ArticleMicrobial cell factories2020
In vivo characterization of the activities of novel cyclodipeptide oxidases: new tools for increasing chemical diversity of bioproduced 2,5-diketopiperazines in Escherichia coli.
Article in Microbial cell factories, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 15 citations in OpenAlex.
- Novel Antimicrobial Activities of Albofungin, Albonoursin, and Ribonucleosides Produced byMolecules (Basel, Switzerland) · 2025Article
- Biosynthesis of Unnatural Cyclodipeptides through Genetic Code Expansion and Cyclodipeptide Synthase Evolution.Journal of the American Chemical Society · 2025Article
- Engineering a Biosynthetic Pathway to Produce (+)-Brevianamides A and B.ACS catalysis · 2025Article
- Broad substrate scope C-C oxidation in cyclodipeptides catalysed by a flavin-dependent filament.Nature communications · 2025Article
- Cyclodipeptide oxidase is an enzyme filament.Nature communications · 2024Article
- Unveiling an indole alkaloid diketopiperazine biosynthetic pathway that features a unique stereoisomerase and multifunctional methyltransferase.Nature communications · 2023Article
- Natural and engineered cyclodipeptides: Biosynthesis, chemical diversity, and engineering strategies for diversification and high-yield bioproduction.Engineering microbiology · 2023Review
- Genome Mining and Metabolic Profiling Reveal Cytotoxic Cyclodipeptides inAntibiotics (Basel, Switzerland) · 2022Article
- Modifications of diketopiperazines assembled by cyclodipeptide synthases with cytochrome PApplied microbiology and biotechnology · 2021Review
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundCyclodipeptide oxidases (CDOs) are enzymes involved in the biosynthesis of 2,5-diketopiperazines, a class of naturally occurring compounds with a large range of pharmaceutical activities. CDOs belong to cyclodipeptide synthase (CDPS)-dependent pathways, in which they play an early role in the chemical diversification of cyclodipeptides by introducing Cα-Cβ dehydrogenations. Although the activities of more than 100 CDPSs have been determined, the activities of only a few CDOs have been characterized. Furthermore, the assessment of the CDO activities on chemically-synthesized cyclodipeptides has shown these enzymes to be relatively promiscuous, making them interesting tools for cyclodipeptide chemical diversification. The purpose of this study is to provide the first completely microbial toolkit for the efficient bioproduction of a variety of dehydrogenated 2,5-diketopiperazines.
resultsWe mined genomes for CDOs encoded in biosynthetic gene clusters of CDPS-dependent pathways and selected several for characterization. We co-expressed each with their associated CDPS in the pathway using Escherichia coli as a chassis and showed that the cyclodipeptides and the dehydrogenated derivatives were produced in the culture supernatants. We determined the biological activities of the six novel CDOs by solving the chemical structures of the biologically produced dehydrogenated cyclodipeptides. Then, we assessed the six novel CDOs plus two previously characterized CDOs in combinatorial engineering experiments in E. coli. We co-expressed each of the eight CDOs with each of 18 CDPSs selected for the diversity of cyclodipeptides they synthesize. We detected more than 50 dehydrogenated cyclodipeptides and determined the best CDPS/CDO combinations to optimize the production of 23.
conclusionsOur study establishes the usefulness of CDPS and CDO for the bioproduction of dehydrogenated cyclodipeptides. It constitutes the first step toward the bioproduction of more complex and diverse 2,5-diketopiperazines.
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