Epipolythiodioxopiperazine-Based Natural Products: Building Blocks, Biosynthesis and Biological Activities

Epipolythiodioxopiperazines (ETPs) are fungal secondary metabolites that share a 2,5-diketopiperazine scaffold built from two amino acids and bridged by a sulfide moiety. Modifications of the core and the amino acid side chains, for example by methylations, acetylations, hydroxylations, prenylations, halogenations, cyclizations, and truncations create the structural diversity of ETPs and contribute to their biological activity. However, the key feature responsible for the bioactivities of ETPs is their sulfide moiety. Over the last years, combinations of genome mining, reverse genetics, metabolomics, biochemistry, and structural biology deciphered principles of ETP production. Sulfurization via glutathione and uncovering of the thiols followed by either oxidation or methylation crystallized as fundamental steps that impact expression of the biosynthesis cluster, toxicity and secretion of the metabolite as well as self-tolerance of the producer. This article showcases structure and activity of prototype ETPs such as gliotoxin and discusses the current knowledge on the biosynthesis routes of these exceptional natural products.

Automated summary

This article discusses the structure, activity, and biosynthesis routes of epipolythiodioxopiperazines (ETPs), which are fungal secondary metabolites. ETPs exhibit structural diversity due to modifications of the core and amino acid side chains, with the sulfide moiety being the key feature responsible for their bioactivities. Recent studies have elucidated the principles of ETP production, including sulfurization via glutathione, disulfide bond cleavage, and subsequent oxidation or methylation reactions, which impact the expression of biosynthesis clusters, metabolite toxicity and secretion, and self-tolerance of the producer.