modifications such as amidation and crosslinking

Abstract

Peptide processing is an important post-translational function that converts newly synthesized pro-peptides into their biologically active mature forms. In this review we discuss two such processes, peptide amidation and ribosomally synthesized post-translationally modified peptide (RiPP) synthesis. The first step in peptide amidation is catalyzed by copper, utilizing a single enzyme peptidylglycine monooxygenase (PHM), while RiPP chemistry can utilize Fe-containing radical SAM enzymes and in a more recent discovery Cu-containing burpitide cyclases. For PHM we describe the canonical mechanism built on three decades of structural, spectroscopic and computational work that posits mononuclear reactivity coupled to long range electron transfer. We discuss this alongside new experimental evidence that suggests instead an open-to-closed conformationally gated mechanism where a binuclear copper entity is the reactive species. Next we describe new insights into RiPP chemistry of thioether formation formed via cysteine to peptidyl-C crosslinking in the radical SAM enzymes PapB and Tte1186. Here Se edge XAS has documented selenocysteine to Fe binding at an auxiliary FeS cluster as an important step in S/Se to peptidyl-C coupling. Finally we examine analogous radical-induced peptide crosslinking in a new class of peptide cyclases termed burpitide cyclases (BpCs) some of which exhibit a striking similarity to PHM, yet show catalytic chemistry leading to a different product profile. These comparisons emphasize how nature leverages very specific properties of metal ions, and their ability to underpin catalysis via radical processes to bring about a variety of important biochemical and biological outcomes.