The Biosynthetic Landscape of Triceptides Reveals Radical SAM Enzymes That Catalyze Cyclophane Formation on Tyr- and His-Containing Motifs.
| Autor: | Sugiyama R; Department of Pharmacy, National University of Singapore, Singapore 117544, Singapore., Suarez AFL; Department of Pharmacy, National University of Singapore, Singapore 117544, Singapore., Morishita Y; Department of Pharmacy, National University of Singapore, Singapore 117544, Singapore., Nguyen TQN; Department of Pharmacy, National University of Singapore, Singapore 117544, Singapore., Tooh YW; Department of Pharmacy, National University of Singapore, Singapore 117544, Singapore., Roslan MNHB; Department of Pharmacy, National University of Singapore, Singapore 117544, Singapore., Lo Choy J; Department of Pharmacology and Toxicology, University of Toronto, Toronto M5S 1A8, Canada., Su Q; Department of Pharmacy, National University of Singapore, Singapore 117544, Singapore., Goh WY; Department of Pharmacy, National University of Singapore, Singapore 117544, Singapore., Gunawan GA; Department of Pharmacy, National University of Singapore, Singapore 117544, Singapore.; Molecular Engineering Lab, Institute of Molecular and Cell Biology, A*STAR, Singapore 138673, Singapore.; Organic & Biomolecular Chemistry, Institute of Sustainability for Chemicals, Energy and Environment, A*STAR, Singapore 138665, Singapore., Wong FT; Molecular Engineering Lab, Institute of Molecular and Cell Biology, A*STAR, Singapore 138673, Singapore.; Singapore Institute of Food and Biotechnology Innovation, A*STAR, Singapore 138673, Singapore., Morinaka BI; Department of Pharmacy, National University of Singapore, Singapore 117544, Singapore. |
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| Jazyk: | angličtina |
| Zdroj: | Journal of the American Chemical Society [J Am Chem Soc] 2022 Jul 06; Vol. 144 (26), pp. 11580-11593. Date of Electronic Publication: 2022 Jun 21. |
| DOI: | 10.1021/jacs.2c00521 |
| Abstrakt: | Peptide-derived cyclophanes inhabit a unique niche in the chemical space of macrocyclic peptides with several examples of pharmaceutical importance. Although both synthetic and biocatalytic methods are available for constructing these macrocycles, versatile (bio)catalysts able to incorporate a variety of amino acids that compose the macrocycle would be useful for the creation of diverse peptide cyclophanes. In this report, we synergized the use of bioinformatic tools to map the biosynthetic landscape of radical SAM enzymes (3-CyFEs) that catalyze three-residue cyclophane formation in the biosynthesis of a new family of RiPP natural products, the triceptides. This analysis revealed 3940 (3113 unique) putative precursor sequences predicted to be modified by 3-CyFEs. Several uncharacterized maturase systems were identified that encode unique precursor types. Functional studies were carried out in vivo in Escherichia coli to identify modified precursors containing His and Tyr residues. NMR analysis of the products revealed that Tyr and His can also be incorporated into cyclophane macrocycles by 3-CyFEs. Collectively, all aromatic amino acids can be incorporated by 3-CyFEs, and the cyclophane formation strictly occurs via a C(sp 2 )-C(sp 3 ) cross-link between the (hetero)aromatic ring to Cβ. In addition to 3-CyFEs, we functionally validated an Fe(II)/α-ketoglutarate-dependent hydroxylase, resulting in β-hydroxylated residues within the cyclophane rings. This study reveals the potential breadth of triceptide precursors and a systematic approach for studying these enzymes to broaden the diversity of peptide macrocycles. |
| Databáze: | MEDLINE |
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