Radical SAM Enzymes in the Biosynthesis of Ribosomally Synthesized and Post-translationally Modified Peptides (RiPPs).

Alhosna Benjdia,Olivier Berteau,Clémence Balty

doi:10.3389/fchem.2017.00087

Abstract

Ribosomally-synthesized and post-translationally modified peptides (RiPPs) are a large and diverse family of natural products. They possess interesting biological properties such as antibiotic or anticancer activities, making them attractive for therapeutic applications. In contrast to polyketides and non-ribosomal peptides, RiPPs derive from ribosomal peptides and are post-translationally modified by diverse enzyme families. Among them, the emerging superfamily of radical SAM enzymes has been shown to play a major role. These enzymes catalyze the formation of a wide range of post-translational modifications some of them having no counterparts in living systems or synthetic chemistry. The investigation of radical SAM enzymes has not only illuminated unprecedented strategies used by living systems to tailor peptides into complex natural products but has also allowed to uncover novel RiPP families. In this review, we summarize the current knowledge on radical SAM enzymes catalyzing RiPP post-translational modifications and discuss their mechanisms and growing importance notably in the context of the human microbiota.

Highlights

Canonical radical SAM enzymes possess a radical SAM domain defined by the Pfam identifier: PF04055
This review focuses on the recent mechanistic insights gained on radical SAM enzymes catalyzing Ribosomally-synthesized and post-translationally modified peptides (RiPPs) post-translational modifications and highlights their growing importance, notably in the context of the human microbiota
In RiPP biosynthetic pathways, several radical SAM enzymes have been identified as catalyzing unusual methyl transfer reactions

Summary

INTRODUCTION

Canonical radical SAM enzymes possess a radical SAM domain defined by the Pfam identifier: PF04055. Edu) databases, there are more than 220,000 radical SAM enzymes predicted to be involved in 85 types of biochemical transformations. The founding members of this enzyme family share as common features: a conserved motif composed of three cysteine residues defined as: CxxxCxxC (where x denotes any amino acid residue), the requirement of a redox active [4Fe-4S] cluster and of S-adenosyl-L-methionine (SAM) (Broderick et al, 2014; Benjdia and Berteau, 2016) (Figure 1). Considerable variations in this cysteine motif have been reported in the last years (Berteau and Benjdia, 2017). While the first radical SAM enzymes characterized such as lysine amino mutase (LAM) (Frey et al, 2008), pyruvate formate lyase activating enzyme (PFL-AE) (Knappe and Schmitt, 1976), ribonucleotide reductase activating enzyme (RNR-AE) (Eliasson et al, 1990) and spore photoproduct lyase

Radical SAM Enzymes in the Biosynthesis of RiPPs

RADICAL SAM ENZYMES INVOLVED IN RIPP METHYL TRANSFER REACTIONS

RADICAL SAM ENZYMES CATALYZING THIOETHER BOND FORMATION IN RIPPS

RADICAL SAM ENZYMES CATALYZING EPIMERIZATION REACTIONS

COMPLEX REARRANGEMENTS IN RIPPS