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Rational and combinatorial tailoring of bioactive cyclic dipeptides.
Tobias W Giessen1, Mohamed A Marahiel2
1Department of Systems Biology, Harvard Medical School, Boston MA, USA ; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston MA, USA.
Frontiers in Microbiology
|August 19, 2015
Summary
Modified cyclic dipeptides, or 2,5-diketopiperazines (DKPs), are microbial compounds with diverse bioactivities. This review highlights DKP-modifying enzymes and their potential in synthetic biology for novel drug discovery.
Area of Science:
- Microbiology
- Biochemistry
- Medicinal Chemistry
Background:
- Modified cyclic dipeptides, particularly 2,5-diketopiperazines (DKPs), are microbial secondary metabolites with significant biological and pharmacological activities.
- Their conformationally constrained scaffold and diverse natural tailoring enzymes make them privileged structures for receptor binding.
- Modifying enzymes install crucial functional groups, dictating the biological properties of the final DKP products.
Purpose of the Study:
- To review DKP modification enzymes found in microbial secondary metabolite gene clusters.
- To explore the distribution and characteristics of these DKP tailoring enzymes.
- To discuss their application potential in combinatorial biosynthesis for novel drug development.
Main Methods:
- Literature review focusing on DKP modification enzymes.
- Analysis of enzyme distribution across microbial gene clusters.
- Highlighting characterized DKP tailoring enzymes and their functions.
- Discussion of synthetic biology and combinatorial biosynthesis approaches.
Main Results:
- DKP modification enzymes are diverse and widespread in microbial secondary metabolite gene clusters.
- Characterized enzymes demonstrate a range of tailoring capabilities crucial for DKP bioactivity.
- These enzymes represent a largely untapped resource for generating structural diversity in DKPs.
Conclusions:
- DKP modification enzymes are key to the functional diversity of these microbial metabolites.
- Their application in combinatorial biosynthesis offers a powerful strategy for discovering new medicinally relevant compounds.
- Further exploration of these enzymes can unlock novel therapeutic agents.
