ArticleJournal of the American Chemical Society2010
Manipulation of thiocillin variants by prepeptide gene replacement: structure, conformation, and activity of heterocycle substitution mutants.
Article in Journal of the American Chemical Society, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 111 citations in OpenAlex.
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- Thiocillin contributes to the ecological fitness ofFrontiers in microbiology · 2023Article
- De Novo Discovery of Thiopeptide Pseudo-natural Products Acting as Potent and Selective TNIK Kinase Inhibitors.Journal of the American Chemical Society · 2022Article
- Accessing Diverse Pyridine-Based Macrocyclic Peptides by a Two-Site Recognition Pathway.Journal of the American Chemical Society · 2022Article
- Thiopeptides Induce Proteasome-Independent Activation of Cellular Mitophagy.ACS chemical biology · 2020Article
- Interception of the Bycroft-Gowland Intermediate in the Enzymatic Macrocyclization of Thiopeptides.Journal of the American Chemical Society · 2020Article
- Minimal lactazole scaffold for in vitro thiopeptide bioengineering.Nature communications · 2020Article
- Fixing the Unfixable: The Art of Optimizing Natural Products for Human Medicine.Journal of medicinal chemistry · 2019Review
- Dehydroamino acids: chemical multi-tools for late-stage diversification.Organic & biomolecular chemistry · 2019Review
- Investigations into PoyH, a promiscuous protease from polytheonamide biosynthesis.Journal of industrial microbiology & biotechnology · 2019Article
- Thiopeptide Pyridine Synthase TbtD Catalyzes an Intermolecular Formal Aza-Diels-Alder Reaction.Journal of the American Chemical Society · 2019Article
- Flexizyme-Enabled Benchtop Biosynthesis of Thiopeptides.Journal of the American Chemical Society · 2019Article
- RiPP antibiotics: biosynthesis and engineering potential.Current opinion in microbiology · 2018Review
- Structural Insights into Thioether Bond Formation in the Biosynthesis of Sactipeptides.Journal of the American Chemical Society · 2017Article
- Elucidating and engineering thiopeptide biosynthesis.World journal of microbiology & biotechnology · 2017Review
- YcaO-Dependent Posttranslational Amide Activation: Biosynthesis, Structure, and Function.Chemical reviews · 2017Review
- Structure-Activity Relationship and Molecular Mechanics Reveal the Importance of Ring Entropy in the Biosynthesis and Activity of a Natural Product.Journal of the American Chemical Society · 2017Article
- Capture of micrococcin biosynthetic intermediates reveals C-terminal processing as an obligatory step for in vivo maturation.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Reconstitution and Minimization of a Micrococcin Biosynthetic Pathway in Bacillus subtilis.Journal of bacteriology · 2016Article
- In Vitro Biosynthesis and Substrate Tolerance of the Plantazolicin Family of Natural Products.ACS chemical biology · 2016Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Bacillus cereus ATCC 14579 converts the C-terminal 14 residues of a 52-mer prepeptide into a related set of eight variants of the thiocillin subclass of thiazolyl peptide antibiotics by a cascade of post-translational modifications that alter 13 of those 14 residues. We have introduced prepeptide gene variants into a knockout strain to conduct an alanine scan of all 14 progenitor residues, as well as a serine scan of the six cysteine residues that are converted to thiazoles in the mature natural product. No mature scaffolds were detected for the S1A and S10A mutants, consistent with their roles as the source of the pyridine core. In both the alanine and serine scans, only one substitution mutant failed to produce a mature scaffold: cysteine 11. Cysteine to serine mutants gave mixture of dehydrations, aromatizations, and unaltered alcohol side chains depending on position. Overall, substitutions that altered the trithiazolylpyridine core or reduced the conformational rigidity of the 26-membered macrocyclic loop led to loss of antibiotic activity. In total, 21 peptide mutants were cultured, from which production of 107 compounds was observed and 94 compounds, representing 17 structural mutants, were assayed for antibiotic activity. High-resolution NMR solution structures were determined for one mutant and one wild-type compound. These structures demonstrate that the tight conformational rigidity of the natural product is severely disrupted by loss of even a single heterocycle, perhaps accounting for the attendant loss of activity in such mutants.
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